Diagnosis

Clinical Recognition

Advanced HCC usually presents with symptoms and signs sufficiently characteristic to allow the diagnosis to be suspected, especially in populations in which this tumor is common or when a risk factor is known to be present (3). In its early stages, however, HCC runs a silent course, making recognition difficult at the only time that the tumor is likely to be amenable to treatment.

Although HCC often coexists with cirrhosis (5), the influence that the cirrhosis exerts on the diagnosis of the tumor differs between regions of high and low (or intermediate) incidence of HCC. In the latter (but also in Japan, a country with a high incidence), HCC commonly develops as a late complication of symptomatic cirrhosis resulting from chronic hepatitis C virus (HCV) infection or alcohol abuse, or both (3,6). The patient has few, if any, symptoms attributable to the tumor. If, in addition, the tumor is small (as it often is in a cirrhotic liver in these regions) it is seldom obvious in the presence of advanced cirrhosis and is discovered only on hepatic imaging, during liver transplantation or other surgical intervention, or at necropsy. The onset of unexplained abdominal pain, weight loss, ascites, or liver enlargement in a patient known to have cirrhosis should alert the clinician to the possibility that HCC has supervened. In contrast, in ethnic Chinese and black African populations the associated cirrhosis either produces no symptoms or the symptoms are overshadowed by those ascribed to the tumor (3,6). Consequently, the cirrhosis is uncovered only during the diagnostic workup or at necropsy. In addition, HCCs in these populations are typically appreciably larger than in those with low or intermediate incidences. Right hypochon-drial or upper abdominal pain, weight loss, and weakness are the most common symptoms, and the patient may also be aware of a mass in the upper abdomen (3,6). The liver is almost always enlarged, sometimes massively so, and tender with an irregular or smooth surface. An arterial bruit, or rarely a friction rub, may be heard over the tumorous liver. Overt jaundice is uncommon when the patient is first seen.

HCC may present in a number of atypical ways (6). These include presentations with obstructive jaundice, hypoglycemia, hypercalcemia, acute hemoperitoneum, Budd-Chiari syndrome, inferior vena caval obstruction, superior mediastinal syndrome, bone pain, Virchow-Trossier node, fever of unknown origin, arterial hypertension, feminization, or skin rashes. Although none is common, an awareness of these presentations may prevent the diagnosis being delayed or even missed.

Tumor Markers

A sensitive and specific serum marker for HCC would greatly facilitate its diagnosis, and a large number of candidates have been advocated over the years (7). None, however, is more useful than the one first described, a-fetoprotein (a-FP).

a-Fetoprotein

Serum concentrations of this glycoprotein are raised in most patients with HCC (7). In countries with a high incidence of the tumor, levels are elevated in as many as 90% of patients and very high concentrations are often attained (the mean value is of the order of 70,000 ng/mL, normal < 20 ng/mL). Serum concentrations are less often raised in countries with a low or intermediate incidence of HCC and the level reached is generally lower (mean of the order of 8000 ng/mL). a-FP production by HCC is age related, younger patients being more likely to have raised levels and to attain very high concentrations (8). The differences between countries may therefore be explained in part by the younger ages of many of the patients in high-risk black African and ethnic Chinese populations. No differences in a-FP concentrations exist between the sexes. Nor is there an obvious correlation between serum a-FP levels and any clinical or biochemical indices or with survival time of the patients. In countries with a low incidence of HCC, a-FP concentrations are generally higher when the tumor coexists with cirrhosis or in patients with current HBV infection, but this is not so in countries where the tumor is common. Although synthesis of a-FP in mice with chemically induced HCC correlates with the degree of differentiation of the tumor, the evidence in this regard in human HCC is conflicting.

As useful as a-FP undoubtedly is in the diagnosis of HCC, it falls short of being an ideal serum marker for the tumor. In addition to the false-negative results already mentioned, several diseases give false-positive results (7). These include a variety of benign hepatic diseases, especially acute and chronic hepatitis and cirrhosis. Serum concentrations of a-FP are usually only slightly raised in these conditions, but moderately or even markedly elevated values are sometimes present. Raised levels also occur in approximately one-third of patients with undifferentiated teratocarcinoma or embryonal cell carcinoma of the ovary or testis, and in about 10% of patients with tumors of endodermal origin. If the threshold concentration of a-FP for the diagnosis of HCC is raised to 400 ng/mL (or 500 ng/mL in some laboratories), most false-positive results can be eliminated while still retaining a 70-75% positivity rate in high incidence countries. Inevitably, however, the positivity rate in low incidence regions falls below 50%.

a-FP is heterogeneous in structure. The microheterogeneity results from differences in the asparagine-linked biantenary oligosaccharide side chain of the molecule, and is the reason for the differential affinity of this glycoprotein for lectins. Reactivity with lens culinaris agglutinin A is helpful in differentiating HCC from benign hepatic diseases, and, to a lesser extent, reactivity with concanavalin A in distinguishing between HCC and other a-FP-producing tumors (7). Differential lectin reactivity is particularly useful in differentiating HCC from benign hepatic diseases when the serum a-FP level is only slightly raised. Small asymptomatic HCCs are usually associated with only modestly elevated a-FP levels, and a number of small benign hepatic masses may mimic HCC on hepatic imaging. Accordingly, reactivity with Lens culinaris agglutinin A can profitably be used in the surveillance of individuals at high risk of developing HCC. The drawback of the method is the cost, especially because the greatest numbers of patients with HCC occur in countries with the least resources.

Des-T-Carboxy Prothrombin

Des-T-carboxy prothrombin (also known as "protein induced by vitamin K absence or antagonism" [PIVKA-II]) is a precursor of vitamin K that has been used as a serum marker for HCC (7). The explanation for the production of des-T-carboxy prothrombin by the tumor is uncertain. Among the suggested causes are a failure of HCC to express the prothrombin T-glutamyl carboxylase gene and abnormal uptake of vitamin K by malignant hepatocytes (9). As a result, the precursor protein accumulates in the tumor and subsequently leaks into the bloodstream. In most populations des-r-carboxy prothrombin is less useful than a-FP as a serum marker of HCC, although the two markers can be used together to increase the sensitivity and specificity of diagnosis (7).

None of the many other candidate serum markers for HCC can match a-FP for sensitivity and specificity and accordingly they are not used in clinical practice.

Imaging

Hepatic imaging plays a central role in the diagnosis both of symptomatic HCCs and of small HCCs during surveillance programs aimed at the early detection of subclinical tumors in high-risk individuals. Nevertheless, with none of the imaging modalities now available is the picture obtained pathognomonic of HCC and definitive diagnosis still depends on histologic examination of the tissue.

Ultrasonography

Ultrasonography is commonly used to confirm the presence of hepatic masses in symptomatic patients (10). It is widely available, not invasive, relatively inexpensive, easy to perform, and detects almost all symptomatic and presymptomatic HCCs. Large tumors usually have a mixed echogenic/echolucent appearance and an ill-defined margin. Apart from delineating the number, size, and distribution of the lesions, ultra-sonography is helpful in evaluating operability of the tumor because of its ability to detect invasion of the portal and hepatic venous systems and the biliary system. In the few symptomatic HCCs invisible on ultrasonography, computed tomography will almost always show the lesion.

Ultrasonography is also the modality of choice for screening the liver during long-term surveillance of individuals at high risk of HCC (10,11). In addition to the advantages already mentioned, ultrasonography can be used repeatedly and is highly sensitive, allowing tumors < 2 cm in diameter and even smaller (which have a better prognosis than larger lesions) to be detected by skilled operators. Moreover, the machine is portable. With very small tumor nodules the ultrasonographic pattern is usually hypoe-choic, but about one-third are hyperechoic, reflecting the presence of fatty metamorphosis or clear cells. Some may be isoechoic. A mosaic pattern with septum formation, a peripheral halo, and posterior echo enhancement is a typical appearance.

Two recent refinements to ultrasonography have added new dimensions to its diagnostic capabilities. Dynamic contrast-enhanced ultrasonography with intraarterial infusion of CO2 microbubbles provides information on the vascularity of small tumors that are undetectable angiographically, and can be used to differentiate HCC from adeno-matous hyperplasia, small hemangiomas, metastases, and focal nodular hyperplasia (10). Color Doppler ultrasonography has advantages over pulsed Doppler ultrasonogra-phy and may be useful in differentiating a small HCC from focal nodular hyperplasia (10). A further refinement is intravenous contrast-enhanced color Doppler ultrasonog-raphy, which is expected to further improve the detection of subclinical HCCs and to aid in the choice of treatment of the tumor (10).

Computed Tomography and Hepatic Angiography

Computed tomography is used in visualizing both symptomatic and small HCCs when ultrasonography is unhelpful, as well as in evaluating operability of the tumor and in planning resection (12). A difference of at least 10 Hounsfield numbers between normal and abnormal areas of the liver is generally needed for accurate detection of liver tumors. Intravenous contrast material infused in conjunction with computed tomography enhances normal liver tissue to a greater degree than most neoplastic tissues and may reveal the pattern of tumor perfusion. It also shows the course, caliber, and patency of blood vessels. Contrast computed tomography may thus facilitate characterization of the tumor. Spiral (helical) computed tomography has the advantage of rapid scanning and allows the peak hepatic enhancement (which occurs 70-120 s after intravenous injection) to be scanned. Tumor enhancement with this method approaches that achieved with arteriography (12,13).

The use of hepatic arteriography in combination with computed tomography further increases the diagnostic capabilities of tomography (12,13). Because HCCs obtain their blood supply from the hepatic artery, computed tomography/ arteriography produces a high attenuation blush of the tumor. In computed tomography/portography injection of contrast material into the superior mesenteric vein causes dense enhancement of portal venous blood and highlights the tumor as a negative image (12,13). Because iodized poppy seed (Lipiodol) is concentrated and retained in tumor tissue, the injection of this material at the end of hepatic arteriography can be used to detect very small HCCs using computed tomography performed after a suitable delay (12,13).

Magnetic Resonance Imaging

This form of imaging is seldom needed for the diagnosis of HCC. Contrast-enhanced magnetic resonance imaging with gadopenetate dimeglumine and fast images with gradient echo sequences or the use of the tissue-specific contrast medium superparamagnetic iron oxide is, however, one of the most accurate ways of differentiating between small HCCs and hemangiomas in the liver (14).

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