There are numerous types of primary liver cancers, both benign and malignant (Table 1). Most of them arise from the main cells constituting the organ, such as hepatocytes (hepatocarcinoma), biliary epithelial cells (cholangiocarcinoma and biliary cystadenocarcinoma), endothelial cells (angiosarcoma, epithelioid hemangioendothelioma), or combinations of these cells with various mesenchymal cells (e.g., hepatoblastoma). These lesions generally do not spread to other organs but within the liver itself, giving rise to multifocal tumors.

Table1. Benign and malignant liver lesions

In addition, due to its high vascularity, the liver has a high incidence of secondary cancers, i.e., metastases from cancers originating in other organs, especially the gastrointestinal tract. Epidemiological data show that up to 50% of patients with colorectal cancer are diagnosed with or develop distant metastases, mainly hepatic, in the years following resection of the primary cancer.

Benign cancers are quite frequent in the population (up to 20%) and are usually discovered incidentally during investigations for other conditions in patients with noncirrhotic liver.

Hepatocarcinoma (HCC), on the other hand, is the most frequent hepatic malignancy.

Diagnosis is based on evaluating clinical history, risk fac tors, laboratory test results, imaging studies, and, in some cases, histopathologic examination of the lesion.

Regarding laboratory tests, in addition to the evaluation of liver parameters, which may be normal in a patient with hepatic neoplasia, the serum concentration of alpha- fetoprotein (AFP) should be evaluated.

AFP is a glycoprotein normally produced by the fetal liver and the vitreous sac during gestation. Its concentrations in amniotic fluid and maternal blood increase progressively during pregnancy, reaching a peak between the 12th and 16th week of gestation and then decreasing until delivery. It is the most abundant protein in fetal circulation; it is like albumin in molecular weight, amino acid sequence, immunological characteristics, and biological functions.

In adults, its levels are generally very low, almost undetectable. However, AFP levels can increase significantly in specific disease conditions, such as HCC. In particular, serum AFP levels are typically higher in advanced HCC than in early HCC, but overall, the levels do not correlate well with clinical features of HCC, such as tumor size or vascular invasion. In addition, not all tumors secrete AFP, and serum concentrations are normal in approximately 40% of individuals with small HCC. High levels of AFP have good specificity for HCC at the expense of low sensitivity. Indeed, it has been generally accepted that serum AFP levels >400 ng/mL (normal value is generally 10–20 ng/mL) in a high-risk patient are diagnostic of HCC, with >95% specificity; however, less than one-fifth of patients with HCC have such elevated AFP levels. Furthermore, AFP levels may increase in different pathological conditions. In particular, the differential diagnosis of elevated circulating AFP levels includes:

• Chronic liver disease without hepatocellular carcinoma

• Pregnancy

• Cancers of gonadal origin (germ and nongerm cell)

 • Other malignant cancers, of which gastric carcinoma is the most common.

Given the sensitivity and specificity issues, serum AFP assessment has been removed from some guidelines as a diagnostic test for HCC. However, the AFP test may be helpful, in combination with the results of other investigations, to guide the management of patients in whom a diagnosis of HCC is suspected. An elevated AFP level in combination with suspicious but nondiagnostic imaging findings may have a positive predictive value in the absence of biopsy.

All patients with a solid liver lesion should have their serum AFP levels checked. If elevated, a diagnosis of HCC becomes more likely, although imaging studies and possibly biopsy are necessary to confirm the diagnosis.

AFP levels are generally normal in patients with benign liver tumors, such as hemangioma, adenoma, and focal nodular hyperplasia.

In the case of cholangiocarcinoma, although nonspecific, some serum tumor markers may be of diagnostic value. Carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) are the two best-studied markers, although their diagnostic utility is limited due to low specificity and sensitivity. Serum CA19.9 levels are widely used to detect cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC). For patients with PSC, periodic CA19.9 measurement is used for cholangiocarcinoma surveillance. In addition, elevated CA19.9 levels before treatment are associated with a worse prognosis, and CA19.9 concentrations >1000 units/mL are consistent with advanced disease, often involving the peritoneum. If initially elevated, serum CA19.9 levels may be useful in monitoring response to treatment and detecting disease recurrence. However, there are limitations to using CA19.9 as a diagnostic marker for cholangiocarcinoma because it is frequently elevated in patients with various benign pancreatico-biliary disorders, including cholangitis, and with other malignancies, including pancreatic carcinoma.

Serum CEA levels may be elevated in cholangiocarcinoma. However, serum CEA is neither sufficiently sensitive nor specific to diagnose cholangiocarcinoma. Many conditions other than cholangiocarcinoma may induce increased serum CEA levels, such as many primary cancers of the gastrointestinal tract, breast cancer, as well as extra-neoplastic causes such as gastritis, peptic ulcer disease, diverticulitis, liver disease, chronic obstructive pulmonary disease, diabetes, and any acute or chronic inflammatory state. However, if levels are elevated, they may be helpful for monitoring therapy.

In contrast, AFP differentiates intrahepatic cholangiocarcinoma from hepatocellular carcinoma. Even in the case of fibrolamellar carcinoma, AFP is not useful for diagnosing and monitoring disease progression. Only 7–11% of patients have an elevated serum level of AFP, with values of 100–200 ng/L.