Hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It constitutes approximately 5% of all cancers partly due to the high endemic rates of hepatitis B infection ¹.

Epidemiology

HCC is the fifth most common cancer in the world and is the third most common cause of cancer-related death (after lung and stomach cancer). The incidence of HCC is rising, largely attributed to a rise in hepatitis C infection¹¹.

The demographics are strongly influenced by the regions in which hepatitis B chronic infection is common, which account for over 80% of cases worldwide. The highest prevalence is in Asia.

In western countries the rate is lower and alcohol accounts for a greater proportion of cases.

Risk factors include ¹:

hepatitis B (HBV) infection -: 10% 5 year cumulative risk ⁵
hepatitis C (HCV) infection -: 30% 5 year cumulative risk
alcoholism -: 8% 5 year cumulative risk
biliary cirrhosis -: 5 % 5 year cumulative risk
food toxins, e.g. aflatoxins
congenital biliary atresia
inborn errors of metabolism
- haemochromatosis -: 21% 5 year cumulative risk
- alpha-1 antitrypsin deficiency
- type 1 glycogen storage disease
- Wilson disease

HCC are typically diagnosed in adults in late middle age or elderly. The tumour is however also identified in the paediatric population where it is the second most common primary liver tumour after hepatoblastoma.

Clinical presentation

Presentation is variable, and in affluent nations is often found in the setting of screening programs for patients with known risk factors. Otherwise presentation may include:

constitutional symptoms
jaundice
portal hypertension from invasion of the portal vein
hepatomegally ~~/ mass~~/mass

Pathology

The origin of HCCs is believed to relate to repeated cycles of necrosis and regeneration, irrespective of cause. In addition the HBV and HCV genome contains genetic material that may predispose cells to accumulate mutations, or disrupts growth control, thus allowing for a second mechanism by which infection with these agents predisposes to HCC ¹.

Typically HCCs appear pale masses within the liver, and may be unifocal, multifocal or diffusely infiltrative at the time of presentation. Microscopically they range from well differentiated to undifferentiated .

Metastasis occurs in the final stages of disease(IVA) and carry a poor prognosis^13-14.The most frequently involved sites are the lung, adrenal glands, lymph nodes, and bone.

Fibrolamellar hepatocellular carcinoma is distinct variant with different demographics and risk factors.

Markers

alpha-fetoprotein (AFP) levels are elevated in 50-75% of cases.

Radiographic features

Hepatocellular carcinomas can have a variety of appearances:

focal (massive)
multifocal (nodular)
diffuse

They receive most of their blood supply from the hepatic artery accounting for its characteristic enhancement pattern : early arterial enhancement with early washout. Hence, a small foci of HCC may be seen within a regenerative liver nodule, as a foci of arterial enhancement (nodule-in-nodule appearance) ¹⁵.

Additionally these tumours have a propensity to invade vascular structures, most commonly the portal vein, but also the hepatic veins, IVC and right atrium. One should remember that a large number of patients will have concomitant cirrhosis, and thus be at risk for bland portal vein thrombosis also.

CT

Several pattern may be seen:

focal HCC
- large usually hypodense mass
- may have necrosis ~~/ fat / calcification~~/fat/calcification
multifocal HCC
- multiple masses of variable attenuation lesions
- may also have central hypodense necrotic portions
diffuse HCC
- may be difficult to distinguish from associated cirrhosis

Enhancement pattern is the key to correct assessment of HCCs. Usually the mass enhances vividly during early arterial (~25 seconds) and then washes out, becoming indistinct or hypodense compared to the rest of the liver at the portal phase.

Additionally they may be associated with a wedge shaped perfusion abnormality due to arterioportal shunts (APS), and this in turn can result in focal fatty change in the normal liver or focal fatty sparing in the diffusely fatty liver ⁷. A halo of focal fatty sparing may also be seen around an HCC in an otherwise fatty liver ⁶.

Portal vein tumour thrombus can be distinguished from bland thrombus by demonstrating enhancement.

Ultrasound

Variable appearance depending on individual lesion, size, and background liver.

Typically a small focal HCC appears hypo echoic compared to normal liver. Larger lesions are heterogeneous due to fibrosis, fatty change, necrosis and calcification ⁸. Again a peripheral halo of hypoechogenicity may be seen with focal fatty sparing.

If diffuse it may be difficult to identify or distinguish from cirrhosis.

MRI

When seen in the setting of cirrhosis, small HCCs need to be distinguished from regenerative and dysplastic nodules (see cirrhosis article)

T1
- variable
- iso or hyperintense c.f. surrounding liver
- hyperintensity may be due to
  - intratumoural fat ⁵
  - decreased intensity in surrounding liver
T1 C+ (Gd)
- enhancement is usually arterial and may be brief
- rapid wash out becoming hypointense c.f. remainder of the liver (96% specific) ⁵. This is on account of the supply to HCCs being from the hepatic artery rather than portal vein
- rim enhancement may persist (referred to as a capsule)
- the larger the lesion the more heterogeneous the enhancement
T2: - variable, typically hyperintense
post SPIO (Iron oxide):- increases sensitivity in diagnosing small HCC’s

DSA -: angiography

threads and streaks’ pattern -: sign of tumour thrombus in portal vein
hypervascular tumour

Staging

There are several staging systems used in hepatocellular carcinoma ¹⁶

Barcelona-Clínic Liver Cancer (BCLC) staging system
CLIP score
Okuda staging system
CUPI (Chinese University Prognostic Index)
TNM staging
Japan Integrated Staging (JIS)
French classification system

Treatment and prognosis

If the lesion is small then resection is possible (partial hepatectomy) and may result in cure, as may liver transplantation with total hepatectomy. The remarkable ability of the liver to regenerate means that up to 2/3^rdsof the liver can be resected ¹⁰. To be suitable for a liver transplantation it is generally agreed that certain criteria should be met (see Milan criteria).

If this is not possible then a variety of options exist including chemotherapy, chemoembolisation, radiofrequency ablation (RFA) and selective internal radiation therapy (SIRT) ¹².

If a tumour is resectable, then 5 year survival is at ~~~ 37~~~37-56% ³.

Differential diagnosis

General imaging differential considerations include:

-<p><strong>Hepatocellular carcinoma (HCC)</strong> is the most common primary <a href="/articles/liver-tumours">malignancy of the liver</a>. It constitutes approximately 5% of all cancers partly due to the high endemic rates of hepatitis B infection <sup>1</sup>.</p><h4>Epidemiology</h4><p>HCC is the fifth most common cancer in the world and is the third most common cause of cancer-related death (after lung and stomach cancer). The incidence of HCC is rising, largely attributed to a rise in hepatitis C infection<sup>11</sup>.</p><p>The demographics are strongly influenced by the regions in which hepatitis B chronic infection is common, which account for over 80% of cases worldwide. The highest prevalence is in Asia.</p><p>In western countries the rate is lower and alcohol accounts for a greater proportion of cases.</p><p>Risk factors include <sup>1</sup>:</p><ul>
~~-<li>hepatitis B (HBV) infection - 10 % 5 year cumulative risk <sup>5</sup>~~
+<p><strong>Hepatocellular carcinoma (HCC)</strong> is the most common primary <a href="/articles/liver-tumours">malignancy of the liver</a>. It constitutes approximately 5% of all cancers partly due to the high endemic rates of hepatitis B infection <sup>1</sup>.</p><h4>Epidemiology</h4><p>HCC is the fifth most common cancer in the world and is the third most common cause of cancer-related death (after lung and stomach cancer). The incidence of HCC is rising, largely attributed to a rise in hepatitis C infection <sup>11</sup>.</p><p>The demographics are strongly influenced by the regions in which hepatitis B chronic infection is common, which account for over 80% of cases worldwide. The highest prevalence is in Asia.</p><p>In western countries the rate is lower and alcohol accounts for a greater proportion of cases.</p><p>Risk factors include <sup>1</sup>:</p><ul>
+<li>hepatitis B (HBV) infection: 10% 5 year cumulative risk <sup>5</sup>
~~-<li>hepatitis C (HCV) infection - 30 % 5 year cumulative risk</li>~~
~~-<li>alcoholism - 8 % 5 year cumulative risk</li>~~
~~-<li>biliary cirrhosis - 5 % 5 year cumulative risk</li>~~
~~-<li>food toxins e.g. aflatoxins</li>~~
+<li>hepatitis C (HCV) infection: 30% 5 year cumulative risk</li>
+<li>alcoholism: 8% 5 year cumulative risk</li>
+<li>biliary cirrhosis: 5 % 5 year cumulative risk</li>
+<li>food toxins, e.g. aflatoxins</li>
~~-<a href="/articles/haemochromatosis">haemochromatosis</a> - 21% 5 year cumulative risk</li>~~
+<a href="/articles/haemochromatosis">haemochromatosis</a>: 21% 5 year cumulative risk</li>
~~-<li>hepatomegally / mass</li>~~
-</ul><h4>Pathology</h4><p>The origin of HCCs is believed to relate to repeated cycles of necrosis and regeneration, irrespective of cause. In addition the HBV and HCV genome contains genetic material that may predispose cells to accumulate mutations, or disrupts growth control, thus allowing for a second mechanism by which infection with these agents predisposes to HCC <sup>1</sup></p><p>Typically HCCs appear pale masses within the liver, and may be unifocal, multifocal or diffusely infiltrative at the time of presentation. Microscopically they range from well differentiated to undifferentiated .</p><p>Metastasis occurs in the final stages of disease(IVA) and carry a poor prognosis<sup>13-14</sup>.The most frequently involved sites are the lung, adrenal glands, lymph nodes, and bone.</p><p><a href="/articles/fibrolamellar-hepatocellular-carcinoma">Fibrolamellar hepatocellular carcinoma</a> is distinct variant with different demographics and risk factors.</p><h5>Markers</h5><ul><li>
-<a href="/articles/afp-elevation">alpha-fetoprotein (AFP) levels are elevated</a> in 50-75 % of cases.</li></ul><h4>Radiographic features</h4><p>Hepatocellular carcinomas can have a variety of appearances:</p><ul>
+<li>hepatomegally/mass</li>
+</ul><h4>Pathology</h4><p>The origin of HCCs is believed to relate to repeated cycles of necrosis and regeneration, irrespective of cause. In addition the HBV and HCV genome contains genetic material that may predispose cells to accumulate mutations, or disrupts growth control, thus allowing for a second mechanism by which infection with these agents predisposes to HCC <sup>1</sup>.</p><p>Typically HCCs appear pale masses within the liver, and may be unifocal, multifocal or diffusely infiltrative at the time of presentation. Microscopically they range from well differentiated to undifferentiated .</p><p>Metastasis occurs in the final stages of disease(IVA) and carry a poor prognosis <sup>13-14</sup>.The most frequently involved sites are the lung, adrenal glands, lymph nodes, and bone.</p><p><a href="/articles/fibrolamellar-hepatocellular-carcinoma">Fibrolamellar hepatocellular carcinoma</a> is distinct variant with different demographics and risk factors.</p><h5>Markers</h5><ul><li>
+<a href="/articles/afp-elevation">alpha-fetoprotein (AFP) levels are elevated</a> in 50-75% of cases.</li></ul><h4>Radiographic features</h4><p>Hepatocellular carcinomas can have a variety of appearances:</p><ul>
-</ul><p>They receive most of their blood supply from the hepatic artery accounting for its characteristic enhancement pattern : early arterial enhancement with early washout. Hence, a small foci of HCC may be seen within a <a href="/articles/regenerative-nodules-in-liver">regenerative liver nodule</a>, as a foci of arterial enhancement (<a href="/articles/nodule-in-nodule-appearance-liver">nodule-in-nodule appearance</a>) <sup>15</sup>.</p><p>Additionally these tumours have a propensity to <strong>invade vascular structures</strong>, most commonly the portal vein, but also the hepatic veins, IVC and right atrium. One should remember that a large number of patients will have concomitant <a href="/articles/cirrhosis">cirrhosis</a>, and thus be at risk for bland <a href="/articles/portal-vein-thrombosis">portal vein thrombosis </a>also.</p><h5>CT</h5><p>Several pattern may be seen</p><ul>
+</ul><p>They receive most of their blood supply from the hepatic artery accounting for its characteristic enhancement pattern : early arterial enhancement with early washout. Hence, a small foci of HCC may be seen within a <a href="/articles/regenerative-nodules-in-liver">regenerative liver nodule</a>, as a foci of arterial enhancement (<a href="/articles/nodule-in-nodule-appearance-liver">nodule-in-nodule appearance</a>) <sup>15</sup>.</p><p>Additionally these tumours have a propensity to <strong>invade vascular structures</strong>, most commonly the portal vein, but also the hepatic veins, IVC and right atrium. One should remember that a large number of patients will have concomitant <a href="/articles/cirrhosis">cirrhosis</a>, and thus be at risk for bland <a href="/articles/portal-vein-thrombosis">portal vein thrombosis </a>also.</p><h5>CT</h5><p>Several pattern may be seen:</p><ul>
~~-<li>may have necrosis / fat / calcification</li>~~
+<li>may have necrosis/fat/calcification</li>
~~-<strong>T2</strong> - variable, typically hyperintense</li>~~
+<strong>T2:</strong> variable, typically hyperintense</li>
~~-<strong>post SPIO (Iron oxide) </strong>- increases sensitivity in diagnosing small HCC’s</li>~~
~~-</ul><h5>DSA - angiography</h5><ul>~~
~~-<li>threads and streaks’ pattern - sign of tumour thrombus in portal vein</li>~~
+<strong>post SPIO (Iron oxide):</strong> increases sensitivity in diagnosing small HCC’s</li>
+</ul><h5>DSA: angiography</h5><ul>
+<li>threads and streaks’ pattern: sign of tumour thrombus in portal vein</li>
~~-</ul><h4><span style="font-size:1.5em; line-height:1em">Staging</span></h4><p>There are several staging systems used in hepatocellular carcinoma <sup>16</sup></p><ul>~~
+</ul><h4>Staging</h4><p>There are several staging systems used in hepatocellular carcinoma <sup>16</sup></p><ul>
-</ul><h4>Treatment and prognosis</h4><p>If the lesion is small then resection is possible (partial hepatectomy) and may result in cure, as may liver transplantation with total hepatectomy. The remarkable ability of the liver to regenerate means that up to 2/3<sup>rds </sup>of the liver can be resected <sup>10</sup>. To be suitable for a liver transplantation it is generally agreed that certain criteria should be met (see <a href="/articles/milan-criteria-in-liver-tranplantation">Milan criteria</a>).</p><p>If this is not possible then a variety of options exist including chemotherapy, chemoembolisation, radiofrequency ablation (RFA) and <a href="/articles/selective-internal-radiation-therapy-sirt">selective internal radiation therapy (SIRT)</a> <sup>12</sup>.</p><p>If a tumour is resectable, then 5 year survival is at ~ 37-56% <sup>3</sup>.</p><h4>Differential diagnosis</h4><p>General imaging differential considerations include</p><ul>
+</ul><h4>Treatment and prognosis</h4><p>If the lesion is small then resection is possible (partial hepatectomy) and may result in cure, as may liver transplantation with total hepatectomy. The remarkable ability of the liver to regenerate means that up to 2/3<sup>rds </sup>of the liver can be resected <sup>10</sup>. To be suitable for a liver transplantation it is generally agreed that certain criteria should be met (see <a href="/articles/milan-criteria-in-liver-tranplantation">Milan criteria</a>).</p><p>If this is not possible then a variety of options exist including chemotherapy, chemoembolisation, radiofrequency ablation (RFA) and <a href="/articles/selective-internal-radiation-therapy-sirt">selective internal radiation therapy (SIRT)</a> <sup>12</sup>.</p><p>If a tumour is resectable, then 5 year survival is at ~37-56% <sup>3</sup>.</p><h4>Differential diagnosis</h4><p>General imaging differential considerations include:</p><ul>

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