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INTRODUCTION Hepatocellular carcinoma is a primary tumor of the liver, which usually develops in the setting of chronic liver disease, particularly viral hepatitis. (See "Epidemiology and etiologic associations of primary hepatocellular carcinoma").
The diagnosis of hepatocellular carcinoma (HCC) can be difficult, and often requires the use of serum markers, one or more imaging modalities, and histologic confirmation. Ideally, tumors should be detected when they are small in patients who are able to withstand therapy. However, HCC is frequently diagnosed late in its course because of the absence of pathognomonic symptoms and the liver's large functional reserve [1,2]. As a result, many patients have untreatable disease when first diagnosed. The median survival following diagnosis is approximately 6 to 20 months . Large tumor size, vascular invasion, poor functional status, and nodal metastases are all associated with a poor outcome [4,5].
This topic review will discuss the clinical and histologic features of HCC, and the various modalities used to diagnose and stage this aggressive tumor. The controversial topic of screening populations at risk for HCC will also be discussed. The treatment of this tumor is presented separately. (See "Systemic treatment for advanced hepatocellular carcinoma").
CLINICAL FEATURES Patients who develop HCC usually have no symptoms other than those related to their chronic liver disease. Suspicion for HCC should be heightened in patients with previously compensated cirrhosis who develop decompensation such as ascites, encephalopathy, jaundice, or variceal bleeding. These complications are often associated with extension of the tumor into the hepatic or portal veins or arteriovenous shunting induced by the tumor .
Some patients may have mild to moderate upper abdominal pain, weight loss, early satiety, or a palpable mass in the upper abdomen. These symptoms often indicate an advanced lesion . Other uncommon presentations include:Obstructive jaundice caused by invasion of the biliary tree, compression of the intrahepatic duct, or rarely, as a result of hemobilia
The physical findings in most patients with HCC reflect the underlying liver disease. Splenomegaly, ascites, jaundice, or other manifestations of decompensated cirrhosis may be evident . Hepatomegaly or a bruit heard over the liver are occasionally present.
Laboratory examination is usually nonspecific. The majority of patients who develop HCC have cirrhosis, and may have thrombocytopenia, hypoalbuminemia, hyperbilirubinemia, and hypoprothrombinemia. Patients are often mildly anemic and may have electrolyte disturbances (eg, hyponatremia, hypokalemia, metabolic alkalosis) associated with defective water handling or with diuretic use. Serum aminotransferases, alkaline phosphatase and gammaglutamyl transpeptidase are often abnormal but in a nonspecific pattern .
Staging The most important factors predicting survival in patients with hepatocellular carcinoma are the tumor's size and the severity of underlying liver disease. The most commonly used staging system (the Okuda system) takes both of these into account (show table 1) . A TNM (tumor, node, metastasis) classification has also been developed but is less useful for determining prognosis since it does not account for the severity of the underlying liver disease (show table 2) . A scoring system derived by the Cancer of the Liver Italian Program (CLIP) has also been proposed. Prospective validation of this system suggested that it was superior to the Okuda system for predicting survival (show table 3) . In one report, the median survival rates for patients with CLIP stages 0, 1, 2, 3, 4, and 5 to 6 were 31, 27, 13, 8, 2, and 2 months, respectively (show figure 1) . (See "Staging and prognostic factors in hepatocellular carcinoma").
Paraneoplastic syndromes Patients with HCC occasionally develop a paraneoplastic syndrome which can manifest as hypoglycemia, erythrocytosis, hypercalcemia, severe watery diarrhea.
Hypoglycemia Hypoglycemia, which usually occurs in advanced HCC, is thought to result from the tumor's high metabolic needs. The hypoglycemia is typically mild and produces no symptoms; however, more severe reductions in the plasma glucose can occur, resulting in lethargy and confusion.
Less than 5 percent of tumors secrete insulin-like growth factor-II, which can act as an insulin agonist, causing severe symptomatic hypoglycemia. This feature can occur early in the course of the disease [15,16].
Erythrocytosis Erythrocytosis in HCC is probably due to secretion of erythropoietin by the tumor [17,18]. Although raised serum erythropoietin levels may be present in up to 23 percent of patients with hepatocellular carcinoma, elevations in hemoglobin concentration or packed cell volume are uncommon, and most patients are anemic upon diagnosis because of other effects of the tumor . (See "Diagnostic approach to the patient with polycythemia").
Hypercalcemia Osteolytic metastases, which are unusual in HCC, can result in hypercalcemia. Hypercalcemia may also be present without bony metastasis due most often to secretion of parathyroid hormone-related protein [19,20]. (See "Hypercalcemia of malignancy").
Watery diarrhea Patients with HCC may present with watery diarrhea. In one study, for example, diarrhea was significantly more common among cirrhotic patients with HCC compared to matched cirrhotic controls (48 versus 9 percent) . Rarely, diarrhea may be severe and intractable, leading to hypokalemia and achlorhydria . The mechanism underlying this syndrome is not fully understood but is probably related to secretion of peptides that cause intestinal secretion. These include vasoactive intestinal polypeptide, gastrin, and peptides with prostaglandin-like immunoreactivity .
Cutaneous features Several cutaneous manifestations have been described in association with HCC; however, none is specific for the diagnosis . These include:Dermatomyositis (see "Clinical manifestations and diagnosis of adult dermatomyositis and polymyositis" and see "Cutaneous manifestations of internal malignancy").
DIAGNOSTIC ISSUES The diagnosis of HCC is often suspected in a patient with underlying liver disease (ie, cirrhosis, chronic viral hepatitis) who develops a rising serum alfa-fetoprotein (AFP) level. In such patients, a CT scan of the liver and/or magnetic resonance imaging (MRI) study is often the initial diagnostic maneuver. In cirrhotic patients, any dominant solid nodule that is not clearly a hemangioma should be considered a HCC unless proven otherwise . If the lesion is hypervascular, has increased T2 signal intensity, demonstrates venous invasion, or is associated with an elevated AFP, the diagnosis is almost certain, and a preoperative biopsy may not be necessary to confirm the diagnosis. Biopsy may be risky in cirrhotic patients, and there is a risk of tumor seeding of the needle tract. (See "Histopathology" below).
If the diagnostic imaging studies are less definitive, follow-up imaging may clarify the diagnosis; dysplastic nodules typically remain stable, while an enlarging dominant lesion more likely represents a HCC. Even stable nodules require close follow-up, since livers containing dysplastic nodules are at high risk to develop HCC in the future .
For non-cirrhotic patients, the diagnosis of HCC should be considered for any hepatic mass that is not clearly a hemangioma or focal nodular hyperplasia, especially if it is hypervascular. In the absence of specific clues to the diagnosis, biopsy may be appropriate. Percutaneous biopsy should only be performed when diagnostic imaging results are uncertain, and the result will directly impact on management. (See "Approach to the patient with a focal liver lesion").
SERUM MARKERS The most commonly used marker for hepatocellular carcinoma is the serum AFP concentration. Several other serologic markers (such as des-gamma-carboxy prothrombin) may indicate the presence of HCC, and used alone or in combination with the serum AFP may improve the diagnostic accuracy. Although these other markers are not used in routine clinical practice, they continue to be a topic of investigation (see below).
Alpha-fetoprotein Alpha-fetoprotein is a glycoprotein which is normally produced during gestation by the fetal liver and yolk sac, the serum concentration of which is often elevated in patients with HCC. Serum levels of AFP do not correlate well with other clinical features of the disease, such as size, stage, or prognosis. Elevated serum AFP occurs in pregnancy, with tumors of gonadal origin, and may be seen in patients with chronic liver disease without HCC such as acute or chronic viral hepatitis .
A rise in serum AFP in a patient with cirrhosis should raise concern that HCC has developed. It is generally accepted that serum levels greater than 500 mcg/L (normal in most laboratories is between 10 and 20 mcg/L) in a high-risk patient is diagnostic of hepatocellular carcinoma . However, HCC is often diagnosed with lower levels of AFP in patients undergoing screening [26,28].
Not all tumors secrete AFP, and serum concentrations are normal in up to 40 percent of small HCCs . Furthermore, an elevated AFP may be more likely in patients with HCC due to viral hepatitis compared to alcoholic liver disease . In a study of 357 patients with hepatitis C and without hepatocellular carcinoma, 23 percent had an AFP >10.0 mcg/L . Elevated levels were associated with the presence of stage III or IV fibrosis, an elevated international normalized ratio, and an elevated serum aspartate aminotransferase level.
AFP levels are normal in the majority of patients with fibrolamellar carcinoma, a variant of HCC (show histology 1) . Cirrhotics with persistently elevated AFP values have an increased risk of developing HCC compared to those with fluctuating or normal levels (29 versus 13 and 2.4 percent, respectively, in one report) .
The sensitivity, specificity, and predictive value for the serum AFP in the diagnosis of HCC depends upon the characteristics of the population under study, the cutoff value chosen for establishing the diagnosis, and the gold-standard used to confirm the diagnosis. A number of studies have described test characteristics in different settings [34,35]. The following estimates were based upon a cutoff value of >20 mcg/L in a systematic review that included five studies :Sensitivity 41 to 65 percent
Two examples (one of which was included in the above study) illustrate the range of findings in the individual reports:
One study included 1069 patients who were chronic carriers of hepatitis B who underwent regular screening with a serum AFP . Serum AFP was greater than 20 mcg/L in 9 of 14 patients with HCC compared to 91 of 964 patients without the tumor, giving an overall sensitivity and specificity of 64 and 91 percent, respectively. However, only 9 of the 100 patients with AFP values greater than 20 mcg/L had HCC (positive predictive value 9 percent) even in this population of patients with a high prevalence of HCC (show table 4).
A case-control study evaluated the diagnostic characteristics of the serum AFP in screening for HCC in patients with different types of chronic liver disease. The following sensitivities and specificities were observed :AFP cutoff 16 mcg/L (sensitivity 62, specificity 89 percent)
At a prevalence of HCC of 5 percent, a serum AFP of 20 mcg/L (the cutoff value the authors considered to be best) had a positive and negative predictive value of 25 and 98 percent, respectively. At a prevalence of 20 percent, these numbers were 61 and 90 percent, respectively. The low positive predictive values observed in both of these studies [34,35] (and the test characteristics described in the systematic review above ) underscore the limitation of using the serum AFP as a screening test for HCC.
Other serum markers Because of the limitations of serum AFP measurements, several other serum markers of HCC used alone or in combination with the serum AFP have been evaluated for diagnosis or determining prognosis in patients with HCC.
As an example, the specific sugar-chain structure of circulating alpha-fetoprotein may be useful for discriminating elevated levels of AFP associated with HCC from those seen in relatively benign liver conditions. One study evaluating this approach compared lectin-reactive profiles (a way of measuring the abnormal AFP) in 33 patients with HCC with 32 cirrhotics without HCC who had elevated serum levels of AFP . Lectin-reactive profiles were significantly higher in 73 percent of the patients who had HCC compared to those with cirrhosis alone.
Des-gamma-carboxy prothrombin (also known as "prothrombin produced by vitamin K absence or antagonism II" [PIVKA II]) has also shown promise in the diagnosis of HCC [38-42]. In one series of 76 patients with HCC, this marker was elevated in 69 with a mean serum concentration of 900 mcg/L; much lower mean values were seen in patients with chronic active hepatitis, metastatic disease to the liver, and normal subjects (10 and 42 mcg/L and undetectable, respectively) . Elevations in des-gamma-carboxy prothrombin are less frequent in tumors less than 3 cm in size (20 percent in one series) . Abnormal prothrombin levels do not correlate well with serum AFP [40,41].
Other markers of HCC that have also been studied include:Tumor-associated isoenzymes of gammaglutamyl transpeptidase 
None of these diagnostic tests have demonstrated superior accuracy compared to the serum AFP.
IMAGING STUDIES The imaging tests most commonly used for the diagnosis of HCC are ultrasound, computed tomography, magnetic resonance imaging, and angiography. Ultrasonography is traditionally used as an imaging study (in conjunction with AFP determination) for screening. A classic appearance on one of these imaging modalities combined with an elevated serum AFP concentration in the appropriate clinical setting is usually sufficient for establishing the diagnosis of HCC. The radiographic appearance of HCC may in part be related to the underlying cause. One study suggested that a nodular appearance was more common in HCC arising in patients with cirrhosis while an infiltrative pattern was more common in patients with chronic hepatitis B .
Ultrasound Although ultrasound cannot distinguish hepatocellular carcinoma from other solid tumors in the liver, it is widely available, noninvasive, and commonly used for screening patients for HCC. Ultrasonography has the added benefit of assessing patency of the hepatic blood supply and the presence of vascular invasion by the tumor. In addition, ultrasound can be used intraoperatively to detect small tumor nodules during hepatic resection.
Sonographic characteristics of a hepatic lesion that are suggestive of HCC include poorly-defined margins and coarse, irregular internal echoes. Small tumors are often hypoechoic. As the tumor grows, the echo pattern tends to become isoechoic or hyperechoic, and HCC can be difficult to distinguish from the surrounding liver . Visualization may be difficult with lesions under the right hemidiaphragm, with overlying bowel gas, and in obese patients.
The accuracy of ultrasound for detecting hepatocellular carcinoma has been evaluated in several reports [30,34,49-51]. In a large prospective study of noncirrhotic hepatitis B carriers, the sensitivity, specificity, and positive predictive value of ultrasound were 71, 93, and 15 percent, respectively . When combined with AFP determination, sensitivity increased to 79 percent. Sensitivity values in other studies have ranged from 78 percent  to much lower values of 40 to 50 percent, particularly when the diagnosis is confirmed by examination of autopsy specimens or the resected liver after transplantation .
New ultrasound technologies, especially the use of ultrasound contrast agents, may improve the accuracy of this modality in the diagnosis of HCC [52,53]. However, given the low positive predictive value, a suspicious lesion observed on ultrasound requires additional studies to confirm the diagnosis and stage the tumor.
Computed tomography Computed tomography (CT) of the liver is often performed to evaluate an abnormality detected on ultrasound (show radiograph 1). In some centers, CT scan is also used a primary screening modality for HCC in patients with cirrhosis. New CT technology has substantially increased its accuracy compared to conventional scanning.
The accuracy of conventional CT scanning was evaluated in a prospective study of 200 patients with cirrhosis prior to liver transplantation . Comparison of CT images was made to detailed histologic evaluation of the explanted liver. Thirty-five cases of HCC and five cases of cholangiocarcinoma were detected in the explanted liver. The sensitivity and specificity of contrast enhanced images for these lesions was 68 and 81 percent, respectively. The low specificity was in part due to nodular changes in the liver, which are often seen in patients with advanced cirrhosis.
The ability of CT to detect HCCs has improved with the development of helical CT technology. This technique involves the rapid administration of contrast material in combination with extremely fast imaging. The arterial phase of enhancement allows for detection of hypervascular HCCs as small as 3 mm (show radiograph 2). The sensitivity of helical CT for detecting HCC may be as high as 90 percent; however its accuracy has not been confirmed with autopsy studies .
Some tumors are isoattenuating on both arterial and portal phase imaging, and may be missed. The addition of delayed phase imaging (triple phase helical CT) may improve detection of these tumors . Greater sensitivity can also be achieved using intraarterial lipoidal, a contrast agent (sensitivity between 93 and 97 percent ). However, this technique is not commonly used given the need for intraarterial injection.
Magnetic resonance imaging Magnetic resonance imaging (MRI) has the advantage of achieving high resolution images of the liver without the use of nephrotoxic contrast agents or ionizing radiation. MRI has a similar sensitivity for the diagnosis of HCC as helical CT . On MRI, HCC appears as a high intensity pattern on T2-weighted images, and a low intensity pattern on T1-weighted images (show radiograph 3) . However, MRI has better sensitivity and specificity compared to CT and US in cirrhotic patients in whom it can be difficult to distinguish an HCC from regenerative nodules . (See "Magnetic resonance imaging of the hepatobiliary tract").
A newer technique (MRI angiography) permits acquisition of a three-dimensional data set within a single breath-hold, incorporating arterial, portal venous and late venous phases . A study comparing this technique to triphasic CT (in which pathologic examination of the explanted liver represented the gold standard) found that it had higher sensitivity for HCC nodules that were 10 mm (76 versus 61 percent).
Helical CT scanning remains the favored technique by most radiologists because of the high cost of MRI, and the long duration required to obtain standard MRI images. The role of MRI angiography is still being determined. MRI may be useful in patients with renal insufficiency or those with an allergy to CT contrast dye (agents). MRI may also be beneficial in cases in which CT results are ambiguous, particularly when the liver is extremely nodular since MRI can differentiate dysplastic nodules from HCC [59,61]. MRI may also be superior to CT scan in distinguishing vascular lesions (such as an hemangioma) and focal fat from HCC.
Angiography The less invasive techniques discussed above have replaced conventional angiography for the diagnosis of HCC. However, angiography continues to be used during chemoembolization of tumors and to control bleeding from ruptured HCC.
CT hepatic arteriography and arterial portography Angiography can be combined with CT or MRI scanning to improve the detection and characterization of HCC [62-66]. The technique involves injection of contrast dye intraarterially (usually in the superior mesenteric, hepatic, or splenic artery) immediately prior to CT or MRI, and obtaining images during the arterial and portal venous phases. This technique has been used for preoperative evaluation of HCC, although it is uncommonly used in the United States. The benefit of CT hepatic arteriography and arterial portography compared to MRI is unclear since it is invasive and does not appear to be more accurate .
Experimental imaging modalities Limited experience with a technetium-99m (99mTc)-labeled anti-alpha-fetoprotein (AFP) Fab' imaging kit suggests that it may have a role in the detection of HCC. A study evaluating the accuracy of the kit in 25 patients with suspected HCC demonstrated detection of the tumor in 20 patients, exclusion in four (confirmed by CT and biopsy), and a false negative result in one .
Gallium scanning Prior to the availability of helical CT and MRI imaging, gallium scanning was used in the diagnosis of HCC [69,70]. It may still have a role in patients in whom the diagnosis remains uncertain after other forms of non-invasive testing, and in whom more aggressive diagnosis is not considered to be appropriate.
Positron emission tomography Several studies have suggested a potential role for (18)F-FDG positron emission tomography (PET) in the detection of HCC, tumor staging, assessing response to therapy and possibly for predicting its course [71-74]. However, its ability to distinguish benign from malignant lesions is unclear [72,73,75,76]. A new tracer, (11)C-acetate, appears improve sensitivity and specificity when used in conjunction with (18)F-FDG PET . Until further data are available, the role of PET scanning in the evaluation of patients with HCC remains uncertain, particularly since the required equipment is not widely available.
HISTOPATHOLOGY A biopsy under ultrasound or CT guidance is often helpful in patients with a focal liver lesion in whom the diagnosis is uncertain. Directed core biopsies are more useful than fine needle biopsy because of the increased amount of tissue obtained and the ability to obtain uninvolved hepatic parenchyma .
Risks of a biopsy include bleeding, and spread of tumor along the needle track. The reported magnitude of the risk ranges from 1.6 to 5 percent [79-83]. On the other hand, others have failed to document an increased risk of needle tract seeding, or any adverse impact of preoperative FNA on long-term outcome in patients undergoing potentially curative resection of HCC . Nevertheless, the potential risk of spreading tumor along the biopsy tract should always be considered in the decision to perform a biopsy, especially in patients in whom surgical resection or liver transplantation might be performed. (See "Resection and cryoablation for hepatocellular carcinoma" and see "Liver transplantation for hepatocellular carcinoma").
The histologic appearance of HCC can range from well-differentiated (with individual hepatocytes appearing nearly identical to normal hepatocytes) to poorly differentiated lesions consisting of large multinucleate anaplastic tumor giant cells. Central necrosis of large tumors is common . Bile globules and acidophilic inclusions are occasionally present.
In some cases, dysplasia rather than carcinoma is diagnosed. There is an ongoing debate about the usefulness of various grades of dysplasia in predicting the ultimate development of HCC.
SCREENING The issue of periodic surveillance of patients at risk for HCC remains contentious from the viewpoint of cost-effectiveness since an improvement in survival has not been consistently demonstrated [26,49,86].
The greatest risk of HCC is in patients who have established cirrhosis, particularly those with viral hepatitis. (See "Epidemiology and etiologic associations of primary hepatocellular carcinoma"). Screening programs that have included patients with viral hepatitis at various histologic stages would be expected to have the lowest incidence of HCC, and provide the least benefit from screening. As an example, in a prospective study of 385 hemophiliacs with chronic viral hepatitis of varying severity who were followed for four years, only six HCCs were detected by yearly screening with serum AFP and ultrasonography; all were multicentric at diagnosis and therefore not resectable . Furthermore, all patients who developed HCC had established cirrhosis.
Similarly, the value of screening patients who are chronic carriers of the hepatitis B virus has generally been disappointing [34,88]. In one series of 1069 chronic HBV carriers, the incidence of new HCC was 0.47 percent per year (compared to 1 to 6 percent per year in cirrhosis ) . Measured at six month intervals, a serum AFP above 20 mcg/L had a sensitivity of only 64 percent for HCC and a specificity of 91 percent; the respective values for ultrasonography were 79 and 94 percent.
Even in patients with established cirrhosis, the benefit of screening is uncertain. This was illustrated in a screening program involving 118 French patients with Child-Pugh A or B cirrhosis who underwent ultrasonography, measurement of serum AFP and des-gamma-carboxyprothrombin every six months, only 1 of 14 cases of HCC detected was surgically resectable at the time of diagnosis .
On the other hand, HCC may be diagnosed at an earlier stage in patients who undergo screening [89-91]. In one study, for example, patients who underwent screening had significantly smaller tumors than those who presented with symptoms, a benefit that translated into improved survival (approximately 35 versus 10 percent at 30 months) . However, the improved survival may in part be accounted for by lead time bias. The issue of lead time bias may have been partially overcome by the long follow-up (16 years) in a population-based study in Alaska that included 1487 HBsAG positive carriers who underwent screening with an AFP every six months . The study subjects had improved survival compared with historic controls who had not undergone screening.
Despite the relative lack of clear evidence, surveillance for HCC in patients with cirrhosis has become accepted by most hepatologists [26,92]. Measurement of AFP and ultrasonography every six months is commonly performed in patients with Child-Pugh class A cirrhosis who would be suitable candidates for partial hepatectomy if an HCC were discovered, and in those patients who are candidates for liver transplantation or percutaneous therapies.
Several studies have attempted to identify patients who are at highest risk for developing HCC, which may help to optimize screening programs [93-96]. Unfortunately, identification of risk factors in patients healthy enough to withstand therapy has proven difficult.
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