Hepatocellular carcinoma

Disquieting
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Diagnosis and reasoning

This patient has presented with vague pain in the right upper abdomen for several days, with no associated symptoms; the gamut of etiologies ranges from hepatic, biliary, and pancreatic, to even renal disease. His examination also turns out to be inconclusive, leaving us without a clear clinical diagnosis. Thus, given the location of the pain, further evaluation via a liver profile and ultrasound scan of the abdomen is probably a good next step. The first of these turns out to be mildly deranged, potentially indicating liver dysfunction; whether this is primary in origin, or secondary to other disease is unclear. However, sonography reveals a surprising and highly concerning finding - a solitary lesion in the left lobe of the liver. The differential diagnosis of solitary lesions of the liver includes benign neoplasms such as hepatic hemangiomas, hepatic adenomas, and focal nodular hyperplasia, as well as malignancies such as hepatocellular carcinoma (HCC), or a hepatic metastasis. In this specific patient, the large size of the lesion is suspicious of malignancy; note also that heavy consumption of alcohol and tobacco are well-known risk factors for HCC. That said, this malignancy is mainly encountered in patients with cirrhosis, although 20% of cases occur in non-cirrhotic livers. Thus, as per the 2014 American College of Gastroenterology (ACG) guidelines on the Diagnosis and Management of Focal Liver Lesions, further evaluation via Four-phase CT imaging of the liver should follow. This reveals arterial phase enhancement with rapid contrast washout during the venous phase, findings which are highly specific and sensitive for the diagnosis of HCC. Surgical resection is the treatment of choice for localized HCC in a noncirrhotic liver with preserved liver function; transarterial chemoembolization (TACE) and radiofrequency ablation are mainly palliative treatments employed in inoperable disease, while Sorafenib is indicated in patients with preserved liver function who are unfit for resection, transplantation, ablation, or TACE. Note that a liver biopsy is not indicated in this patient, as imaging studies have confirmed the diagnosis. While biopsy can be of prognostic value, the same information will be available following histological studies post-surgical resection.


Discussion

Hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers; it is also the most common liver malignancy overall. The condition is most common in Eastern and Southern Asia, and Middle and Western Africa; incidence rates in developed countries are lower. HCC is most closely associated with cirrhosis (particularly alcoholic cirrhosis), with approximately one-third of this population developing the condition. This form of the disease is around 2.5 times more common in men. Twenty percent of cases develop from a non-cirrhotic liver, as a complication of infections such as infectious hepatitis, heritable diseases such as porphyria, hemochromatosis, alpha-1 antitrypsin deficiency, or Wilson's disease, or following ingestion of genotoxic substances such as aflatoxin B1. This variant has a bimodal age distribution in the second and seventh decades of life. Note also that the prevalence of HCC parallels that of viral hepatitis; it is commonly associated with hepatitis B and hepatitis C, with affected patients carrying a 3% to 5% risk of developing HCC. Features associated with cirrhosis such as chronic inflammation, necrosis, regenerative nodule formation and fibrosis are implicated in the pathogenesis of HCC. In patients with chronic HBV infection, integration of the viral genome into hepatocytes is a well-studied pathogenic mechanism. Ongoing research aims to elucidate altered genetic pathways such as p53, PIKCA, B-catenin and hedgehog that may lead to hepatocarcinogenesis. Early HCC is asymptomatic; despite this, an increasing number of individuals are recognized in this stage, because of the routine screening and surveillance of high-risk persons. However, non-cirrhotic HCC is still mostly detected at an advanced stage, and is more likely to be symptomatic at presentation; such patients may experience right upper quadrant (RUQ) pain, weight loss and signs of decompensated liver disease. Where HCC is suspected, imaging studies are the mainstay of diagnosis; in cirrhotic HCC, ultrasonography is the test of choice, with a sensitivity of 89% and specificity greater than 90%. However, sonographic findings are often nonspecific in non-cirrhotic HCC; contrast-enhanced computed tomography (CT) is of value in these individuals. Where detected, liver nodules >1cm warrant a 4-phase multidetector CT scan or dynamic contrast enhanced magnetic resonance imaging (MRI) scan. In the arterial phase, HCC enhances more intensely than the surrounding liver parenchyma, whereas in the venous phase, it enhances less than the surrounding liver parenchyma, a phenomenon known as "washout"; this is highly specific for the condition. If imaging is inconclusive, a biopsy should performed; this should employ all available tumor markers (CD34, CK7, glypican 3, SHP-70, and glutamine synthetase) for improved diagnostic accuracy. Alpha-fetoprotein (AFP) was a widely used biomarker for HCC surveillance and prognosis in the past, with levels exceeding 400 ng/dl considered as being diagnostic of both cirrhotic and noncirrhotic HCC. However, its sensitivity and specificity have been a matter of controversy in recent studies. Note that the Barcelona Clinic Liver Cancer (BCLC) staging system is the staging system of choice for HCC. It considers tumor stage, hepatic functional status, physical status, and cancer-related symptoms to classify the HCC as either very early stage, early stage, intermediate stage, advanced stage, or end-stage. Surgical resection is beneficial for patients with very early stage, non-cirrhotic HCC, or those who have cirrhosis with well-preserved liver function. Pre- or post-resection adjuvant therapy is not recommended, as it has not been known to affect the outcome of surgical resection. Note that tumor recurrence after surgical resection complicates 70% of cases at five years, reflecting either intrahepatic metastases or the development of de novo tumors. Liver transplantation is effective and beneficial for patients with solitary tumors of 5cm or less, or up to three nodules measuring 3cm, according to the Milan criteria. The five-year survival rate of patients with early stage HCC who undergo liver transplant exceeds 70%. Percutaneous ablation is an option for candidates with early and intermediate stage disease who are unsuitable for resection or transplantation. Radiofrequency ablation (RFA) is the first choice among the available methods for local ablation in tumors under 2cm, and ethanol injection is used to ablate tumors over 2cm. This procedure allows for a 70% five-year survival rate. Transarterial chemoembolization (TACE) is recommended as a first line, non-curative therapy for patients with large, multifocal HCC who do not have vascular invasion or extrahepatic spread. Sorafenib, an oral multi-tyrosine kinase inhibitor, is recommended as the first-line measure for patients with preserved liver function who are unable to benefit from any of the modalities listed earlier. Overall, HCC is still associated with a poor prognosis depending on the stage of disease at diagnosis, clinical status of the patient and whether the tumor type shows a propensity for angioinvasion. Patients in the very early and early stages who receive curative treatments have a five-year survival rate of 40% to 70%, with a median survival of over 60 months; at the other end of the spectrum, end-stage HCC has a median survival of just 3 months.


Take home messages

  1. Classical HCC usually arises from a cirrhotic liver. However, a variety of congenital and acquired conditions can induce the development of HCC in a non-cirrhotic liver as well.
  2. Patients at high risk for developing this condition are strongly advised to undergo regular screening and surveillance for early detection and appropriate management.
  3. The BCLC staging system is useful to arrive at an accurate diagnosis, decide the best course of management and predict prognosis.
  4. Very early to intermediate stage disease carries a fair prognosis with timely and appropriate treatment. Meanwhile, advanced and end-stage HCC have a poor prognosis, with management focused on palliative and supportive care.

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