3: Aggressive HCC: Is surveillance ever enough?

The patient is a 58-year-old African American man with hepatitis C virus (HCV) infection, diagnosed in 1991 as a result of screening when he went to donate blood. His only risk factor for HCV infection was receipt of a blood transfusion in 1971.

Past Medical History

Type 2 diabetes Degenerative joint disease Rheumatoid arthritis Major depressive disorder (recurrent)

Hepatitis C Course

1971 Estimated time of infection 1991 HCV detected 2000 First seen in hepatitis C clinic 9 years after initial diagnosis Alanine aminotransferase (ALT): elevated to twice normal limit Platelet count: normal HCV genotype 1 viral load: 505,000 copies/mL Liver biopsy: Grade 2 activity, Stage 1 fibrosis 2000 Treatment: Patient requested HCV treatment Received standard interferon and ribavirin (dosage not available) Treatment stopped after 6 months because of nonresponse 2001 Entered clinical trial for retreatment course (regimen not known) After 6 months, treatment again discontinued secondary to nonresponse 2002-2007 Patient continued HCV clinic appointments, every 6 months 2002-2004 Transaminases: normal Platelet count: normal Computed tomography (CT) scan: normal 2004 Transaminases rose to 4 times upper limit of normal Ultrasound imaging results (February 2004): negative Ultrasound imaging (September 2004) Liver enzymes improved back to ALT level of 47 U/L 2005 (June) Transaminases acutely elevated again to 4 times upper limit of normal Alpha-fetoprotein (AFP): 14 µg/L (twice normal limit) Liver ultrasound imaging repeated, with normal results 2005 (September) Repeat AFP: 9 µg/L 2005 (December) Repeat AFP: 19 µg/L Platelet count: normal CT scan detects no liver mass Second liver biopsy: now Grade 3 activity and Stage 2-3 fibrosis 2006 (February) Repeat AFP: 18 µg/L Patient seen in clinic 2006 (August) Repeat AFP: 24 µg/L Patient no-showed for clinic visit and no-showed for ultrasound imaging appointment 2007 (February) AFP: 208 µg/L An abdomen CT scan with/without contrast showed liver and spleen normal in size and enhanced normally after contrast administration. However, the delayed image 3 revealed small low-density lesions in the dome of the right lobe, and possibly a force lesion near the tip of the right lobe. The largest was a 1.2-cm rounded lesion in the dome of the liver, with a CT density of 23 Hounsfield units. The other lesions were too small to measure accurately. Ultrasound or magnetic resonance imaging (MRI) was recommended for further evaluation. Upon ultrasound scan of abdomen, 1.5-cm hypoechoic lesion in dome of the right lobe liver laterally was not demonstrated to be a cyst. A second, 1-cm lesion further posteriorly and inferiorly in the right lobe of the liver displayed similar echo characteristics. A third lesion seen on CT scan was not visualized on this ultrasound examination. An endoscopic ultrasound examination was ordered but later canceled by the provider and not rescheduled. 2007 (April) Repeat AFP: 884 µg/L An MRI examination of the abdomen detected a 10-cm, lobulated mass lesion in the dome of the right lobe of the liver and multiple other smaller lesions (1.7-cm or less) in the right lobe, with 2 small lesions in left lobe not excluded. The findings could represent multicentric hepatoma, metastatic disease, or a combination of hepatoma and metastatic disease. 2007 (May) A CT-guided fine-needle liver biopsy revealed degenerated hepatic parenchyma, highly suspicious for HCC. The patient underwent initial transcatheter chemoembolization for HCC. Synopsis: This case involves the development of a 10-cm hepatoma in an HCV patient without previously known cirrhosis. The patient was a previous nonresponder to HCV treatment, with Stage 2-3 fibrosis detected by liver biopsy and a normal platelet count.

Speaker 1: This case is very heartbreaking because the patient was followed closely for a long time, and there was no evidence that he had developed cirrhosis. He had been getting imaging tests and having AFP checked, although a little over a year passed (from December 2005 to February 2007) without imaging. However, the AFP was checked during that interval and was elevated only slightly.

Is there anything that could have been done in this case? Were there risk factors that developed to indicate the need for a more aggressive approach to HCC screening? If so, what approach should have been taken? Could anything have been done to recognize HCC earlier in this patient?

Speaker 2: This patient had an aggressive HCC--by the time it was detected, it was too late. The natural history of HCC is variable: One third to one half of liver cancers tend to be very aggressive, with genetic alterations and high mutation rates. I don't know if you can ever catch these cancers in a stage at which they can be cured by local resection, or transplantation, no matter how carefully you screen for them. The HCC cases with which we're having success involve patients who have a more indolent course, which allows a wider time frame for early intervention. If you approach HCC surveillance with a notion that perfect surveillance will lead to perfect results, you're going to be disappointed. Even with colon cancer, for which we thought perfect surveillance would lead to perfect results, we're not doing quite as well as we thought. But colon cancer is in many ways an ideal disease, with a relatively indolent progressive course that provides a very wide window of opportunity to cure it when it is found. There are a lot of liver cancers that we have no chance of curing, and I think this was one. A tumor that pops up this fast and grows this quickly does not allow enough time to prepare for transplantation.

Interestingly, I don't think this patient ever met criteria for HCC screening in the first place, so I am not sure what tipped off the care providers to conduct AFP tests and imaging screens from the start. So, whether the HCC in this case was detected by screening or whether it was revealed because of its own natural course, neither the treatment strategy nor the outcome for this patient would have been affected.

One of the reasons we have developed algorithms for the treatment of HCC, including the allowance of time to see what smaller lesions are doing, is to provide an opportunity to see how those tumors behave. The really aggressive ones become apparent, and you would not take a patient with such aggressive HCC to transplant. The algorithm allows you to figure out which are the more indolent HCC cases, so there is time for those patients to receive a transplant, and they usually do reasonably well.

Speaker 1: I would like to emphasize a point: If you're going to get a CT scan, get a triple-phase CT scan! You cannot accept a CT scan done by the emergency room technicians as "good enough." It is not. It has to be high quality. It has to include arterial-venous phase imaging.

1. HCC can develop and progress very aggressively in some cases. Occasionally, HCC can develop in a patient who is precirrhotic (by all measures), and these most likely are the more aggressive types of HCC.

2. AFP measurement is not a good test for the initial detection of HCC. In this case, by the time the AFP showed a significant rise, there were already 3 HCC lesions present.

3. When screening for HCC, it is recommended that ultrasound imaging be used every 6-12 months for cirrhotic patients with HCV.

4. When you suspect that HCC may be present, by definition you are no longer "screening," but working up symptoms or signs. In a work-up, as opposed to screening, triple-phase CT is likely to be the better imaging test to choose.

5. In the case presented here, the providers' choice of when to use CT vs when to use ultrasound does not seem to follow a clear rationale. At times, CT scans were ordered even though there were no changes in presentation. At other times, when significant changes occurred (such as 2 episodes of transaminases flaring), ultrasound imaging was ordered but not CT scans.

	Ann Busch, Liver Transplant Clinical Nurse Specialist, Portland VAMC
	Sue Currie, Associate Director, HCRC, San Francisco VAMC
	Guadalupe Garcia-Tsao, Director, HCRC, Connecticut VAMC
	Douglas Heuman, Liver Transplant Program Director, Richmond VAMC
	Alexander Monto, Director, HCRC, San Francisco VAMC
	Roberta Ruimy, Manager, Liver/Kidney Transplant Programs, Portland VAMC
	Brenda Salvas, Health System Specialist, Manager, Liver and Kidney Transplant Program, VA Transplant Program, VA Central Office, Washington, DC
	Anna Sasaki, Staff Physician, Portland VAMC
	Kristine Stick, Nurse Practitioner for Hepatology, San Francisco VAMC
	Suchat Wongcharatrawee, Associate Director HCRC, Connecticut VAMC

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