ฉ2005 UpToDate
New Search Table of Contents My UpToDate Feedback Help Log Out

Official reprint from UpToDate

Clinical features, diagnosis, and screening for primary hepatocellular carcinoma

Jonathan M Schwartz, MD
Robert L Carithers, Jr, MD

UpToDate performs a continuous review of over 330 journals and other resources. Updates are added as important new information is published. The literature review for version 13.1 is current through December 2004; this topic was last changed on August 25, 2004. The next version of UpToDate (13.2) will be released in June 2005.

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 [3]. 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 [6].

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 [1]. Other uncommon presentations include:

  bullet Obstructive jaundice caused by invasion of the biliary tree, compression of the intrahepatic duct, or rarely, as a result of hemobilia

  bullet Diarrhea [7]

  bullet Bone pain or dyspnea due to metastases

  bullet Intraperitoneal bleeding due to tumor rupture. Tumor rupture is often associated with severe abdominal pain and hypotension, and is most commonly diagnosed by peritoneal lavage and laparotomy. CT scan typically demonstrates a liver mass and free intraperitoneal blood. Angiography and embolization of the bleeding vessel can be an effective method of managing this life-threatening complication (show radiograph 1) [8].

  bullet Fever may develop in association with central tumor necrosis

  bullet Paraneoplastic syndromes (see below)

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 [9]. 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 [10].

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) [11]. 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) [12]. 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) [13]. 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) [14]. (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 [17]. (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) [7]. Rarely, diarrhea may be severe and intractable, leading to hypokalemia and achlorhydria [21]. 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 [21].

  Cutaneous features — Several cutaneous manifestations have been described in association with HCC; however, none is specific for the diagnosis [22]. These include:

  bullet Dermatomyositis (see "Clinical manifestations and diagnosis of adult dermatomyositis and polymyositis" and see "Cutaneous manifestations of internal malignancy").

  bullet Pemphigus foliaceus, a superficial blistering disease similar to pemphigus vulgaris except it rarely involves the mucous membranes. Blisters often appear as shallow erosions associated with erythema, scale and crust formation, which may resemble severe seborrheic dermatitis. (See "Pemphigus and bullous pemphigoid", section on Pemphigus foliaceus).

  bullet The sign of Leser-Trelat, which refers to the sudden appearance of multiple seborrheic keratoses often with an inflammatory base in association with skin tags and acanthosis nigricans. (See "Cutaneous manifestations of internal malignancy").

  bullet Pityriasis rotunda, which is characterized by multiple, round or oval, sharply demarcated scaling patches.

  bullet Porphyria cutanea tarda (PCT), in which exposure to the sun and/or minor trauma leads to skin erythema and the development of vesicles and bullae that may become hemorrhagic. Although PCT has been recognized in patients with HCC related to a variety of risk factors, PCT in patients with HCC may be a marker for underlying hepatitis C virus infection [23]. (See "Porphyria cutanea tarda and hepatitis C virus infection").

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 [24]. 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 [25].

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 [26].

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 [27]. 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 [29]. Furthermore, an elevated AFP may be more likely in patients with HCC due to viral hepatitis compared to alcoholic liver disease [30]. In a study of 357 patients with hepatitis C and without hepatocellular carcinoma, 23 percent had an AFP >10.0 mcg/L [31]. 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) [32]. 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) [33].

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 [36]:

  bullet Sensitivity 41 to 65 percent

  bullet Specificity 80 to 94 percent

  bullet Positive likelihood ratio 3.1 to 6.8

  bullet Negative likelihood ratio 0.4 to 0.6

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 [34]. 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 [35]:

  bullet AFP cutoff 16 mcg/L (sensitivity 62, specificity 89 percent)

  bullet AFP cutoff 20 mcg/L (sensitivity 60, specificity 91 percent)

  bullet AFP cutoff 100 mcg/L (sensitivity 31, specificity 99 percent)

  bullet AFP cutoff 200 mcg/L (sensitivity 22, specificity 99 percent)

At a prevalence of HCC of 5 percent, a serum AFP of greater than or equal to20 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 [36]) 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 [37]. 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) [38]. Elevations in des-gamma-carboxy prothrombin are less frequent in tumors less than 3 cm in size (20 percent in one series) [41]. Abnormal prothrombin levels do not correlate well with serum AFP [40,41].

Other markers of HCC that have also been studied include:

  bullet Tumor-associated isoenzymes of gammaglutamyl transpeptidase [43]

  bullet Urinary transforming growth factor-beta-1 [44]

  bullet Serum levels of circulating intercellular adhesion molecule-1 [45]

  bullet Serum alpha-L-fucosidase activity [46]

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 [47].

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 [48]. 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 [34]. When combined with AFP determination, sensitivity increased to 79 percent. Sensitivity values in other studies have ranged from 78 percent [51] 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 [50].

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 [54]. 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 [55].

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 [56]. Greater sensitivity can also be achieved using intraarterial lipoidal, a contrast agent (sensitivity between 93 and 97 percent [57]). 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 [58]. 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) [48]. 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 [59]. (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 [60]. 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 greater than or equal to10 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 [67].

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 [68].

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 [77]. 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 [78].

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 [84]. 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 [85]. 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 [87]. 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 [26]) [34]. 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 [51].

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) [90]. 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 [91]. 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.

Use of UpToDate is subject to the Subscription and License Agreement.

1.  Kew, MC, Dos Santos, HA, Sherlock, S. Diagnosis of primary cancer of the liver. Br Med J 1971; 4:408.
2.  Schwartz, JM, Larson, AM, Gold, PJ, et al. Hepatocellular carcinoma: A one year experience at a tertiary referral center in the United States (abstract). Hepatology 1999; 30:278A.
3.  A new prognostic system for hepatocellular carcinoma: A retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998; 28:751.
4.  Bruix, J. Treatment of hepatocellular carcinoma. Hepatology 1997; 25:259.
5.  Llovet, JM, Bustamante, J, Castells, A, et al. Natural history of untreated nonsurgical hepatocellular carcinoma. Rationale for the design and evaluation of therapeutic trials. Hepatology 1999; 29:62.
6.  Sugano, S, Miyoshi, K, Suzuki, T, et al. Intrahepatic arteriovenous shunting due to hepatocellular carcinoma and cirrhosis, and its change by transcatheter arterial embolization. Am J Gastroenterol 1994; 89:184.
7.  Bruix, J, Castells, A, Calvet, X, et al. Diarrhea as a presenting symptoms of hepatocellular carcinoma. Dig Dis Sci 1990; 35:681.
8.  Chearanai, O, Plengvanit, U, Asavanich, C, et al. Spontaneous rupture of primary hepatoma: Report of 63 cases with particular reference to the pathogenesis and rationale for treatment by hepatic artery ligation. Cancer 1983; 51:1532.
9.  Kew, MC. Tumors of the liver. In: Hepatology: A textbook of liver disease, Zakim, D, Boyer, T (Eds), WB Saunders Company, Philadelphia 1996. p.1513.
10.  Lai, CL, Ng, RP, Hypokalemia, AS. The diagnostic value of the ratio of serum gamma-glutamyl transpeptidase to alkaline phosphatase in alcoholic liver disease. Scand J Gastroenterol 1982; 17:41.
11.  Okuda, K, Ohtuki, T, Obata, H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment: Study of 850 patinets. Cancer 1985; 56:918.
12.  Hermanek, P, Sobin, LH, eds. UICC TNM classification of malignant tumors, 4th ed, 2nd rev. Springer, Berlin 1992.
13.  Prospective validation of the CLIP score: A new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology 2000; 31:840.
14.  Farinati, F, Rinaldi, M, Gianni, S, Naccarato, R. How should patients with hepatocellular carcinoma be staged? Validation of a new prognostic system. Cancer 2000; 89:2266.
15.  Eastman, RC, Carson, RE, Orloff, DG, et al. Glucose utilization in a patient with hepatoma and hypoglycemia. Assessment by positron emission tomography. J Clin Invest 1992; 89:1958.
16.  Tietge, UJ, Schofl, C, Ocran, KW, et al. Hepatoma with severe non-islet cell tumor hypoglycemia. Am J Gastroenterol 1998; 93:997.
17.  Kew, M, Fisher, J. Serum erythropoietin concentrations in patients with hepatocellular carcinoma. Cancer 1986; 58:2485.
18.  Sakisaka, S, Watanabe, M, Tateishi, H, et al. Erythropoietin production in hepatocellular carcinoma cells associated with polycythemia: Immunohistochemical evidence. Hepatology 1993; 18:1357.
19.  Knill-Jones, RP, Buckle, RM, Parsons, V, et al. Hypercalcemia and increased parathyroid-hormone activity in a primary hepatoma. Studies before and after hepatic transplantation. N Engl J Med 1970; 282:704.
20.  Yen, TC, Hwang, SJ, Wang, CC, et al. Hypercalcemia and parathyroid hormone-related protein in hepatocellular carcinoma. Liver 1993; 13:311.
21.  Steiner, E, Velt, P, Gutierrez, O, et al. Hepatocellular carcinoma presenting with intractable diarrhea. A radiologic-pathologic correlation. Arch Surg 1986; 121:849.
22.  Gregory, B, Ho, V. Cutaneous manifestations of gastrointestinal disorders. Part I. J Am Acad Dermatol 1992; 26:153.
23.  Lim, HW, Mascaro, JM. The porphyrias and hepatocellular carcinoma. Dermatol Clin 1995; 13:135.
24.  Gogel, BM, Goldstein, RM, Kuhn, JA, et al. Diagnostic evaluation of hepatocellular carcinoma in a cirrhotic liver. Oncology (Huntingt) 2000; 14:15.
25.  Borzio, M, Fargion, S, Borzio, F, et al. Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development. J Hepatol 2003; 39:208.
26.  Collier, J, Sherman, M. Screening for hepatocellular carcinoma. Hepatology 1998; 27:273.
27.  Wu, JT. Serum alpha-fetoprotein and its lectin reactivity in liver disease: A review. Ann Clin Lab Sci 1990; 20:98.
28.  Lok, AS, Lai, CL. Alpha-fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: Role in the early detection of hepatocellular carcinoma. Hepatology 1989; 9:110.
29.  Chen, D, Sung, J, Shen, J, et al. Serum alpha-fetoprotein in early stages of human hepatocellular carcinoma. Gastroenterology 1984; 86:1404.
30.  Fasani, P, Sangiovanni, A, De Fazio, C, et al. High prevalence of multinodular hepatocellular carcinoma in patients with cirrhosis attributable to multiple risk factors. Hepatology 1999; 29:1704.
31.  Hu, KQ, Kyulo, NL, Lim, N, et al. Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol 2004; 99:860.
32.  Soreide, O, Czerniak, A, Bradpiece, H, et al. Characteristics of fibrolamellar hepatocellular carcinoma. A study of nine cases and review of the literature. Am J Surg 1986; 151:518.
33.  Colombo, M, De Franchis, R, Del Ninno, E, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991; 325:675.
34.  Sherman, M, Peltekian, KM, Lee, C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: Incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 1995; 22:432.
35.  Trevisani, F, D'Intino, PE, Morselli-Labate, AM, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 2001; 34:570.
36.  Gupta, S, Bent, S, Kohlwes, J. Test Characteristics of alpha-Fetoprotein for Detecting Hepatocellular Carcinoma in Patients with Hepatitis C. A Systematic Review and Critical Analysis. Ann Intern Med 2003; 139:46.
37.  Sato, Y, Nakata, K, Kato, Y, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med 1993; 328:1802.
38.  Liebman, HA, Furie, BC, Tong, MJ, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med 1984; 310:1427.
39.  Nomura, F, Ishijama, M, Horikoshi, A, et al. Determination of serum des-gamma-carboxy prothrombin levels in patients with small-sized hepatocellular carcinoma: Comparison of the conventional enzyme immunoassay and two modified methods. Am J Gastroenterol 1996; 91:1380.
40.  Aoyagi, Y, Oguro, M, Yanagi, M, et al. Clinical significance of simultaneous determinations of alpha-fetoprotein and des-gamma-carboxy prothrombin in monitoring recurrence in patients with hepatocellular carcinoma. Cancer 1996; 77:1781.
41.  Weitz, IC, Liebman, HA. Des-gamma-carboxy (abnormal) prothrombin and hepatocellular carcinoma: A critical review. Hepatology 1993; 18:990.
42.  Marrero, JA, Su, GL, Wei, W, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients. Hepatology 2003; 37:1114.
43.  Kew, MC, Wolf, P, Whittaker, D, et al. Tumor associated isoenzymes of gamma-glutamyl transferase in the serum of patients with hepatocellular carcinoma. Br J Cancer 1984; 50:451.
44.  Tsai, FJ, Jeng, JE, Chuang, LY. et al. Clinical evaluation of urinary transforming growth factor-beta1 and serum alpha-fetoprotein as tumour markers of hepatocellular carcinoma. Br J Cancer 1997; 75:1460.
45.  Hamazaki, K, Gochi, A, Shimamura, H, et al. Serum levels of circulating intercellular adhesion molecule 1 in hepatocellular carcinoma. Hepatogastroenterology 1996; 43:229.
46.  Takahashi, H, Saiabara, T, Iwamura, S, et al. Serum alpha-L-fucosidase activity and tumor size in hepatocellular carcinoma. Hepatology 1994; 19:1414.
47.  Benvegnu, L, Noventa, F, Bernardinello, E, et al. Evidence for an association between the aetiology of cirrhosis and pattern of hepatocellular carcinoma development. Gut 2001; 48:110.
48.  Ishiguchi, T, Shimamoto, K, Fukatsu, H, et al. Radiologic diagnosis of hepatocellular carcinoma. Semin Surg Oncol 1996; 12:164.
49.  Larcos, G, Sorokopud, H, Berry, G, Farrell, GC. Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: An evaluation. AJR Am J Roentgenol 1998; 171:433.
50.  Dodd, GD, Miller, WJ, Baron, RL, et al. Detection of malignant tumors in end-stage cirrhotic livers: Efficacy of sonography as a screening technique. AJR Am J Roentgenol 1992; 159:727.
51.  Pateron, D, Ganne, N, Trinchet, JC, et al. Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 1994; 20:65.
52.  Whittingham, TA. New and future developments in ultrasonic imaging. Br J Radiol 1997; 70 Spec No:S119.
53.  Hayakawa, S, Goto, H, Hirooka, Y, et al. A new ultrasound imaging method in the abdominal area: Harmonic imaging without an enhancing agent (abstract). Gastroenterology 1998; 114:1253.
54.  Miller, WJ, Baron, RL, Dodd, GD III, Federle, MP. Malignancies in patients with cirrhosis: CT sensitivity and specificity in 200 consecutive transplant patients. Radiology 1994; 193:645.
55.  Hollett, MD, Jeffrey, RB Jr, Nino-Murcia, M, et al. Dual-phase helical CT of the liver: Value of arterial phase scans in the detection of small (<1.5 cm) malignant hepatic neoplasms. AJR Am J Roentgenol 1995; 164:879.
56.  Lim, JH, Choi, D, Kim, SH, et al. Detection of hepatocellular carcinoma: Value of adding delayed phase imaging to dual-phase helical CT. AJR Am J Roentgenol 2002; 179:67.
57.  Ngan, H. Lipiodol computerized tomography: How sensitive and specific is the technique in the diagnosis of hepatocellular carcinoma? Br J Radiol 1990; 63:771.
58.  Szklaruk, J, Silverman, PM, Charnsangavej, C. Imaging in the diagnosis, staging, treatment, and surveillance of hepatocellular carcinoma. AJR Am J Roentgenol 2003; 180:441.
59.  Libbrecht, L, Bielen, D, Verslype, C, et al. Focal lesions in cirrhotic explant livers: Pathological evaluation and accuracy of pretransplantation imaging examinations. Liver Transpl 2002; 8:749.
60.  Burrel, M, Llovet, JM, Ayuso, C, et al. MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: An explant correlation. Hepatology 2003; 38:1034.
61.  Lencioni, R, Mascalchi, M, Caramella, D, Bartolozzi, C. Small hepatocellular carcinoma: Differentiation from adenomatous hyperplasia with color Doppler ultrasound and dynamic Gd-DTPA enhanced MR imaging. Abdom Imaging 1996; 21:41.
62.  Heiken, J, Weiman, P, Lee, J, et al. Detection of focal hepatic masses: Prospective evaluation with CT, delayed CT, CT during arterial portography and MR imaging. Radiology 1989; 171:47.
63.  Yu, JS, Kim, KW, Lee, JT, Yoo, HS. MR imaging during arterial portography for assessment of hepatocellular carcinoma: Comparison with CT during arterial portography. AJR Am J Roentgenol 1998; 170:1501.
64.  Kanematsu, M, Hoshi, H, Murakami, T, et al. Detection of hepatocellular carcinoma in patients with cirrhosis: MR imaging versus angiographically assisted helical CT. AJR Am J Roentgenol 1997; 169:1507.
65.  Murakami, T, Oi, H, Hori, M, et al. Helical CT during arterial portography and hepatic arteriography for detecting hypervascular hepatocellular carcinoma. AJR Am J Roentgenol 1997; 169:131.
66.  Kanematsu, M, Hoshi, H, Imaeda, T, et al. Detection and characterization of hepatic tumors: Value of combined helical CT hepatic arteriography and CT during arterial portography. AJR Am J Roentgenol 1997; 168:1193.
67.  Choi, D, Kim, S, Lim, J, et al. Preoperative detection of hepatocellular carcinoma: ferumoxides-enhanced mr imaging versus combined helical CT during arterial portography and CT hepatic arteriography. AJR Am J Roentgenol 2001; 176:475.
68.  Dresel, S, Kirsch, CM, Tatsch, K. et al. Detection of hepatocellular carcinoma with a new alpha-fetoprotein antibody imaging kit. J Clin Oncol 1997; 15:2683.
69.  Nagasue, N. Gallium scanning in the diagnosis of hepatocellular carcinoma: A clinicopathologic study of 45 patients. Clin Radiol 1983; 34:139.
70.  Serafini, AN, Jeffers, LJ, Reddy, KR, et al. Early recognition of recurrent hepatocellular carcinoma utilizing gallium-67 citrate scintigraphy. J Nucl Med 1988; 29:712.
71.  Shiomi, S, Nishiguchi, S, Ishizu, H, et al. Usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose for predicting outcome in patients with hepatocellular carcinoma. Am J Gastroenterol 2001; 96:1877.
72.  Ho, YJ, Jeng, LB, Yang, MD, et al. A trial of single photon emission computed tomography of the liver with technetium-99m tetrofosmin to detect hepatocellular carcinoma. Anticancer Res 2003; 23:1743.
73.  Iwata, Y, Shiomi, S, Sasaki, N, et al. Clinical usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose in the diagnosis of liver tumors. Ann Nucl Med 2000; 14:121.
74.  Trojan, J, Schroeder, O, Raedle, J, et al. Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma. Am J Gastroenterol 1999; 94:3314.
75.  Jeng, LB, Changlai, SP, Shen, YY, et al. Limited value of 18F-2-deoxyglucose positron emission tomography to detect hepatocellular carcinoma in hepatitis B virus carriers. Hepatogastroenterology 2003; 50:2154.
76.  Schroder, O, Trojan, J, Zeuzem, S, Baum, RP. Limited value of fluorine-18-fluorodeoxyglucose PET for the differential diagnosis of focal liver lesions in patients with chronic hepatitis C virus infection. Nuklearmedizin 1998; 37:279.
77.  Ho, CL, Yu, SC, Yeung, DW. 11C-acetate PET imaging in hepatocellular carcinoma and other liver masses. J Nucl Med 2003; 44:213.
78.  Bru, C, Maroto, A, Bruix, J, et al. Diagnostic accuracy of fine-needle aspiration biopsy in patients with hepatocellular carcinoma. Dig Dis Sci 1989; 34:1765.
79.  John, T, Garden, O. Needle track seeding of primary and secondary liver carcinoma after percutaneous liver biopsy. HPB Surg 1993; 6:199.
80.  Durand, F, Regimbeau, JM, Belghiti, J, et al. Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma. J Hepatol 2001; 35:254.
81.  Huang, GT, Sheu, JC, Yang, PM. et al. Ultrasound-guided cutting biopsy for the diagnosis of hepatocellular carcinoma a study based on 420 patients. J Hepatol 1996; 25:334.
82.  Kim, SH, Lim, HK, Lee, WJ, et al. Needle-tract implantation in hepatocellular carcinoma: frequency and CT findings after biopsy with a 19.5-gauge automated biopsy gun. Abdom Imaging 2000; 25:246.
83.  Ohlsson, B, Nilsson, J, Stenram, U, et al. Percutaneous fine-needle aspiration cytology in the diagnosis and management of liver tumours. Br J Surg 2002; 89:757.
84.  Ng, KK, Poon, RT, Lo, CM, et al. Impact of preoperative fine-needle aspiration cytologic examination on clinical outcome in patients with hepatocellular carcinoma in a tertiary referral center. Arch Surg 2004; 139:193.
85.  Robbins, S, Kumar, V. Basic Pathology, 4th ed, WB Saunders, Philadelphia 1987. p.598.
86.  Saab, S, Ly, D, Nieto, J, et al. Hepatocellular carcinoma screening in patients waiting for liver transplantation: A decision analytic model. Liver Transpl 2003; 9:672.
87.  Tradati, F, Colombo, M, Mannucci, PM, et al. A prospective multicenter study of hepatocellular carcinoma in Italian hemophiliacs with chronic hepatitis C. Blood 1998; 91:1173.
88.  McMahon, BJ, Alberts, SR, Wainwright, RB, et al. Prospective study of 1400 hepatitis B surface antigen-positive Alaska native carriers. Arch Intern Med 1990; 150:1051.
89.  Trevisani, F, Cantarini, MC, Labate, AMM, et al. Surveillance for hepatocellular carcinoma in elderly Italian patients with Cirrhosis: Effects on cancer staging and patient survival. Am J Gastroenterol 2004; 99:1477.
90.  Yuen, MF, Cheng, CC, Lauder, IJ, et al. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31:330.
91.  McMahon, BJ, Bulkow, L, Harpster, A, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: A 16-year population-based study. Hepatology 2000; 32:842.
92.  Oka, H, Tamori, A, Kuroki, T, et al. Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 1994; 19:61.
93.  Serfaty, L, Aumaitre, H, Chazouilleres, O, et al. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. Hepatology 1998; 27:1435.
94.  Fattovich, G, Giustina, G, Degos, F, et al. Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology 1997; 112:463.
95.  Bonis, PA, Tong, MJ, Blatt, LM, et al. A predictive model for the development of hepatocellular carcinoma, liver failure, or liver transplantation for patients presenting to clinic with chronic hepatitis C. Am J Gastroenterol 1999; 94:1605.
96.  Velazquez, RF, Rodriguez, M, Navascues, CA, et al. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis. Hepatology 2003; 37:520.

New Search Table of Contents My UpToDate Feedback Help Log Out
ฉ2005 UpToDate • •