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Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4209-4211 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.0523
Chronic Asymptomatic Hepatitis B Presenting With Metastatic Hepatocellular CarcinomaSanta Clara Valley Medical Center, San Jose, CA A 59-year-old Vietnamese male without any significant past medical history presented with an inability to walk over the previous 2 days. He complained of a right hip mass that had grown in size over 8 months and right lower extremity weakness over 6 months that had progressively worsened to the point that he was using crutches. Physical exam was remarkable for soft tissue swelling encompassing the right hip, displacing abdominal contents to the left side. The mass was hard and nontender to palpation, and there was no hepatosplenomegaly. All laboratory findings, including liver function tests, were unremarkable except for the hepatitis B virus (HBV) surface antigen that was positive. Computed tomography revealed a large mass measuring 18 x 17 x 16 cm arising from the right pelvic wing with resulting destructive changes that appeared suggestive of a primary bone malignancy (Fig 1). The scan also revealed small metastatic foci in several lumbar vertebrae and two lesions in the liver with heterogeneous enhancement and attenuation measuring 2 cm and 2.8 cm in diameter. There was no mediastinal lymphadenopathy or parenchymal disease and no evidence of liver cirrhosis. The right pelvic mass biopsy revealed a poorly differentiated tumor with small cells and oval nuclei (Fig 2A) that stained positive for Hepatocyte-Specific Antigen-1 (Fig 2B) Cytokeratin 5.2 (Fig 2C) and Thyroid Transcription Factor-1 (Fig 2D) leading to a diagnosis of metastatic hepatocellular carcinoma (HCC). Negative cytokeratin stains (CK7, CK 20) ruled out a chondrosarcoma.1 An alpha-fetoprotein level checked in retrospect was found to be greater than 400,000 ng/mL. The patient was referred to radiation oncology for palliative radiation therapy and received zolendroic acid for his skeletal metastases.
Global incidence of chronic HBV infection is estimated to be 350 million people, a majority of whom are part of the Eastern and South East Asian population. It has been estimated that 53% of the global incidence of HCC is related to HBV.2,3 Recent studies have elucidated specific risk factors for the development of HCC in patients with chronic HBV infection. A 10-year prospective study by Yang et al4 noted that with all factors being equal, there is a six-fold increase in the rate of development of HCC in people with chronic HBV who test positive for the hepatitis B e antigen than those who do not. Another independent risk factor is HBV DNA viral load. The incidence of HCC increases with serum HBV DNA level from a cumulative incidence rate of 1.3% for people with HBV DNA titers less than 300 to 14.9% for people with HBV DNA titers greater than 1 million.5 Therefore, patients who are known to be chronic carriers of HBV can be tested for these surrogate markers and be risk stratified. Most of the controlled studies for HCC screening with ultrasound and the alpha-fetoprotein marker have been performed in patients with chronic HBV. The main study to provide definitive support for screening was performed by Zhang et al,6 where it was noted that there was a 37% increase in survival in the group of patients with chronic HBV who were screened biannually with both modalities than in those who were not. Screening methods for HCC are still controversial but should be pursued in these patients, as early detection is associated with improved survival. Diagnosing HCC before it metastasizes offers the hope of resection and has an excellent prognosis especially when it develops in the absence of liver cirrhosis. Historically, metastases from HCC were thought to be rare due to this disease usually being found in end-stage cirrhotics. A retrospective study by Chen et al7 in 1984 found metastases in 13% of patients with HCC on their postmortem exams. A more recent review in 2000 found metastases in as many as 37% of the postmortem cohort, almost three times as many as the previous study noted.8 The cohort was composed of patients who had succumbed to liver cirrhosis and HCC, all from a number of different causes; HBV was only a small part of the cohort. The pattern of spread was found to be similar irrespective of the initial cause of HCC. Asaka et al9 attempted to elucidate this pattern in their study and found that the most frequent sites of metastases were the lung (53.8%), bone (38.5%), and lymph nodes (33.8%). The portal vein, adrenal gland, peritoneum, skin, brain, and muscle were other sites that the cancer was found. The increased incidence of HCC metastasis, especially to the bone, prompted Iguchi et al10 to analyze its characteristic clinical features. The most common location of bone metastases was the vertebra followed by the pelvis and then the ribs, in that order. This was consistent with previous studies that indicated the vertebrae and the pelvis were the major sites of hepatic metastases.11 When looking specifically at patients with bone lesions, portal thrombus was found in about half of these patients. It is hypothesized that dissemination of HCC cells to the vertebra may occur through the portal vein–vertebral vein plexuses, and this could explain the unexpectedly high incidence of vertebral bony metastasis in HCC.11 Both an early diagnosis and timely treatment of bone metastases are thus called for in the follow-up of patients with HCC. Most people initially diagnosed with HCC present with progressive symptoms of their liver cirrhosis and are eventually found to have an elevated screening serum alpha-fetoprotein level or an incidental finding on ultrasound or a computed tomography scan. The difference with chronic HBV is that it can progress to HCC without going through the stage of liver cirrhosis. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Dabbs D: Diagnostic Immunohistochemistry (ed 2). Pittsburgh, PA, Churchill Livingstone, 2006, pp 184-191 2. Montalto G, Cervello M, Giannitrapani L, et al: Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci 963:13-20, 2002[Medline] 3. Parkin DM, Bray FI, Devesa SS: Cancer burden in the year 2000: The global picture. Eur J Cancer 37:S4-S66, 2001 (suppl 8)[Medline] 4. Yang HI, Lu SN, Liaw YF, et al: Hepatitis B antigen and the risk of hepatocellular carcinoma. N Engl J Med 347:168-174, 2002 5. Chen CJ, Yang HI, Su J: Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295:65-73, 2006 6. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 130:417-422, 2004[Medline] 7. Tsai GL, Liu JD, Siauw CP, et al: Thoracic roentgenologic manifestations in primary carcinoma of the liver. Chest 86:430-434, 1984[CrossRef][Medline] 8. Katyal S, Oliver J, Peterson M, et al: Extrahepatic metastases of hepatocellular carcinoma. Radiology 216:698-703, 2000 9. Natsuizaka M, Omura T, Akaike T, et al: Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol 20:1781-1787, 2005[CrossRef][Medline] 10. Fukutomi M, Yokota M, Chuman H, et al: Increased incidence of bone metastases in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 13:1083-1088, 2001[CrossRef][Medline] 11. Nielsen OS, Munro AJ, Tannock IF. Bone metastases: Pathophysiology and management policy. J Clin Oncol 9:509-524, 1991[Abstract]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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