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The changing characteristics of hepatocellular cancer in Hawaii over time Linda L. Wong, M.D.a,b,c,*, Makoto Ogihara, M.D.a,b, Junfang Ji, Ph.D.c, Naoky Tsai, M.D.d a
Department of Surgery, John A. Burns School of Medicine, University of Hawaii, 550 South Beretania Street, Suite 403, Honolulu, Hawaii 96813, USA; bTransplant Center, Queens Medical Center, Honolulu, HI, USA; cCancer Center, University of Hawaii, Honolulu, HI, USA; dLiver Center, Queens Medical Center, Honolulu, HI, USA
KEYWORDS: Hepatocellular cancer; Liver resection; Liver transplant; Viral hepatitis; Metabolic factors
Abstract BACKGROUND: The incidence of hepatocellular cancer (HCC) is increasing, and we sought to characterize the differences and trends in HCC over 2 decades in Hawaii. METHODS: This retrospective study of 821 HCC cases analyzed risk factors, diabetes, alphafetoprotein (AFP), tumor characteristics, and treatment, comparing 5-year eras (1993 to 2012). RESULTS: With succeeding eras, there were fewer Asians, immigrants, and hepatitis B–related HCC. Hepatitis C, diabetes, hyperlipidemia, and body mass index have increased. Over time, more patients had normal AFP, and normal AFP was seen more often in nonviral HCC (49.6% vs 33.2%, P 5 .007). Over time, the proportion of patients who underwent resection or transplant was stable, but fewer patients underwent no therapy. CONCLUSIONS: Characteristics of HCC are changing, and diagnosis may be more difficult as metabolic factors are becoming more important than viral factors. AFP seems to be a less important biomarker, and clearly, better diagnostic tools will be necessary to identify HCC in the future. Ó 2014 Elsevier Inc. All rights reserved.
Hepatocellular cancer (HCC) is the fifth most common cancer in men and ninth most common cancer in women globally with an estimated 750,000 new cases diagnosed in 2012. Overall, this is a deadly cancer with one of the highest mortality to incidence ratios at .95. It is the second most common cause of cancer mortality with 600,000 deaths annually.1 Although 85% of these cases occur in less Wong: Speaker for Bayer and Onyx, Tsai: Research and Grants Gilead, BMS, Janssen, AbbVie, Beckman; Speakers bureau- Gilead, BMS, Janssen, AbbVie, Salix, Bayer; Advisory board-Gilead, AbbVie, BMS. * Corresponding author. Tel.: 11-808-523-5033; fax: 11-808-5284940. E-mail address: [email protected] Manuscript received March 23, 2014; revised manuscript June 12, 2014 0002-9610/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2014.06.036
developed countries, HCC is one of the few cancers that is increasing in incidence in the United States. In 2010, there were 24,304 new cases and 20,304 deaths because of HCC.1,2 Globally, an estimated 80% of HCC cases have hepatitis B or C as a risk factor with more of these cases related to hepatitis B (75%) and a smaller proportion (10% to 20%) because of hepatitis C.3 Diabetes, obesity, and nonalcoholic steatohepatitis are increasingly identified as risk factors that will likely play a greater role in the upcoming years.4,5 Many epidemiologic studies from various places in the world have shown these risk factors have different influences on the incidence of HCC.6–13 This is likely related to the prevalence of a particular risk factor in that country. It is often difficult to quantify this risk exactly as underdeveloped countries may have limited resources to support detailed tumor registries. In the United
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States, we have comprehensive tumor registries and administrative or billing databases; however, these databases often have limited information on ethnicity, viral hepatitis, body mass index (BMI), and some of the newer risk factors such as diabetes, obesity, and nonalcoholic steatohepatitis. These databases are often based on billing codes and may be dependent on the variable skills of the staff entering this information. Hawaii is the state in the United States with the highest incidence of HCC at 10.8 per 100,000 and the second highest death rate at 5.9 per 100,000.2 The large proportion of Asian and Pacific Islander ethnic groups and continued immigration probably account for this high incidence for many years. Our group of physicians has been carefully collecting detailed information on HCC cases for more than 20 years. This study hopes to reveal the changing patterns of risk factors and presentation of HCC over time in Hawaii.
‘‘Asian’’ (including Filipinos), or ‘‘Pacific Islander.’’ Patients who did not fit into one of these categories or were of mixed ethnicity were subsequently classified as ‘‘other.’’ Patients of mixed race with 50% Pacific Islander ethnicity were categorized as ‘‘Pacific Islander.’’ Data collected on medical history included diabetes mellitus, hyperlipidemia, smoking, and risk factors for HCC including viral hepatitis, alcohol abuse (defined as .2 alcoholic beverages daily for at least 10 years), and other chronic liver diseases. Information was based on available medical records and interview by a single physician, without use of a structured questionnaire. Patients who did not report hyperlipidemia but had a lipid-lowering agent on their current medication list were also classified as having hyperlipidemia. Measured height and weight were used to determine BMI. Obesity was defined as BMI of 30 or more. Laboratory data collected included bilirubin, albumin, prothrombin time, creatinine, alanine aminotransferase, aspartate aminotranferase, platelet count, and AFP. Laboratory data that were used for the study had been obtained within 2 weeks of initial visit or drawn at the time of the visit. Bilirubin, prothrombin time with international normalized ratio, and creatinine were used to calculate the Model for End-Stage Liver Disease score. The size, number, and location of the tumors were used to determine the Tumor– Node–Metastases stage according to the American Joint Commission on Cancer (AJCC) staging manual.17 The proportion of patients with HCC detected by screening was noted. Although our Liver Center recommends that community physicians screen viral hepatitis and chronic liver disease patients with AFP and liver ultrasound every 6 months, there was no uniform screening protocol used in the cohort. Referring physicians used a combination of AFP and imaging (ultrasound, CT scan, or MRI) at variable intervals. HCC was deemed to be found on ‘‘screening’’ if the referring physician stated that screening was done and the patient had a previous imaging study from 3 to 12 months prior. HCC not found on screening was either found with symptoms (pain, abdominal mass, weight loss, jaundice) or asymptomatically with imaging done for unrelated reasons.
Methods administrative or billing Patients This is a retrospective analysis of 821 HCC cases referred over a 20-year period (1993 to 2012) to our group of physicians who are associated with the medical center with the only liver transplant program in Hawaii and the only referral center for liver disease and surgery for American territories of the Pacific Basin (including Samoa, Guam, Saipan, and the Marshall Islands). Patients also included foreign nationals from Asian countries, including China, Japan, Korea, and the Philippines, who sought medical care in the United States. This clinic and the transplant center were initially affiliated with Hawaii Medical Center East (formerly St Francis Medical Center) and after 2012, the Queens Medical Center. This center sees about 60% to 70% of the HCC cases in Hawaii. This study was approved by the University of Hawaii Institutional Review Board. HCC was diagnosed histologically by percutaneous biopsy or at surgery. In the first decade and consistent with the previous United Network for Organ Sharing policy regarding transplant for HCC, patients without histologic confirmation were included if they had a history of chronic liver disease and a mass at least 2 cm in size seen on 2 imaging studies (ultrasound, computed tomographic [CT] scan, or MRI) and one of the following1: vascular blush seen on CT scan or MRI,2 alpha-fetoprotein (AFP) greater than 200 ng/mL, or3 arteriogram confirming the tumor.14 More recently, the diagnosis of HCC was made with only imaging if a contrast-enhanced study (dynamic CT or MRI) showed typical arterial enhancement with ‘‘washout’’ in the venous phase as described by the American Association for the Study of Liver Disease guidelines.15,16 Information on demographics, medical history, laboratory results, tumor characteristics, treatment, and survival was collected via clinical interview. Demographic data included age, sex, birthplace, and the patient’s self-reported ethnicity. Ethnicity was then categorized as ‘‘White,’’
Treatments Treatments included liver resection, transplantation, ablative therapies (including radiofrequency ablation, cryosurgery, transarterial chemoembolization, and percutaneous ethanol injection), and systemic therapies. Liver resection was considered in Child’s A patients and early Child’s B patients (Childs–Turcotte–Pugh score of 7, without any evidence of ascites or encephalopathy). Liver transplants were considered in patients who were unresectable but met Milan criteria (single tumor ,5 cm or 2 to 3 tumors, each ,3 cm). Liver transplant was also considered in patients who underwent resection but had a recurrence more than 6 months after surgery, provided the recurrent tumor met Milan criteria, and there was no disease progression while awaiting transplant. Since 2007, liver transplant was
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considered in single tumors less than 6.5 cm that were downstaged to meet Milan criteria. All liver resections and transplants were performed by members of our surgical group. Most patients on the transplant list underwent percutaneous radiofrequency ablation or transarterial chemoembolization while waiting for a donor. Treatment was summarized by whether the patient had a liver resection, transplant, or no therapy. For liver transplant patients, no donor organs were obtained from executed prisoners or other institutionalized persons. Patients were followed long term with imaging every 3 months after surgery or locally ablative therapies for the first year and then every 4 to 6 months after this. Of 821 patients in the cohort, 418 expired during the 17-year study period, 189 are currently alive and are being actively followed, and 11 patients (1.8%) have been lost to followup. Deaths were also confirmed using the Social Security Death Index and local newspaper obituaries.
Data analysis All analyses were performed using Excel and SPSS statistical software. Categorical variables were analyzed using both ANOVA and chi-square analysis. Odds ratios with 95% confidence intervals were calculated based on the comparison with era 1. When the number of patients for a variable in era 1 was less than 10, era 2 was used as the index for calculating odds ratios with 95% confidence intervals. Continuous variables were compared using ANOVA between the 4 eras. P values ,.05 were considered significant.
Results Clinical characteristics of patients In the cohort of 821 patients, there were 618 men (75%) and 203 women with overall mean age of 61.7 years (range 22 to 94 years). Ethnic distribution was as follows: Asian (n 5 519), White (n 5 156), Pacific Islander (n 5 112), and other (n 5 30). Detailed Asian ethnicity was as follows: Japanese (n 5 205), Filipino (n 5 120), Chinese (n 5 102), Korean (n 5 52), Southeast Asian (n 5 33), and more than 1 Asian ethnicity (n 5 7). Risk factors in the overall cohort included 260 patients (31.7%) who were hepatitis B surface antigen positive and 76 patients (9.3%) who were only hepatitis B core antibody positive. Hepatitis C positivity occurred in 309 patients (37.6%). Approximately 42.8% (467 patients) used alcohol significantly in the past and 56.9% (467 patients) were smokers. In terms of metabolic risk factors, 245 patients (29.8%) were diabetics, 293 (35.7%) had hypertension, and 150 (18.3%) had hyperlipidemia. Mean BMI was 26.6%, and 16.1% (133 patients) met criteria for obesity. Of the 821 patients, 661 had a disease for which they could have undergone screening and surveillance as recommended by
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the American Association for the Study of Liver Disease.14,15 Of these 661 patients, 162 (24.5%) had their HCC found with screening or surveillance. Tumor characteristics in the cohort included the mean tumor size of the largest tumor that was 6.17 cm. About 65% of patients had a single tumor, and the remainder had multiple tumors or diffuse disease. Milan criteria were met in 326 patients (39.7%), and 465 patients (56.6%) had AJCC stage 1 disease. Only 33 patients (4%) presented with ruptured HCC. AFP was normal in 293 patients (35.7%). In terms of treatments, 163 patients (19.9%) underwent liver resection, 69 patients (8.4%) had liver transplantation, and 228 (27.8%) had no treatment either because they were too ill or they refused treatment.
Comparison of risk factors and clinical presentation for HCC patients among 4 eras To investigate the changing patterns of risk factors and clinical presentation of HCC patients over time, 821 cases were separated into four 5-year eras from 1993 to 2012. Trends of demographics and risk factors over the 4 eras are shown in Table 1. Race was different over the eras with fewer Asians and more Whites noted in the later eras. The influence of hepatitis B decreased and hepatitis C increased in the later eras (Fig. 1). There was no difference in smoking or alcohol use between the eras. Metabolic factors differed over the eras with a clear increase in BMI and influence of hyperlipidemia with time. Laboratory studies over time are noted in Table 2 with more patients having a normal AFP over the eras. There was no difference in mean bilirubin, albumin, creatinine, platelet count, or AFP at presentation between the 4 eras. Although more patients had NASH in the recent eras, the percentage was similar over time. In the entire cohort, 49.6% of NASH patients and 33.2% of non-NASH patients had a normal AFP (P 5 .007). Over time, there is a trend in seeing smaller tumors at diagnosis and more tumors that were AJCC stage I and met Milan criteria. There were no differences in the proportion of tumors that were single tumors or presented with rupture across the 4 eras. Although the Model for End-Stage Liver Disease scores seemed to increase slightly over the eras from 9.6 to 11.1, this was not significantly different. HCC was found with surveillance in 17.9% of patients in the first era, 10.2% in era 2, 9% in era 3, and 32.5% in the most recent era (Tables 1 and 3). In terms of treatment, although the proportion of patients who underwent liver resection or transplant was unchanged with time, fewer patients (21.6%) in the most recent era had no treatment (Fig. 2).
Survival Mean survival improved over succeeding eras: era 1, 894 days (612.3); era 2, 1316 days (6145.3); era 3, 1238 days (695.2); and era 4, 1544.5 (668.7). This was
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4 Table 1
Demographics, risk factors by era
Characteristic Age (y) Males Race Asian White PacIsl US born HBV1 HCV1 Diabetes1 Hyperlipidemia Hypertension BMI (kg/m2) Obesity (BMI . 30)
Era 1 (1993–1997), n 5 85
Era 2 (1998–2002), n 5 159
Era 3 (2003–2008), n 5 234
Era 4 (2009–2012), n 5 343
62.4 6 12.8 57 (67.1%)
60.0 6 11.8 115 (72.3%)
61.3 6 12.0 187 (79.9%)
62.6 6 11.0 259 (75.5%)
65 (76.5%) 11 (12.9%) 9 (10.5%) 35/61 (57.3%) 36/81 (44.4%) 23 (27%) 28/83 (33.7%) 5/75 (6.7%) 1/4 (25%) 24.84 5/43 (11.6%)
117 (73.6%) 24 (15.1%) 15 (9.4%) 79/143 (55.2%) 61 (38.4%) 51 (32.1%) 49 (30.8%) 15/152 (9.9%) 27/48 (56.3%) 25.87 14/95 (14.7%)
148 (63.2%) 43 (18.4%) 38 (16.2%) 138/231 (59.7%) 67 (28.6%) 100 (42.7%) 58 (24.8%) 42/222 (18.9%) 97/193 (50.3%) 26.57 36/192 (18.8%)
189 (55.1%) 78 (22.7%) 50 (14.6%) 209/335 (62.4%) 96 (28%) 135 (39.4%) 119 (34.7%) 88 (25.7%) 299/335 (89.5%) 26.97 77/339 (22.7%)
P-value NS NS P 5 .001
NS P, P, NS P, P, P5 NS
.0001 .0001 .0001 .0001 .045
BMI 5 body mass index; HBV 5 hepatitis B virus; HCV 5 hepatitis C virus; NS 5 nonsignificant; PacIsl 5 Pacific Islander. Bold values are significantly different from Era 1.
significantly improved over the eras with P , .0001 by the log-rank test. Median survival was 475, 487, and 468 days for eras 1, 2, and 3, respectively, but the median survival could not be calculated for the most recent era as this had not been reached yet.
Comments The incidence of HCC in the United States is increasing, and although we have attributed this to various risk factors that have changed over time, this study truly shows the multiple intervening factors that have contributed to this increase. These factors include the increase in hepatitis B because of vertical transmission, followed by the decrease because of hepatitis B vaccination and antiviral agents that
may have reduced the development of HCC.18–22 Next, the epidemic of hepatitis C in the 1970s because of blood transfusions and high-risk behaviors contributed to more HCC followed by a decrease potentially because of screening of blood donors and effective hepatitis C therapy.23,24 Finally, most recently, the increase in obesity and diabetes has ignited the epidemic of nonalcoholic fatty liver disease and steatohepatitis. Hawaii continues to have much HCC and, perhaps, we have observed different trends compared with elsewhere in the United States. With respect to hepatitis B, we have not seen a dramatic decrease in this epidemic because of improved vaccination and better treatment as we continue to have immigration from Asia and Pacific Island nations where universal vaccination is not practiced consistently. Our most recent group emigrated from the US territoriesdincluding
Figure 1 Viral risk factors by era. Number of patients with hepatitis B and C, coinfection with hepatitis B and C, or no viral risk factors. HBV 5 hepatitis B virus; HCV 5 hepatitis C virus.
L.L. Wong et al. Table 2
Changing characteristics of hepatocellular cancer in Hawaii
5
Laboratory studies, tumor characteristics, and treatment by era
Characteristic
Era 1 (1993–1997), n 5 85
Era 2 (1998–2002), n 5 159
Era 3 (2003–2008), n 5 234
Era 4 (2009–2012), n 5 343
P-value
Normal AFP (,20 ng/dL) Protime INR Tumor size (cm) Milan criteria met AJCC stage I Cirrhotic Liver transplant Liver resection No therapy Two or more therapies
21 (24.7%) 1.00 7.53 16 (18.8%) 45 (52.9%) 54 (63.5%) 4 (4.7%) 15 (17.6%) 28 (32.9%) 16 (18.8%)
55 (34.6%) 1.09 6.78 49 (30.8%) 83 (52.2%) 123 (77.4%) 18 (11.3%) 37 (23.3%) 48 (30.2%) 36 (22.6%)
76 (32.5%) 1.14 6.22 101 (43.2%) 141 (60.3%) 183 (78.2%) 21 (9.0%) 51 (21.8%) 78 (33.3%) 61 (26.1%)
141 (41.1%) 1.22 5.55 160 (46.6%) 196 (57.1%) 230 (67%) 26 (7.6%) 60 (17.5%) 74 (21.6%) 103 (30%)
P5 P, P5 P, NS P, NS NS P5 NS
.005 .001 .001 .0001 .0001
.008
AFP 5 alpha-fetoprotein; AJCC 5 American Joint Commission on Cancer; INR 5 international normalized ratio. Bold values are significantly different from Era 1.
Micronesia, the Marshall Islands, Chuuk, and Guam, where the prevalence of hepatitis B is estimated at 12% to 20%.25,26 Poor conditions and health care in these Pacific Island nations have prompted many to seek medical care in Hawaii. These patients are not consistently screened for hepatitis B, cannot always afford antiviral medication, and do not undergo regular surveillance for HCC. Our cohort had 26 patients who immigrated from these small Pacific Island nations, 23 of whom had hepatitis B, 4 had hepatitis C (1 was coinfected), and only 1 of the 26 patients had their HCC found with surveillance. Language and cultural barriers likely contribute to health care disparity in this population.27 With respect to hepatitis C, Hawaii continues to see immigrants from Southeast Asia and Japan, where hepatitis C accounts for up to 80% to 90% of HCC cases.28,29 Southeast Asians also have a high
prevalence of hepatitis C, and in our group, 57% of the 33 HCC cases were hepatitis C positive.30 Treatment of hepatitis B and C may have potentially changed the incidence of HCC in the United States. A pooled analysis of 20 studies demonstrated a reduction in HCC among hepatitis C patients who undergo interferonbased treatment and are able to clear the virus.31 Unfortunately, in Hawaii, access to treatment for hepatitis C is limited as we have only 1 center dedicated to liver disease. The high cost and side effects associated with hepatitis C treatment and the need for compliance often limit therapy. Language and cultural barriers in Hawaii, where 18.1% of the population is foreign born (compared with 12.9% in the United States), also contribute to the lack of treatment with antivirals.32 Patients who cannot
Table 3 Odds ratios of significant factors between the eras (odds ratio performed compared with era 1 unless era 1 had ,10 patients and then era 2 used) Characteristic Males Race Asian White PacIsl HBV surfAg1 HCV1 Hyperlipidemia Hypertension HCC found with surveillance HCC found with surveillance (those with screenable disease) Milan criteria met Cirrhotic No therapy performed
Era 1 (1993–1997), n 5 85
Era 2 (1998–2002), n 5 159
Era 3 (2003–2008), n 5 234
Era4 (2009–2012), n 5 343
1.00
1.25 (.72–2.22)
1.95 (1.12–3.40)
1.52 (.91–2.54)
1.00 1.00 1.00 1.00 1.00 1.00 d 1.00 1.00
.86 1.20 .88 .78 1.89 1.53 1.00 .52 .47
.53 1.51 1.63 .50 2.01 3.27 .79 .43 .41
.38 1.98 1.44 .49 1.75 4.47 6.4 2.22 2.35
1.00 1.00 1.00
1.92 (1.01–3.64) 1.96 (1.10–3.49) .88 (.50–1.55)
(.46–1.58) (.55–2.58) (.37–2.10) (.45–1.39) (.72–4.97) (.53–4.39) (.24–.12) (.22–1.03)
HBV 5 hepatitis B virus surface antigen; HCV 5 hepatitis C virus; PacIsl 5 Pacific Islander. Bold values are significantly different from Era 1.
(.30–.93) (.74–3.10) (.76–3.55) (.30–.85) (1.17–3.47) (1.24–8.60) (.42–1.49) (.21–.89) (.19–.85)
3.28 (1.79–5.98) 3.56 (1.47–4.47) 1.02 (.60–1.73)
(.22–.65) (1.01–3.92) (.68–3.06) (.30–.80) (1.03–2.95) (1.74–11.45) (3.32–12.58) (1.21–4.06) (1.26–4.38)
3.77 (2.10–6.76) 1.17 (.72–1.92) .56 (.33–.94)
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Figure 2 Treatment for HCC by era. Numbers of patients by era and primary initial treatment received. Other therapy includes any locoregional or systemic treatment other than resection or transplant.
afford treatment or are noncompliant inevitably present with decompensated liver disease or HCC. Hopefully, the advent of interferon-free antivirals for hepatitis C will increase the number of treated patients and decrease hepatitis C virus–related HCC. Finally, there is the epidemic of obesity, fatty liver disease, and NASH. How these factors exactly contribute to HCC development is not completely clear, and more studies are necessary. Obesity-associated HCC has been viewed as a complex molecular mechanism including chronic inflammation because of adipose tissue remodeling, proinflammatory adipokines, lipotoxicity, lipid accumulation, insulin resistance, and, perhaps, changes in gut microbiota.33 Hepatocarcinogenesis is a multifaceted process involving the interaction of multiple genetic and environmental factors, so it may be difficult to pinpoint the contribution of each of these factors.34 A recent review of 17 cohort studies suggests that the association between fatty liver disease/NASH and increase in HCC is mostly limited to those with cirrhosis. Fatty liver disease/NASH was associated with a cumulative HCC mortality rate of 0% to 3% over study periods 5.6 to 21 years. Those with NASH-related cirrhosis had a cumulative HCC incidence of 2.4% to 12.8% with 3.2 to 7.8 years of follow-up.35 Hawaii has an increasing prevalence of obesity and diabetes, but in the absence of liver biopsies on nontumor tissue, the presence of fatty liver disease and NASH is not completely clear. Our study very clearly shows that over time, there has been a steady increase in the BMI of these HCC patients and the proportion of patients with obesity. There is also a very clear trend of increased hyperlipidemia over the succeeding eras, and although it is possible that physicians may be better at testing and reporting lipid panels in the later eras, an increase from 6.7% to 25.7% is unlikely to be entirely because of entirely to enhanced awareness of hyperlipidemia.
This study is limited in that it is from a single center; however, it is the only dedicated liver center for a state that is overburdened with HCC. Our center’s prominence in the community, central location, and emphasis on multidisciplinary management has resulted in increased referral of HCC cases. We currently see about 70% of Hawaii’s HCC cases and have carefully collected data on these patients for more than 20 years. We have instituted better teaching and outreach to the community physicians and clinics to promote screening for hepatitis B in the immigrant population and surveillance for HCC in the at-risk populations. As a consequence, 32.5% of our current HCC patients had their HCC found with screening or surveillance, which is better than the ‘‘less than 20%’’ reported in the United States overall.36 In our study, more liver resections were performed although the proportion of patients who underwent resection has not changed over time. The liver transplant rate is also unchanged and likely because of a relatively stable number of available deceased donor livers. We are likely identifying smaller or earlier stage HCC in the elderly and poor surgical candidates who subsequently undergo nonoperative therapies. This is evident by the lower proportion of patients who had no therapy in the most recent era. So why is it important that the rest of the United States understand the characteristics of a small state’s HCC? Asians and Pacific Islanders are the 2 fastest growing nonHispanic ethnic groups in the United States. From 2000 to 2010, the number of Asians in the United States increased 43.3% and Pacific Islanders increased 35.4%. The Asian population has been increasing in every region in the United States with the highest increase in the South at 69.2%. Although more than half of the Pacific Islanders live in Hawaii or California, they are migrating across the United States with the highest increase in the South (65.6%) during this time period.37 Physicians across the United States will need to deal with these ethnic groups and their especially high risk for HCC because of both viral
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hepatitis endemic in their native country and the influence of Western diet and metabolic factors. Furthermore, it is these same metabolic risk factors that may contribute to the epidemic of HCC that the United States is just beginning to experience. It is important that each individual center adjust their surveillance practices and community education based on the ethnicity and risks factors of the referral population in their local area. This study also showed that AFP has become a progressively less helpful marker over time and metabolic factors, and NASH may be affecting its overall usefulness. Further improvements in imaging technology and discovery of new biomarkers will be a priority as we manage HCC in the future.
References 1. GLOBOCAN 2008. International Agency for Research on Cancer, World Health Organization. Available at: www.globocan.iarc.fr. Accessed December 8, 2013. 2. National Cancer Institute, Cancer Statistics. Available at: www.cancer. gov. Accessed December 8, 2013. 3. Perez JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45:529–38. 4. Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2005;9:191–211. 5. McGlynn KA, London WT. The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis 2011;15: 223–43. 6. Oso´rio FM, Lauar GM, Lima AS, et al. Epidemiological aspects of hepatocellular carcinoma in a referral center of Minas Gerais, Brazil. Arq Gastroenterol 2013;50:97–100. 7. Fenoglio L, Serraino C, Castagna E, et al. Epidemiology, clinicaltreatment patterns and outcome in 256 hepatocellular carcinoma cases. World J Gastroenterol 2013;19:3207–16. 8. Shaker MK, Abdella HM, Khalifa MO, et al. Epidemiological characteristics of hepatocellular carcinoma in Egypt: a retrospective analysis of 1313 cases. Liver Int 2013;33:1601–6. 9. Olal SO, Akere A, Otegbayo JA, et al. Are patients with primary hepatocellular carcinoma infectious of hepatitis B, C and D viruses? Afr J Med Med Sci 2012;41:187–91. 10. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013;47:S2–6. 11. Valizadeh N, Mehdioghli R, Behroozian R, et al. Etiologic and epidemiologic study of hepatocellular carcinoma in West Azarbaijan of Iran (2006–2011). Med Paediatr Oncol 2012;33:221–3. 12. Dunbar JK, Dillon J, Garden OJ, et al. Increasing survival of hepatocellular carcinoma patients in Scotland: a review of National Cancer Registry Data. HPB (Oxford) 2013;15:279–85. 13. Dhanasekaran R, Limaye A, Cabrera R. Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics. Hepatic Med Evid Res 2012;4:19–37. 14. United Network for Organ Sharing. Policy 3.6.4.4. Available at: www. optn.transplant.hrsa.gov. Accessed May 20, 2009.
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15. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–2. 16. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. 17. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009. p. 191–9. 18. Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccines: a 20 year follow-up study. J Natl Cancer Inst 2009;101:1348–55. 19. Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 2013;57:399–408. 20. Kurokawa M, Hiramatsu N, Oze T, et al. Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus infection. J Gastroenterol 2012;47:577–85. 21. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis b virus infection. Hepatology 2013;58:98–107. 22. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 35:1521–31. 23. Ditah I, Ditah F, Devaki P, et al. The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010. J Hepatol 2014;60:815–22. 24. Williams I. Epidemiology of hepatitis C in the United States. Am J Med 1999;107:2S–9S. 25. Hepatitis B Infection Rates by Country Available at: www.pkids.org; 2003. Accessed December 24, 2013. 26. Kowdley K, Wang CC, Roberts H, et al. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology 2012;56:422–33. 27. Ramsey KW, Davis J, French G. Perspectives of Chuukese patients and their health care providers on the use of different sources of interpreters. Hawaii J Med Public Health 2012;71:249–52. 28. Kiyosawa K, Umemura T, Ichijo T, et al. Hepatocellular carcinoma: recent trends in Japan. Gastroenterology 2004;127:s17–26. 29. Yoshizawa H. Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: projection to other countries in the foreseeable future. Oncology 2002;62:8–17. 30. Nguyen LH, Nguyen MH. Systematic review: Asian patients with chronic hepatitis C infection. Alimen Pharmacol Ther 2013;37:921–36. 31. Singal AK, Singh A, Jaganmohan S, et al. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis. Clin Gastroenterol Hepatol 2010;8:192–9. 32. United States Census Bureau, Quick Facts on Hawaii. Available at: www.census.gov. Accessed December 29, 2013. 33. Karagozian R, Derda´k Z, Baffy G. Obesity-associated mechanisms of hepatocarcinogenesis. Metabolism 2014;63:607–17. 34. Ding J, Wang H. Multiple interactive factors in hepatocarcingenesis. Cancer Lett 2014;346:17–23. 35. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10:1342–59. 36. Davila JA, Morgan RO, Richardson PA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 2010;52:132–41. 37. United States Census Bureau, Asians Fastest Growing Race or Ethnic Group in 2012, Census Bureau Reports. Available at: www.census. gov/newsroom/releases/archives/population/CB13-112.html. Accessed December 29, 2013.
The changing characteristics of hepatocellular cancer in Hawaii over time Linda L. Wong, M.D.a,b,c,*, Makoto Ogihara, M.D.a,b, Junfang Ji, Ph.D.c, Naoky Tsai, M.D.d a
Department of Surgery, John A. Burns School of Medicine, University of Hawaii, 550 South Beretania Street, Suite 403, Honolulu, Hawaii 96813, USA; bTransplant Center, Queens Medical Center, Honolulu, HI, USA; cCancer Center, University of Hawaii, Honolulu, HI, USA; dLiver Center, Queens Medical Center, Honolulu, HI, USA
KEYWORDS: Hepatocellular cancer; Liver resection; Liver transplant; Viral hepatitis; Metabolic factors
Abstract BACKGROUND: The incidence of hepatocellular cancer (HCC) is increasing, and we sought to characterize the differences and trends in HCC over 2 decades in Hawaii. METHODS: This retrospective study of 821 HCC cases analyzed risk factors, diabetes, alphafetoprotein (AFP), tumor characteristics, and treatment, comparing 5-year eras (1993 to 2012). RESULTS: With succeeding eras, there were fewer Asians, immigrants, and hepatitis B–related HCC. Hepatitis C, diabetes, hyperlipidemia, and body mass index have increased. Over time, more patients had normal AFP, and normal AFP was seen more often in nonviral HCC (49.6% vs 33.2%, P 5 .007). Over time, the proportion of patients who underwent resection or transplant was stable, but fewer patients underwent no therapy. CONCLUSIONS: Characteristics of HCC are changing, and diagnosis may be more difficult as metabolic factors are becoming more important than viral factors. AFP seems to be a less important biomarker, and clearly, better diagnostic tools will be necessary to identify HCC in the future. Ó 2014 Elsevier Inc. All rights reserved.
Hepatocellular cancer (HCC) is the fifth most common cancer in men and ninth most common cancer in women globally with an estimated 750,000 new cases diagnosed in 2012. Overall, this is a deadly cancer with one of the highest mortality to incidence ratios at .95. It is the second most common cause of cancer mortality with 600,000 deaths annually.1 Although 85% of these cases occur in less Wong: Speaker for Bayer and Onyx, Tsai: Research and Grants Gilead, BMS, Janssen, AbbVie, Beckman; Speakers bureau- Gilead, BMS, Janssen, AbbVie, Salix, Bayer; Advisory board-Gilead, AbbVie, BMS. * Corresponding author. Tel.: 11-808-523-5033; fax: 11-808-5284940. E-mail address: [email protected] Manuscript received March 23, 2014; revised manuscript June 12, 2014 0002-9610/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2014.06.036
developed countries, HCC is one of the few cancers that is increasing in incidence in the United States. In 2010, there were 24,304 new cases and 20,304 deaths because of HCC.1,2 Globally, an estimated 80% of HCC cases have hepatitis B or C as a risk factor with more of these cases related to hepatitis B (75%) and a smaller proportion (10% to 20%) because of hepatitis C.3 Diabetes, obesity, and nonalcoholic steatohepatitis are increasingly identified as risk factors that will likely play a greater role in the upcoming years.4,5 Many epidemiologic studies from various places in the world have shown these risk factors have different influences on the incidence of HCC.6–13 This is likely related to the prevalence of a particular risk factor in that country. It is often difficult to quantify this risk exactly as underdeveloped countries may have limited resources to support detailed tumor registries. In the United
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States, we have comprehensive tumor registries and administrative or billing databases; however, these databases often have limited information on ethnicity, viral hepatitis, body mass index (BMI), and some of the newer risk factors such as diabetes, obesity, and nonalcoholic steatohepatitis. These databases are often based on billing codes and may be dependent on the variable skills of the staff entering this information. Hawaii is the state in the United States with the highest incidence of HCC at 10.8 per 100,000 and the second highest death rate at 5.9 per 100,000.2 The large proportion of Asian and Pacific Islander ethnic groups and continued immigration probably account for this high incidence for many years. Our group of physicians has been carefully collecting detailed information on HCC cases for more than 20 years. This study hopes to reveal the changing patterns of risk factors and presentation of HCC over time in Hawaii.
‘‘Asian’’ (including Filipinos), or ‘‘Pacific Islander.’’ Patients who did not fit into one of these categories or were of mixed ethnicity were subsequently classified as ‘‘other.’’ Patients of mixed race with 50% Pacific Islander ethnicity were categorized as ‘‘Pacific Islander.’’ Data collected on medical history included diabetes mellitus, hyperlipidemia, smoking, and risk factors for HCC including viral hepatitis, alcohol abuse (defined as .2 alcoholic beverages daily for at least 10 years), and other chronic liver diseases. Information was based on available medical records and interview by a single physician, without use of a structured questionnaire. Patients who did not report hyperlipidemia but had a lipid-lowering agent on their current medication list were also classified as having hyperlipidemia. Measured height and weight were used to determine BMI. Obesity was defined as BMI of 30 or more. Laboratory data collected included bilirubin, albumin, prothrombin time, creatinine, alanine aminotransferase, aspartate aminotranferase, platelet count, and AFP. Laboratory data that were used for the study had been obtained within 2 weeks of initial visit or drawn at the time of the visit. Bilirubin, prothrombin time with international normalized ratio, and creatinine were used to calculate the Model for End-Stage Liver Disease score. The size, number, and location of the tumors were used to determine the Tumor– Node–Metastases stage according to the American Joint Commission on Cancer (AJCC) staging manual.17 The proportion of patients with HCC detected by screening was noted. Although our Liver Center recommends that community physicians screen viral hepatitis and chronic liver disease patients with AFP and liver ultrasound every 6 months, there was no uniform screening protocol used in the cohort. Referring physicians used a combination of AFP and imaging (ultrasound, CT scan, or MRI) at variable intervals. HCC was deemed to be found on ‘‘screening’’ if the referring physician stated that screening was done and the patient had a previous imaging study from 3 to 12 months prior. HCC not found on screening was either found with symptoms (pain, abdominal mass, weight loss, jaundice) or asymptomatically with imaging done for unrelated reasons.
Methods administrative or billing Patients This is a retrospective analysis of 821 HCC cases referred over a 20-year period (1993 to 2012) to our group of physicians who are associated with the medical center with the only liver transplant program in Hawaii and the only referral center for liver disease and surgery for American territories of the Pacific Basin (including Samoa, Guam, Saipan, and the Marshall Islands). Patients also included foreign nationals from Asian countries, including China, Japan, Korea, and the Philippines, who sought medical care in the United States. This clinic and the transplant center were initially affiliated with Hawaii Medical Center East (formerly St Francis Medical Center) and after 2012, the Queens Medical Center. This center sees about 60% to 70% of the HCC cases in Hawaii. This study was approved by the University of Hawaii Institutional Review Board. HCC was diagnosed histologically by percutaneous biopsy or at surgery. In the first decade and consistent with the previous United Network for Organ Sharing policy regarding transplant for HCC, patients without histologic confirmation were included if they had a history of chronic liver disease and a mass at least 2 cm in size seen on 2 imaging studies (ultrasound, computed tomographic [CT] scan, or MRI) and one of the following1: vascular blush seen on CT scan or MRI,2 alpha-fetoprotein (AFP) greater than 200 ng/mL, or3 arteriogram confirming the tumor.14 More recently, the diagnosis of HCC was made with only imaging if a contrast-enhanced study (dynamic CT or MRI) showed typical arterial enhancement with ‘‘washout’’ in the venous phase as described by the American Association for the Study of Liver Disease guidelines.15,16 Information on demographics, medical history, laboratory results, tumor characteristics, treatment, and survival was collected via clinical interview. Demographic data included age, sex, birthplace, and the patient’s self-reported ethnicity. Ethnicity was then categorized as ‘‘White,’’
Treatments Treatments included liver resection, transplantation, ablative therapies (including radiofrequency ablation, cryosurgery, transarterial chemoembolization, and percutaneous ethanol injection), and systemic therapies. Liver resection was considered in Child’s A patients and early Child’s B patients (Childs–Turcotte–Pugh score of 7, without any evidence of ascites or encephalopathy). Liver transplants were considered in patients who were unresectable but met Milan criteria (single tumor ,5 cm or 2 to 3 tumors, each ,3 cm). Liver transplant was also considered in patients who underwent resection but had a recurrence more than 6 months after surgery, provided the recurrent tumor met Milan criteria, and there was no disease progression while awaiting transplant. Since 2007, liver transplant was
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Changing characteristics of hepatocellular cancer in Hawaii
considered in single tumors less than 6.5 cm that were downstaged to meet Milan criteria. All liver resections and transplants were performed by members of our surgical group. Most patients on the transplant list underwent percutaneous radiofrequency ablation or transarterial chemoembolization while waiting for a donor. Treatment was summarized by whether the patient had a liver resection, transplant, or no therapy. For liver transplant patients, no donor organs were obtained from executed prisoners or other institutionalized persons. Patients were followed long term with imaging every 3 months after surgery or locally ablative therapies for the first year and then every 4 to 6 months after this. Of 821 patients in the cohort, 418 expired during the 17-year study period, 189 are currently alive and are being actively followed, and 11 patients (1.8%) have been lost to followup. Deaths were also confirmed using the Social Security Death Index and local newspaper obituaries.
Data analysis All analyses were performed using Excel and SPSS statistical software. Categorical variables were analyzed using both ANOVA and chi-square analysis. Odds ratios with 95% confidence intervals were calculated based on the comparison with era 1. When the number of patients for a variable in era 1 was less than 10, era 2 was used as the index for calculating odds ratios with 95% confidence intervals. Continuous variables were compared using ANOVA between the 4 eras. P values ,.05 were considered significant.
Results Clinical characteristics of patients In the cohort of 821 patients, there were 618 men (75%) and 203 women with overall mean age of 61.7 years (range 22 to 94 years). Ethnic distribution was as follows: Asian (n 5 519), White (n 5 156), Pacific Islander (n 5 112), and other (n 5 30). Detailed Asian ethnicity was as follows: Japanese (n 5 205), Filipino (n 5 120), Chinese (n 5 102), Korean (n 5 52), Southeast Asian (n 5 33), and more than 1 Asian ethnicity (n 5 7). Risk factors in the overall cohort included 260 patients (31.7%) who were hepatitis B surface antigen positive and 76 patients (9.3%) who were only hepatitis B core antibody positive. Hepatitis C positivity occurred in 309 patients (37.6%). Approximately 42.8% (467 patients) used alcohol significantly in the past and 56.9% (467 patients) were smokers. In terms of metabolic risk factors, 245 patients (29.8%) were diabetics, 293 (35.7%) had hypertension, and 150 (18.3%) had hyperlipidemia. Mean BMI was 26.6%, and 16.1% (133 patients) met criteria for obesity. Of the 821 patients, 661 had a disease for which they could have undergone screening and surveillance as recommended by
3
the American Association for the Study of Liver Disease.14,15 Of these 661 patients, 162 (24.5%) had their HCC found with screening or surveillance. Tumor characteristics in the cohort included the mean tumor size of the largest tumor that was 6.17 cm. About 65% of patients had a single tumor, and the remainder had multiple tumors or diffuse disease. Milan criteria were met in 326 patients (39.7%), and 465 patients (56.6%) had AJCC stage 1 disease. Only 33 patients (4%) presented with ruptured HCC. AFP was normal in 293 patients (35.7%). In terms of treatments, 163 patients (19.9%) underwent liver resection, 69 patients (8.4%) had liver transplantation, and 228 (27.8%) had no treatment either because they were too ill or they refused treatment.
Comparison of risk factors and clinical presentation for HCC patients among 4 eras To investigate the changing patterns of risk factors and clinical presentation of HCC patients over time, 821 cases were separated into four 5-year eras from 1993 to 2012. Trends of demographics and risk factors over the 4 eras are shown in Table 1. Race was different over the eras with fewer Asians and more Whites noted in the later eras. The influence of hepatitis B decreased and hepatitis C increased in the later eras (Fig. 1). There was no difference in smoking or alcohol use between the eras. Metabolic factors differed over the eras with a clear increase in BMI and influence of hyperlipidemia with time. Laboratory studies over time are noted in Table 2 with more patients having a normal AFP over the eras. There was no difference in mean bilirubin, albumin, creatinine, platelet count, or AFP at presentation between the 4 eras. Although more patients had NASH in the recent eras, the percentage was similar over time. In the entire cohort, 49.6% of NASH patients and 33.2% of non-NASH patients had a normal AFP (P 5 .007). Over time, there is a trend in seeing smaller tumors at diagnosis and more tumors that were AJCC stage I and met Milan criteria. There were no differences in the proportion of tumors that were single tumors or presented with rupture across the 4 eras. Although the Model for End-Stage Liver Disease scores seemed to increase slightly over the eras from 9.6 to 11.1, this was not significantly different. HCC was found with surveillance in 17.9% of patients in the first era, 10.2% in era 2, 9% in era 3, and 32.5% in the most recent era (Tables 1 and 3). In terms of treatment, although the proportion of patients who underwent liver resection or transplant was unchanged with time, fewer patients (21.6%) in the most recent era had no treatment (Fig. 2).
Survival Mean survival improved over succeeding eras: era 1, 894 days (612.3); era 2, 1316 days (6145.3); era 3, 1238 days (695.2); and era 4, 1544.5 (668.7). This was
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4 Table 1
Demographics, risk factors by era
Characteristic Age (y) Males Race Asian White PacIsl US born HBV1 HCV1 Diabetes1 Hyperlipidemia Hypertension BMI (kg/m2) Obesity (BMI . 30)
Era 1 (1993–1997), n 5 85
Era 2 (1998–2002), n 5 159
Era 3 (2003–2008), n 5 234
Era 4 (2009–2012), n 5 343
62.4 6 12.8 57 (67.1%)
60.0 6 11.8 115 (72.3%)
61.3 6 12.0 187 (79.9%)
62.6 6 11.0 259 (75.5%)
65 (76.5%) 11 (12.9%) 9 (10.5%) 35/61 (57.3%) 36/81 (44.4%) 23 (27%) 28/83 (33.7%) 5/75 (6.7%) 1/4 (25%) 24.84 5/43 (11.6%)
117 (73.6%) 24 (15.1%) 15 (9.4%) 79/143 (55.2%) 61 (38.4%) 51 (32.1%) 49 (30.8%) 15/152 (9.9%) 27/48 (56.3%) 25.87 14/95 (14.7%)
148 (63.2%) 43 (18.4%) 38 (16.2%) 138/231 (59.7%) 67 (28.6%) 100 (42.7%) 58 (24.8%) 42/222 (18.9%) 97/193 (50.3%) 26.57 36/192 (18.8%)
189 (55.1%) 78 (22.7%) 50 (14.6%) 209/335 (62.4%) 96 (28%) 135 (39.4%) 119 (34.7%) 88 (25.7%) 299/335 (89.5%) 26.97 77/339 (22.7%)
P-value NS NS P 5 .001
NS P, P, NS P, P, P5 NS
.0001 .0001 .0001 .0001 .045
BMI 5 body mass index; HBV 5 hepatitis B virus; HCV 5 hepatitis C virus; NS 5 nonsignificant; PacIsl 5 Pacific Islander. Bold values are significantly different from Era 1.
significantly improved over the eras with P , .0001 by the log-rank test. Median survival was 475, 487, and 468 days for eras 1, 2, and 3, respectively, but the median survival could not be calculated for the most recent era as this had not been reached yet.
Comments The incidence of HCC in the United States is increasing, and although we have attributed this to various risk factors that have changed over time, this study truly shows the multiple intervening factors that have contributed to this increase. These factors include the increase in hepatitis B because of vertical transmission, followed by the decrease because of hepatitis B vaccination and antiviral agents that
may have reduced the development of HCC.18–22 Next, the epidemic of hepatitis C in the 1970s because of blood transfusions and high-risk behaviors contributed to more HCC followed by a decrease potentially because of screening of blood donors and effective hepatitis C therapy.23,24 Finally, most recently, the increase in obesity and diabetes has ignited the epidemic of nonalcoholic fatty liver disease and steatohepatitis. Hawaii continues to have much HCC and, perhaps, we have observed different trends compared with elsewhere in the United States. With respect to hepatitis B, we have not seen a dramatic decrease in this epidemic because of improved vaccination and better treatment as we continue to have immigration from Asia and Pacific Island nations where universal vaccination is not practiced consistently. Our most recent group emigrated from the US territoriesdincluding
Figure 1 Viral risk factors by era. Number of patients with hepatitis B and C, coinfection with hepatitis B and C, or no viral risk factors. HBV 5 hepatitis B virus; HCV 5 hepatitis C virus.
L.L. Wong et al. Table 2
Changing characteristics of hepatocellular cancer in Hawaii
5
Laboratory studies, tumor characteristics, and treatment by era
Characteristic
Era 1 (1993–1997), n 5 85
Era 2 (1998–2002), n 5 159
Era 3 (2003–2008), n 5 234
Era 4 (2009–2012), n 5 343
P-value
Normal AFP (,20 ng/dL) Protime INR Tumor size (cm) Milan criteria met AJCC stage I Cirrhotic Liver transplant Liver resection No therapy Two or more therapies
21 (24.7%) 1.00 7.53 16 (18.8%) 45 (52.9%) 54 (63.5%) 4 (4.7%) 15 (17.6%) 28 (32.9%) 16 (18.8%)
55 (34.6%) 1.09 6.78 49 (30.8%) 83 (52.2%) 123 (77.4%) 18 (11.3%) 37 (23.3%) 48 (30.2%) 36 (22.6%)
76 (32.5%) 1.14 6.22 101 (43.2%) 141 (60.3%) 183 (78.2%) 21 (9.0%) 51 (21.8%) 78 (33.3%) 61 (26.1%)
141 (41.1%) 1.22 5.55 160 (46.6%) 196 (57.1%) 230 (67%) 26 (7.6%) 60 (17.5%) 74 (21.6%) 103 (30%)
P5 P, P5 P, NS P, NS NS P5 NS
.005 .001 .001 .0001 .0001
.008
AFP 5 alpha-fetoprotein; AJCC 5 American Joint Commission on Cancer; INR 5 international normalized ratio. Bold values are significantly different from Era 1.
Micronesia, the Marshall Islands, Chuuk, and Guam, where the prevalence of hepatitis B is estimated at 12% to 20%.25,26 Poor conditions and health care in these Pacific Island nations have prompted many to seek medical care in Hawaii. These patients are not consistently screened for hepatitis B, cannot always afford antiviral medication, and do not undergo regular surveillance for HCC. Our cohort had 26 patients who immigrated from these small Pacific Island nations, 23 of whom had hepatitis B, 4 had hepatitis C (1 was coinfected), and only 1 of the 26 patients had their HCC found with surveillance. Language and cultural barriers likely contribute to health care disparity in this population.27 With respect to hepatitis C, Hawaii continues to see immigrants from Southeast Asia and Japan, where hepatitis C accounts for up to 80% to 90% of HCC cases.28,29 Southeast Asians also have a high
prevalence of hepatitis C, and in our group, 57% of the 33 HCC cases were hepatitis C positive.30 Treatment of hepatitis B and C may have potentially changed the incidence of HCC in the United States. A pooled analysis of 20 studies demonstrated a reduction in HCC among hepatitis C patients who undergo interferonbased treatment and are able to clear the virus.31 Unfortunately, in Hawaii, access to treatment for hepatitis C is limited as we have only 1 center dedicated to liver disease. The high cost and side effects associated with hepatitis C treatment and the need for compliance often limit therapy. Language and cultural barriers in Hawaii, where 18.1% of the population is foreign born (compared with 12.9% in the United States), also contribute to the lack of treatment with antivirals.32 Patients who cannot
Table 3 Odds ratios of significant factors between the eras (odds ratio performed compared with era 1 unless era 1 had ,10 patients and then era 2 used) Characteristic Males Race Asian White PacIsl HBV surfAg1 HCV1 Hyperlipidemia Hypertension HCC found with surveillance HCC found with surveillance (those with screenable disease) Milan criteria met Cirrhotic No therapy performed
Era 1 (1993–1997), n 5 85
Era 2 (1998–2002), n 5 159
Era 3 (2003–2008), n 5 234
Era4 (2009–2012), n 5 343
1.00
1.25 (.72–2.22)
1.95 (1.12–3.40)
1.52 (.91–2.54)
1.00 1.00 1.00 1.00 1.00 1.00 d 1.00 1.00
.86 1.20 .88 .78 1.89 1.53 1.00 .52 .47
.53 1.51 1.63 .50 2.01 3.27 .79 .43 .41
.38 1.98 1.44 .49 1.75 4.47 6.4 2.22 2.35
1.00 1.00 1.00
1.92 (1.01–3.64) 1.96 (1.10–3.49) .88 (.50–1.55)
(.46–1.58) (.55–2.58) (.37–2.10) (.45–1.39) (.72–4.97) (.53–4.39) (.24–.12) (.22–1.03)
HBV 5 hepatitis B virus surface antigen; HCV 5 hepatitis C virus; PacIsl 5 Pacific Islander. Bold values are significantly different from Era 1.
(.30–.93) (.74–3.10) (.76–3.55) (.30–.85) (1.17–3.47) (1.24–8.60) (.42–1.49) (.21–.89) (.19–.85)
3.28 (1.79–5.98) 3.56 (1.47–4.47) 1.02 (.60–1.73)
(.22–.65) (1.01–3.92) (.68–3.06) (.30–.80) (1.03–2.95) (1.74–11.45) (3.32–12.58) (1.21–4.06) (1.26–4.38)
3.77 (2.10–6.76) 1.17 (.72–1.92) .56 (.33–.94)
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Figure 2 Treatment for HCC by era. Numbers of patients by era and primary initial treatment received. Other therapy includes any locoregional or systemic treatment other than resection or transplant.
afford treatment or are noncompliant inevitably present with decompensated liver disease or HCC. Hopefully, the advent of interferon-free antivirals for hepatitis C will increase the number of treated patients and decrease hepatitis C virus–related HCC. Finally, there is the epidemic of obesity, fatty liver disease, and NASH. How these factors exactly contribute to HCC development is not completely clear, and more studies are necessary. Obesity-associated HCC has been viewed as a complex molecular mechanism including chronic inflammation because of adipose tissue remodeling, proinflammatory adipokines, lipotoxicity, lipid accumulation, insulin resistance, and, perhaps, changes in gut microbiota.33 Hepatocarcinogenesis is a multifaceted process involving the interaction of multiple genetic and environmental factors, so it may be difficult to pinpoint the contribution of each of these factors.34 A recent review of 17 cohort studies suggests that the association between fatty liver disease/NASH and increase in HCC is mostly limited to those with cirrhosis. Fatty liver disease/NASH was associated with a cumulative HCC mortality rate of 0% to 3% over study periods 5.6 to 21 years. Those with NASH-related cirrhosis had a cumulative HCC incidence of 2.4% to 12.8% with 3.2 to 7.8 years of follow-up.35 Hawaii has an increasing prevalence of obesity and diabetes, but in the absence of liver biopsies on nontumor tissue, the presence of fatty liver disease and NASH is not completely clear. Our study very clearly shows that over time, there has been a steady increase in the BMI of these HCC patients and the proportion of patients with obesity. There is also a very clear trend of increased hyperlipidemia over the succeeding eras, and although it is possible that physicians may be better at testing and reporting lipid panels in the later eras, an increase from 6.7% to 25.7% is unlikely to be entirely because of entirely to enhanced awareness of hyperlipidemia.
This study is limited in that it is from a single center; however, it is the only dedicated liver center for a state that is overburdened with HCC. Our center’s prominence in the community, central location, and emphasis on multidisciplinary management has resulted in increased referral of HCC cases. We currently see about 70% of Hawaii’s HCC cases and have carefully collected data on these patients for more than 20 years. We have instituted better teaching and outreach to the community physicians and clinics to promote screening for hepatitis B in the immigrant population and surveillance for HCC in the at-risk populations. As a consequence, 32.5% of our current HCC patients had their HCC found with screening or surveillance, which is better than the ‘‘less than 20%’’ reported in the United States overall.36 In our study, more liver resections were performed although the proportion of patients who underwent resection has not changed over time. The liver transplant rate is also unchanged and likely because of a relatively stable number of available deceased donor livers. We are likely identifying smaller or earlier stage HCC in the elderly and poor surgical candidates who subsequently undergo nonoperative therapies. This is evident by the lower proportion of patients who had no therapy in the most recent era. So why is it important that the rest of the United States understand the characteristics of a small state’s HCC? Asians and Pacific Islanders are the 2 fastest growing nonHispanic ethnic groups in the United States. From 2000 to 2010, the number of Asians in the United States increased 43.3% and Pacific Islanders increased 35.4%. The Asian population has been increasing in every region in the United States with the highest increase in the South at 69.2%. Although more than half of the Pacific Islanders live in Hawaii or California, they are migrating across the United States with the highest increase in the South (65.6%) during this time period.37 Physicians across the United States will need to deal with these ethnic groups and their especially high risk for HCC because of both viral
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Changing characteristics of hepatocellular cancer in Hawaii
hepatitis endemic in their native country and the influence of Western diet and metabolic factors. Furthermore, it is these same metabolic risk factors that may contribute to the epidemic of HCC that the United States is just beginning to experience. It is important that each individual center adjust their surveillance practices and community education based on the ethnicity and risks factors of the referral population in their local area. This study also showed that AFP has become a progressively less helpful marker over time and metabolic factors, and NASH may be affecting its overall usefulness. Further improvements in imaging technology and discovery of new biomarkers will be a priority as we manage HCC in the future.
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