Hepatocellular Carcinoma (HCC) Management for the Primary Care Provider
A 62-year-old male with history of diabetes mellitus, hypertension, end-stage renal disease on hemodialysis, and hepatitis C virus (HCV) presented to our clinic for an acute appointment complaining of intermittent right upper quadrant pain for about 3 months. The pain was not associated with food intake and he had been using over-the-counter acetaminophen with minimal relief. He denied any radiation of the pain. He also denied weight loss, melena, or other constitutional symptoms. He had been diagnosed with HCV about 10 years ago and over time had developed cirrhosis with significant ascites. He was not a candidate for therapy at that time due to his excessive alcohol consumption. He was also non-compliant with his appointments and had been previously slow to follow up with our clinic and the hepatology clinic.
Physical examination. The patient’s vitals were unremarkable. His physical exam was pertinent for right upper quadrant pain to deep palpation with no rebound tenderness or guarding. He also had abdominal ascites with +2 lower extremity pitting edema. He appeared nonicteric and his pulmonary and cardiac exams were unremarkable. No lymphadenopathy was appreciated on exam. He had no rashes but a few spider angiomatas were visible on his chest.
Laboratory and radiology results. Patient’s labs were significant for hyponatremia with a sodium measuring 132 mmol/L, an elevated alkaline phosphate at 332 IU/L and elevated alpha-fetoprotein (AFP) at 40.1 ng/mL. Aspartate aminotransferase, alanine aminotransferase, and total bilirubin remained normal. Amylase and lipase were also within the normal range. His hepatitis C antibody was reactive with an elevated viral load. His hepatitis B surface antigen was nonreactive.
To further evaluate his intermittent pain, a right upper quadrant ultrasound was initially pursued, showing a large liver mass (Figure 1). A CT scan and MRI of the abdomen confirmed the findings, showing a rather large heterogeneous lesion measuring approximately 7.6 x 7.1 x 7.1 cm in the right lobe of the liver with early cirrhosis (Figure 2). Moderate ascites was present as well. The patient subsequently underwent a biopsy of the liver lesion confirming the final diagnosis of hepatocellular carcinoma (HCC).
Discussion: Liver cancer is the second most common cause of cancer-related death in adult men worldwide.1 It is the fifth most common cancer worldwide and the seventh most common cancer in adult women.1,2 HCC accounts for the majority of liver cancer diagnosed. Hepatitis B accounts for 50% of the cases of HCC worldwide and is the primary risk factor of HCC among the Asian population.3 Other major risk factors include hepatitis C and alcohol-induced liver disease.1 Patients affected by HCV showing advanced fibrosis or cirrhosis are 15 to 20 times more at risk for developing HCC.1
In patients with cirrhosis or advanced fibrosis, HCC surveillance is recommended via ultrasonography of the liver in addition to measurement of AFP every 6 to 12 months. Most experts use a 6-month screening interval even though there is no data to support 6 months over annual screening. CT and MRI are not recommended for HCC surveillance.1,4 HCC is rare in HCV infected patients with no fibrosis and hence surveillance is not recommended for these patients.1
Once detected on ultrasound and/or AFP levels (> 400 ng/mL highly predictive of HCC), patients should undergo further imaging with 4-phase multidetector CT or dynamic contrast-enhanced MRI, with both modalities required for diagnosis of lesions measuring 1 to 2 cm.4 For hepatic lesions consisting of atypical features on CT/MRI or lesions in noncirrhotic liver, image-guided biopsy may be done to confirm diagnosis.4 Risk of tumor seeding associated with biopsy in patient with HCC has been reported as low. 1
Numerous staging systems have been proposed for management of HCC such as TNM staging, Okuda system, Cancer of Liver Italian Program score and Barcelona Clinic Liver Cancer staging classification (BCLC), with the latter being the most commonly used system in Europe and United States.1,2 The BCLC staging classification includes number and size of liver lesions, patient’s performance status, presence of cancer symptoms, and degree of liver function (as determined by Child-Pugh classification). 4 BCLC classification system classifies patients into very-early stage, early stage, intermediate stage, advanced stage and terminal stage.
Patients with single, <2 cm lesion, asymptomatic with no evidence of extrahepatic spread are classified as very-early stage HCC. Surgical resection is recommended for very-early stage HCC without cirrhosis or if they have cirrhosis with well-preserved liver function, normal bilirubin, and hepatic vein pressure gradient <10 mm Hg.1,4 Surgical resection is associated with 90% overall survival rate.1,4 Radiofrequency therapy is an equally effective treatment for lesions <2 cm and has recently replaced alcohol injections as second choice of therapy. There is no consensus as to whether radiofrequency is superior to surgical resection for small tumors.2
Early-stage HCC comprises of patients with a single lesion <5 cm or up to 3 lesions, each measuring <3 cm in the setting of preserved liver function. These patients can also undergo surgical resection (if there is no portal hypertension), but the best therapeutic option is considered to be liver transplantation. Local ablative therapy is usually reserved for patients that are not eligible for transplant. The 5-year risk of HCC recurrence after resection is approximately 70% due to continued presence of chronic liver disease and cirrhosis.1,2,4
Patients with larger size and or multiple hepatic lesions but, with compensated cirrhosis, no cancer-related symptoms, and no evidence of vascular invasion are classified as intermediate. The best step in management of these patients is transarterial chemoembolization (TACE), as a bridge to liver transplantation (if waiting time is more than 6 months) and has been associated with significant survival benefit.1,2,4 TACE comprises the injection of chemotherapeutic agents into the blood vessels feeding the tumor. It works by blocking the arterial blood supply to the tumor creating a hypoxic environment for the cancer cells resulting in tumor necrosis.2,4
Advanced-stage HCC involves patients with symptoms related to HCC, or extrahepatic spread. TACE has been shown to increase survival for selected patients, but oral chemotherapy such as sorafenib remains the primary therapy. Other novel agents are still being developed. Lastly, patients with liver failure secondary to HCC, with cancer symptoms, or metastasis are classified as end-stage. These patients usually have 1-year survival of <10%. Palliative treatments are best reserved for these patients.1
Outcome of the case. Our patient was found to have a single lesion in his liver with no metastatic disease. He was classified as having intermediate HCC and referred to our hepatology clinic for additional care including possible treatments with TACE. Due to his continued alcohol use, multiple missed appointments, and noncompliant behavior, treatment of his chronic HCV and HCC proved difficult and limited.
References:
1. El-Serag HB, Hepatocellular Carcinoma. N Engl J Med. 2011;365(12):1118-1127.
2. Raza A, Sood GK. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J Gastroenterol. 2014;20(15):4115-4127.
3. Davila JA, Morgan RO, Shaib Y, et al. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology. 2004(5);127:1372-1380.
4. Bruix, J, Sherman, Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208-1236.