Markedly Increased Rate of Primary Liver Malignancies at Autopsy in Male US Veterans
Authors: Aqsa Nasir, Juan C. Manivel, Hira Yousaf, Jeffrey H. Albrecht, Richard Dykoski, Hector Mesa
Journal: Clinical Gastroenterology and Hepatology (2016)

The ratio of metastatic to primary malignant liver tumors varies widely worldwide: in the United States the ratio is 40:1 and in South East Asia the ratio is <1. These marked variations are mostly the result of differences in the incidence of primary liver neoplasms.1Ananthakrishnan A. Gogineni V. Saeian K. Epidemiology of primary and secondary liver cancers.Semin Interv Radiol. 2006; 23: 47-63Crossref PubMed Scopus (131) Google Scholar We performed an autopsy study in a cohort of US veterans and found a markedly increased rate of primary tumors. Histologic slides from the liver and electronic medical records from complete autopsies performed between 2005 and 2014 at a veterans hospital were included. Cases with uninterpretable histology or incomplete clinical data were excluded. Primary and secondary liver malignancies were differentiated on the basis of clinical, pathologic, and radiologic findings. Traditional and emerging risk factors for liver cancer were retrieved from the electronic medical records or evaluated on the histologic slides. Body mass index at autopsy and in the previous 3 years was recorded, to assess for obesity-associated fatty liver disease. Statistical analysis was performed using MedCalc Statistical Software version 16.8 (MedCalc Software bvba, Ostend, Belgium; https://www.medcalc.org; 2016). The study was performed in compliance with institutional guidelines (Veterans Health Administration handbook 1200.05). A total of 405 cases were included, all male consistent with a veterans population. Forty-six (11%) had malignant tumors: 36 (78%) metastases and 10 (22%) primary. The ratio of metastases to primary liver tumors was 3.5:1. Average age at diagnosis in the metastatic and primary cohorts was 66.3 and 69.5 years, respectively. The most common metastases by site were lung (39%), pancreas (19%), and colorectal (8%), and by histology pancreatic adenocarcinoma (19%), small cell carcinoma (14%), pulmonary squamous cell carcinoma (11%), and colonic adenocarcinoma (11%). Among primary liver cancers hepatocellular carcinoma (HCC) (n = 6; 60%) and mixed HCC/cholangiocarcinoma (n = 3; 30%) were most common. Statistically significant risk factors for primary liver cancer were cirrhosis (odds ratio [OR], 18.7; 95% confidence interval, 3.4–102.8; P = .0008) and chronic hepatitis C (OR, 16.5; 95% confidence interval, 2.9–93.2; P = .0015). There was an increased, but not significant rate of steatohepatitis in the primary cohort (OR, 3.3; 95% confidence interval, 0.7–15.5; P = .12). There were no differences in the frequency of alcohol abuse (OR, 0.9; P = .87), smoking (OR, 0.6; P = .42), diabetes mellitus (OR, 1.2; P = .82), and body mass index at autopsy (Student t test, 0.96; P = .34) or 3 years prior (Student t test, 0.69; P = .48). Among the cirrhosis cases 6 of 10 were associated with hepatitis C. All cases were negative for hepatitis B (Table 1).Table 1Study ResultsMetastases by site and histologyOriginN = 36 (n [%])Histologic typeN = 36 (n [%])Lung14 (38.8)Adenocarcinoma pancreas7 (19.4)Pancreas7 (19.4)Small cell carcinoma lung5 (13.9)Colorectal4 (11.1)Squamous cell carcinoma lung4 (11.1)Genitourinary tract3 (8.3)Adenocarcinoma colon4 (11.1)Upper gastrointestinal tract2 (5.6)Adenocarcinoma lung3 (8.3)Skin1 (2.8)Malignant melanoma (unknown primary site in 1 case)2 (5.5)Head and neck1 (2.8)Large cell neuroendocrine carcinoma lung1 (2.8)Mesothelium1 (2.8)Large cell undifferentiated carcinoma lung1 (2.8)Ileum1 (2.8)Squamous cell carcinoma esophagus1 (2.8)Unknown2 (5.6)Squamous cell carcinoma right tonsil/tongue base1 (2.8)Adenocarcinoma stomach1 (2.8)Well-differentiated neuroendocrine carcinoma ileum1 (2.8)Papillary renal cell carcinoma, type 21 (2.8)High-grade urothelial carcinoma, urinary bladder1 (2.8)Poorly differentiated squamous cell carcinoma penis1 (2.8)Small cell carcinoma (unknown primary)1 (2.8)Malignant mesothelioma1 (2.8)Primary liver malignancies by histologic typeBody mass indexHistologic typeN = 10 (n [%])Primary n = 10Metastatic n = 36T95% CIP valueHepatocellular carcinoma6 (60)Mean at autopsy24.125.70.96-1.7 to 4.9.34Mixed hepatocellular and cholangiocarcinoma3 (30)SD3.54.9Mean 3-y prior27.729.10.69-2.6 to 5.4.48Angiosarcoma1 (10)SD4.35.9Risk Factors for primary liver cancer in primary versus metastatic groupsRisk factorPrimary N = 10 (n [%])Metastatic N = 36 (n [%])Ratio primary/metastasisOR95% CIP valueCirrhosis7 (70)4 (11)6.418.73.4–102.8.0008aChronic hepatitis C6 (60)3 (8)7.516.52.9–93.2.0015aChronic hepatitis B0 (0)0 (0)————Steatohepatitis4 (40)6 (17)2.43.30.7–15.5.12Alcohol abuse5 (50)19 (53)0.90.90.2–3.6.87Tobacco abuse5 (50)23 (64)0.80.60.1–2.3.42Diabetes mellitus4 (40)13 (36)1.11.20.3–5.0.8295% CI, 95% confidence interval; OR, odds ratio; P, significance; SD, standard deviation; T, Student t test. Open table in a new tab 95% CI, 95% confidence interval; OR, odds ratio; P, significance; SD, standard deviation; T, Student t test. The ratio of metastatic to primary liver tumors in veterans was 3.5:1, markedly different from the general US population. Significant risk factors for HCC in veterans were cirrhosis and hepatitis C. There was an increased rate of steatohepatitis, and no differences in the rates of alcohol abuse, smoking, diabetes mellitus, and body mass index. The similar average age at diagnosis in both groups excludes possible differences in toxic exposures during military service. The prevalence of hepatitis C in veterans is 2- to 3-fold than in the general population because of exposure to traditional risk factors.2Dominitz J.A. Boyko E.J. Koepsell T.D. et al.Elevated prevalence of hepatitis C infection in users of United States veteran medical centers.Hepatology. 2005; 41: 88-96Crossref PubMed Scopus (182) Google Scholar, 3El-Serag H.B. Engels E.A. Landgren O. et al.Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: a population-based study of U.S. veterans.Hepatology. 2009; 49: 116-123Crossref PubMed Scopus (233) Google Scholar Our findings are consistent with a recent retrospective study using electronic medical records, which reported a 2.5-fold increase in HCC in veterans from 2001 to 2013, largely attributable to hepatitis C.4Beste L.A. Leipertz S.L. Green P.K. et al.Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001-2013.Gastroenterology. 2015; 149: 1471-1482Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar The VA performs large-scale screening and treatment programs for hepatitis C and the number of infection related–HCC cases is expected to decline in the 2020s.3El-Serag H.B. Engels E.A. Landgren O. et al.Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: a population-based study of U.S. veterans.Hepatology. 2009; 49: 116-123Crossref PubMed Scopus (233) Google Scholar However, a recent study by Davila et al.5Davila J.A. Henderson L. Kramer J.R. et al.Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States.Ann Intern Med. 2011; 154: 85-93Crossref PubMed Scopus (235) Google Scholar correlated the high occurrence of HCC to insufficient surveillance of hepatitis C and cirrhosis in the VA system. Forty percent of the cases with cirrhosis were unrelated to hepatitis C, and none caused by hepatitis B. Given the increased rate of steatohepatitis, and high rates of alcohol abuse in both cohorts, it is likely that most of these cases represent alcoholic cirrhosis. Epidemiologic studies have shown 2.5-fold lifetime prevalence of alcoholism in veterans compared with nonveterans.6Richards M.S. Goldberg J. Rodin M.B. et al.Alcohol consumption and problem drinking in white male veterans and nonveterans.Am J Public Health. 1989; 79: 1011-1015Crossref PubMed Scopus (28) Google Scholar Emerging risk factors, such as smoking, diabetes, and obesity, do not seem as relevant.7Atchison E.A. Gridley G. Carreon J.D. et al.Risk of cancer in a large cohort of U.S. veterans with diabetes.Int J Cancer. 2011; 128: 635-643Crossref PubMed Scopus (195) Google Scholar HCC and mixed HCC/cholangiocarcinoma were the most common primary malignancies, in keeping with the epidemiology of cirrhosis/hepatitis C–related cases.1Ananthakrishnan A. Gogineni V. Saeian K. Epidemiology of primary and secondary liver cancers.Semin Interv Radiol. 2006; 23: 47-63Crossref PubMed Scopus (131) Google Scholar Worldwide, the most common metastases are lung, colon, stomach, and pancreas.1Ananthakrishnan A. Gogineni V. Saeian K. Epidemiology of primary and secondary liver cancers.Semin Interv Radiol. 2006; 23: 47-63Crossref PubMed Scopus (131) Google Scholar In our study the most common were lung, pancreas, and colorectal, reflecting the increased incidence of pancreatic adenocarcinoma among veterans, associated with tobacco and alcohol use, diabetes, and pancreatitis, and the low prevalence of gastric cancer in the United States.7Atchison E.A. Gridley G. Carreon J.D. et al.Risk of cancer in a large cohort of U.S. veterans with diabetes.Int J Cancer. 2011; 128: 635-643Crossref PubMed Scopus (195) Google Scholar, 8Everhart J.E. Kruszon-Moran D. Perez-Perez G.I. et al.Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States.J Infect Dis. 2000; 181: 1359-1363Crossref PubMed Scopus (269) Google Scholar We report a markedly increased frequency of HCC in US veterans at autopsy associated with chronic hepatitis C, cirrhosis, and steatohepatitis. Strategies to prevent and treat these disorders are important public health goals for the Veterans Affairs System.