Primary Hepatic Neoplasms. estimated 560,000 new cases per year. There is tremendous regional variation in incidence of

Transcription

1 Primary Hepatic Neoplasms Hepatocellular Carcinoma Incidence and Epidemiology Worldwide, hepatocellular carcinoma is the 3 rd most common causes of cancer death with an estimated 560,000 new cases per year. There is tremendous regional variation in incidence of hepatocellular carcinoma. Extremely high rates are seen in sub-saharan Africa, Eastern Asia, Japan, and Korea. Intermediate rates are observed in Singapore, Native Americans, and portions of South America. Hepatocellular carcinoma is uncommon in the United States; the incidence is one-tenth the rate of many countries in Southeast Asia. Nonetheless, hepatocellular carcinoma is increasing in the United States and is a major source of morbidity and mortality. Higher rates are seen African Americans and other minority groups. The variation in the incidence of hepatocellular carcinoma is closely related to regional variations in the prevalence of chronic hepatitis B and C infection and circulating hepatitis B surface antigen. All forms of cirrhosis are associated with an increased risk of hepatocellular carcinoma, but the risk is particularly high in patients with cirrhosis secondary to chronic viral infection. Hepatocellular carcinoma can complicate chronic viral hepatitis B prior to the development of cirrhosis. Hemochromatosis is associated with a high rate of HCC in cirrhotic patients. Of the 90% of patients with hepatocellular carcinoma who have coexistent cirrhosis, there is consistently a male predominance, and in the United States, the male-to-female ratio is >2:1. Other environmental exposures associated with hepatocellular carcinoma include Aflatoxin B1, a toxic metabolite of an Aspergillus species that often contaminates grains and nuts, has been demographically linked to hepatocellular carcinoma. At least a portion of the geographic variation in hepatocellular carcinoma rates may be related to differences in levels of

2 aflatoxin B1 in food. Long-term exposure to vinyl chloride or androgenic steroids have also been associated with an increased incidence of hepatocellular carcinoma. The epidemiologic association with anabolic steroids may partially explain the male-to-female ratio in hepatocellular carcinoma. Etiology and Pathogenesis Although the precise molecular mechanisms of hepatocellular carcinogenesis are not fully understood, hepatocellular carcinoma probably results from activation of proto-oncogenes, deactivation of tumor suppressor genes (e.g., p53 and prb), changes in growth factors or growth factor signaling processes (e.g. IGF or TGF), changes in telomere length and activity, microsatellite instability. Genetic injury may result from a variety of sources. Perhaps the best described is random integration of the hepatitis B virus (HBV) genome into the host genome, as well as transactivating features of the Hepatitis B x protein which can activate protooncogenes such as c-myc and c-fos. Although hepatitis C virus is an RNA virus and does not have the same direct mutagenic capacity as HBV, any chronic inflammatory state can generate free radicals capable of inducing genetic injury. Additionally the HCV core protein appears to be a cell signaling activator. Similarly, the regenerative response in cirrhosis may lead to chromosomal rearrangements that foster unrestrained proliferation. Multiple genetic abnormalities have been identified in HCC and in dysplastic nodules. However, it is likely that the process is multifactorial and further genetic studies are needed. Additionally, for reasons that remain poorly defined, some forms of cirrhosis, such as hemochromatosis and tyrosinemia, have exceptionally high incidences of hepatocellular carcinoma, whereas other diseases, such as Wilson s disease and autoimmune hepatitis, have exceptionally low incidences of hepatocellular

3 carcinoma. Further characterization of the cellular and genetic events leading to hepatocellular carcinoma may clarify these discrepancies. Clinical Features Ninety percent of patients with hepatocellular carcinoma have superimposed cirrhosis. The clinical presentations of hepatocellular carcinoma may be subtle; many of the presenting signs and symptoms are often mistakenly attributed to coexisting cirrhosis. Nonspecific symptoms of fatigue, anorexia, weight loss, and jaundice are common. Patients may complain of right upper quadrant pain or increasing abdominal girth. Hepatocellular carcinoma may cause wellcompensated cirrhosis to become decompensated, with progressive ascites, encephalopathy, jaundice, or hemorrhage. Invasion of the portal and less commonly hepatic veins, can greatly worsen portal hypertension leading to refractory ascites or variceal bleeding. HCC should be suspected in all new cases of portal vein thrombosis. Occasionally, patients with poorly differentiated tumors present with protracted fever and, rarely, with a paraneoplastic syndrome or metastatic disease, usually bony pain or dyspnea from pulmonary tumor emboli or malignant pleural effusion. On physical examination, most patients exhibit hepatomegaly or a discrete mass. Rarely patients with hepatocellular carcinoma present with an acute abdomen resulting from tumor rupture and hemoperitoneum, which is catastrophic but can be treated with arterial embolization, or hemobilia and jaundice from invasion of the bile ducts. In general, abdominal pain in patients with HCC is a poor prognostic sign. Findings on Diagnostic Testing Laboratory Studies Patients presenting with hepatocellular carcinoma as their first manifestation of chronic liver disease should have a complete serologic evaluation to determine the cause of cirrhosis.

4 Aminotransferase levels are often mildly elevated but they can be normal; levels are determined by the underlying liver disease. Alkaline phosphatase levels may be particularly elevated if the tumor assumes an infiltrative pattern. In advanced tumors, serum bilirubin levels may be markedly elevated owing to compromised hepatocellular reserve or, less commonly, extrahepatic bile duct obstruction. Other laboratory abnormalities observed in hepatocellular carcinoma include rare instances of paraneoplastic hypercalcemia and erythrocytosis. Large tumors have been associated with hypoglycemia of uncertain cause. Tumor Markers Hepatocellular carcinoma is associated with several serum tumor markers. The marker most often used is serum a-fetoprotein (AFP), the glycosylated protein expressed in proliferating fetal hepatocytes. After the first year of life, AFP levels decrease to <10 ng per ml, but several chronic inflammatory states, including viral hepatitis, are associated with AFP elevations to 10 to 100 ng per ml. Although chronic hepatitis in the setting of cirrhosis may be associated with levels in the hundreds, levels of >400 ng per ml usually are caused by hepatocellular carcinoma. A level of AFP of >1000 ng per ml associated with a liver mass is diagnostic of hepatocellular carcinoma. Unfortunately, AFP is only elevated in 60% to 70% of patients with hepatocellular carcinoma and may only be mildly elevated in small tumors, compromising the measurements of sensitivity of AFP as a screening test for early hepatocellular carcinoma. Other tumors (e.g., testicular, ovarian, gastric) and gallbladder carcinoma are also associated with increased serum levels of AFP. Carcinoembryonic antigen is rarely elevated; marked elevations in the setting of a liver mass suggest metastatic adenocarcinoma. Structural Studies

5 Several imaging modalities can be used to identify and stage hepatocellular carcinoma. The challenge is to distinguish a small tumor from the regenerative changes associated with cirrhosis. Ultrasound is sensitive for detecting small hepatocellular carcinomas (<2 cm). The hyperechoic pattern in these small tumors differentiates them from hypoechoic metastatic lesions. Ultrasound may be less reliable in distinguishing a small hepatocellular carcinoma from a benign hemangioma, which is also typically hyperechoic. Larger hepatocellular carcinomas are often hypoechoic and may be difficult to differentiate from metastatic lesions, but coexisting cirrhosis or elevated levels of AFP may provide additional diagnostic evidence. A computed tomographic (CT) scan is 80% to 90% sensitive for detecting hepatocellular carcinoma. A spiral CT scan obtains arterial and venous phase contrast images with a single dose of contrast agent. Hepatocellular carcinoma typically is a vascular tumor with marked arterial phase enhancement; the rapid washout of contrast agent leads to the appearance of a hypodense lesion during the venous phase. A hemangioma can be distinguished by a characteristic peripheral-to-central filling pattern and prolonged contrast enhancement. Ultrasound and CT scans demonstrate various patterns of hepatocellular carcinoma growth and extension. One-third of hepatocellular carcinomas are infiltrating, with poorly defined borders. Another one-third are expanding tumors that are well defined and encapsulated. A small percentage of them manifest as multicentric, space-occupying lesions or large pedunculated masses extending from the liver surface. CT scans are especially useful in defining the tumor capsule and invasion of the portal vein. The accuracy of magnetic resonance imaging (MRI) is similar to that of three phase spiral CT scanning and avoids the potential adverse effects of intravenous contrast agents. MRI is the procedure of choice for differentiating hemangioma from hepatocellular carcinoma and may be more sensitive for identifying small hypervascular lesions.

6 A focal area of increased uptake of 99m Tc-sulfur colloid on an image is virtually diagnostic of the benign lesion, focal nodular hyperplasia, but an unenhanced, or cold mass, does not differentiate hepatocellular carcinoma from metastatic disease or hepatic adenoma. Given the ability to diagnose HCC reliably without biopsy using AFP and CT or MRI, this test is raely used. Angiography is used primarily to define the vascular anatomy in patients being considered for resection or for chemoembolization. If there is a high index of suspicion for hepatocellular carcinoma and all other imaging tests fail to localize a mass, CT scans after lipiodol injection may be useful. Lipiodol is an iodinated preparation of poppy seed oil that hepatocellular carcinoma cells preferentially concentrate and retain. Intra-arterial injection of lipiodol is followed 2 weeks later by CT scanning. Lipiodol injection can carry some risk of hepatic dysfunction, particularly in patients with portal vein thrombosis. Hepatocellular carcinoma appears as a focal area of enhancement. The most sensitive means of detecting hepatocellular carcinoma is intraoperative ultrasound and laparoscopic biopsy. Given the invasiveness of these last two procedures, repeat CT or MRI scanning after an interval of 2-3 months is an alternative means of identifying hepatocellular carcinoma in patients in whom hepatocellular carcinoma is suspected but not detected on initial noninvasive imaging. Screening with ultrasound and AFP every 6 months in patients with cirrhosis and vertical transmission of HBV without cirrhosis is recommended, with CT or MRI for any unclear lesions or unexplained elevation in AFP. Histologic Studies When a patient with cirrhosis develops a new hypervascular liver mass associated with elevation of serum AFP levels, a biopsy to confirm hepatocellular carcinoma is usually not be necessary. The risk of bleeding induced by ultrasound- or CT-guided core biopsy of hepatocellular

7 carcinoma is significant, and there is a small (3-5%) risk of needle track spread. Small-gauge needle aspiration often fails to diagnose HCC, which often requires architectural features for diagnosis. Histologic examination usually reveals cords of undifferentiated hepatocytes, but some tumors are well differentiated and may be difficult to differentiate from a benign hepatic adenoma particularly on cytology. Management and Course Surgical Therapy The only option for long-term survival with hepatocellular carcinoma is complete surgical excision of the tumor. Unfortunately, resection is limited to unilateral disease in Child A cirrhotic patients; thus resectability rates range from 5% to 20%. In determining the suitability of a patient for resection, the stage of the tumor and postresection residual hepatic function need to be considered. Any patient with jaundice or significant portal hypertension (wedged hepatic vein pressure gradient > 10 mm Hg or varices) will not tolerate further loss of hepatic function. Similarly, any patient with distant metastasis or diffuse hepatic involvement will not benefit from surgery. After successful resection, measurement of serum AFP levels is a useful means of detecting disease recurrence. The 5-year recurrence rate for patients with resectable tumors is 50% among surviviors due to de novo HCC or growth of unrecognized intrahepatic metastases. Orthotopic liver transplantation (OLT) for patients with HCC offers significant advantages over partial hepatectomy since it can be employed for patients with advanced liver disease and it removes the existing cancer, and the diseased liver with its underlying neoplastic potential. Numerous studies have shown that results with liver transplantation are superb in patients with single lesions < 5 cm or up to 3 lesions < 3 cm each (Stage I-II disease). Patients who meet these Milan criteria are now given additional priority for OLT. Other studies have suggested that

8 larger tumors can also be transplanted, e.g UCSF criteria which extends to 8 cm HCC, suggesting the current algorithm may be too restrictive. Despite the additional priority given to HCC, given the potential for tumor growth and spread on the waiting, many centers treat the lesions prior to OLT with ablation and/or chemoembolization therapies (see below). None of these therapies has been subjected to randomized controlled trials in combination with OLT and, therefore, the optimal approach remains to be ascertained. Living donor liver transplantation has also been used to shorten waiting time and may be an optimal use of the reduced size graft due to the usually reasonably preserved hepatic function in HCC patients. The impact of regeneration on the risk of HCC recurrence after LDLT remains controversial. For patients who are not candidates for surgical approaches, locoregional forms of treatment are reasonable. These options include percutaneous alcohol injection (PEI), radiofrequency ablation (RFA), and transcatheter arterial chemoembolization (TACE) and will be discussed in the following paragraphs. Percutaneous alcohol injection Percutaneous alcohol injection (PEI) has become a widely accepted form of therapy for small, localized HCC. The advantage of PEI over other local ablative minimally invasive therapies is its relatively simple technique and low cost. PEI can be safely performed in patients who are not candidates for resection or OLT, even in the presence of advanced cirrhosis. HCC less than 3 cm in size and fewer than three nodules are suitable for PEI. Absolute alcohol kills cells likely through a combination of cellular dehydration, coagulative necrosis and vascular thrombosis.

9 PEI is associated with a complication rate of 1.7% and a 0.1% mortality rate. Patients may experience abdominal pain and low-grade fever. Contraindications to PEI include massive ascites, coagulopathy, and obstructive jaundice. Survival with PEI in most studies is equivalent to surgical resection and relates to the severity of the underlying liver disease. Radiofrequency ablation Radiofrequency ablation (RFA) uses thermal energy generated with an alternating electric current generator in the radiofrequency range (200 to 1200 khz) to create focal coagulative necrosis. RFA is usually performed by a percutaneous approach, but can be done laparoscopically or during open surgery for difficult to reach lesions. Ultrasound guidance is used to place the probe. in the out patient department. Lesions up to 5 cm or more can be treated but lesions near large blood vessels are poorly treated since they the blood acts as a heat sink. Spiral contrast enhanced CT scanning is usually used to assess tumor necrosis after RFA as the lesions rarely shrink and the degree of enhancement with contrast will provide an estimate of viable tumor. The results of RFA appear comparable to other ablative techniques though there is increased concern about needle track seeding due to the larger caliber probe used with RFA. Transcatheter arterial chemoembolization (TACE) TACE uses angiographic embolization of the arterial supply with lipiodol, gelfoam, or microspheres, in combination with the local delivery of high levels of chemotherapeutic agent(s), e.g. doxorubicin, mitomycin C, cisplatin, to create ischemic and cytotoxic damage to the HCC. The technique spares normal liver as it receives only 20% to 30% of its blood flow from the

10 hepatic artery. In contrast, HCC will receive 80% to 100% of its blood flow from the hepatic artery. Risks of TACE include contrast allergy, renal insufficiency, increased LFT s, and bleeding. Fever and right upper quadrant pain are common and many center routinely use postprocedure antibiotics. Hepatic abscesses are rare however, as is ischemic cholecystitis. Advanced cirrhosis with hyperbilirubunemis (usually > 3-5 mg/dl or INR > 1.7) is a relative contraindication for TACE because of the risk of liver failure. Other contraindications include hepatic encephalopathy, biliary obstruction, portal vein occlusion, portosystemic shunt, a transjugular intrahepatic portosystemic shunt (TIPS) device, or creatinine > 1.8. The efficacy of TACE is determined by the size of the lesion. Because TACE also avoids the risk of needle track seeding, transplant centers often use CE as a bridge to transplantation for HCC patients. TACE prevents progression of the lesions and potential micrometastases while the patient waits for a donor organ. The role of CE as a palliative procedure remains controversial, however recent data suggests a survival advantage to TACE but not embolization without chemotherapy. Cytotoxic chemotherapy HCC is unfortunately refractory to most available cytotoxic therapies. Moreover, the presence of cirrhosis with impaired clearance of drugs metabolized by the liver increases drug toxicity. Leucopenia and thrombocytopenia from splenic sequestration can exacerbate bone marrow toxicity. The overall response rate is <20% for systemic chemotherapy. Intra-arterial therapy with a pump has been tried but has not been shown to impact survival. Newer trials with blackade of neoangiogenesis and other agents are awaited. Hormonal and other therapy

11 The presence of androgen receptors in tumors and the male predominance of HCC led to the use of antiandrogen therapy for this cancer. Similarly, the presence of estrogen receptors in the liver also lead to the use of tamoxifen (an antiestrogen) for the treatment of this disease. Thalidomide with and without TACE is also being studied. Though current data has not supported a survival benefit with any of these therapies, the lower toxicity and lack of efficacy of systemic cytotoxic therapy has led to their use in patients with advanced or disseminated disease in some centers. Fibrolamellar Hepatocellular Carcinoma Fibrolamellar hepatocellular carcinoma is clinically and pathologically distinct from the hepatocellular carcinoma that complicates cirrhosis. Fibrolamellar hepatocellular carcinoma is not typically associated with cirrhosis. It often occurs in young adults; there is no sex predominance. Patients usually present with abdominal pain, weight loss, hepatomegaly, and an abdominal mass. Serum AFP levels are characteristically normal and imaging procedures often demonstrate intralesional calcification or, rarely, a central scar. Prognosis is favorable relative to the more common variant of hepatocellular carcinoma. Fifty percent to 75% of patients have resectable tumors, and long-term survival is common. Transplantation should be considered in this group given the decreased propensity of fibrolamellar hepatocellular carcinoma to metastasize and the younger age of the patient population. Hepatoblastoma Less than 1% of primary liver tumors are derived from fetal hepatocytes and are termed hepatoblastomas. Most cases occur in young children, but adults may be affected. Patients present with abdominal pain, weight loss, and a palpable right upper quadrant mass. Unlike

12 fibrolamellar tumors, serum AFP levels usually are elevated, but similar to fibrolamellar tumors, calcification is often evident on ultrasound or CT images. At the time of presentation, a hepatoblastoma often is massive in size. Complete surgical excision is the optimal treatment, but chemotherapy may be beneficial for unresectable tumors. Long-term survival averages 25%. Mesenchymal Tumors Mesenchymal tumors account for <1% of primary malignant liver neoplasms. Angiosarcoma is associated with exposure to anabolic steroids, arsenic, and vinyl chloride. Other histologic variants include rhabdomyosarcoma, leiomyosarcoma, and liposarcoma. Patients often present later in life with advanced disease at presentation and survival is limited. Benign Liver Masses Hepatic Adenomas The incidence of benign hepatic adenomas has increased with the use of oral contraceptives. Isolated adenomas occur mainly in women who are of reproductive age. These lesions are usually found incidentally on abdominal imaging performed for other reasons. However, they can grow to large sizes before symptoms occur; most symptomatic patients present with abdominal pain or a palpable abdominal mass. Intratumor hemorrhage and rupture are frequent complications, especially if the adenoma is associated with contraceptive use. Rarely, patients present with hepatic adenomatosis, characterized by multiple adenomas throughout the liver. These patients frequently have glycogen storage disorders, and malignant degeneration is a welldescribed complication. Hepatic adenomas are at risk for malignant degeneration though this risk is small for isolated lesions. Additionally, well-differentiated hepatocellular carcinoma may be difficult to distinguish from adenomas, and histologic misclassification of hepatocellular carcinoma as adenoma may later be interpreted as malignant transformation. Adenomas typically

13 appear as hypodense areas on CT scans and as cold lesions on 99m Tc sulfur colloid images. MRI will show the absence of a central scar seen in focal nodular hyperplasia. Discontinuing oral contraceptives may result in resolution, but if the lesion persists or hepatocellular carcinoma is suspected, surgical excision is recommended. Focal Nodular Hyperplasia Focal nodular hyperplasia is a space-occupying lesion composed of all of the normal cell populations usually found in the liver, including reticuloendothelial cells. The etiology is unknown. Lesions usually are detected incidentally during imaging procedures performed for unrelated symptoms. Twenty-five percent are multicentric and most are <5 cm. Diagnosis is often possible based on a classic appearance on imaging procedures. CT or MRI scans may demonstrate a central stellate scar that is often calcified. 99m Tc sulfur colloid imaging often but not invariably demonstrates a focal area of increased signal as a result of the presence of reticuloendothelial cells. Adenomas, hepatocellular carcinoma, and metastatic tumors are characteristically photopenic, appearing as cold spots on 99m Tc sulfur colloid images. Focal nodular hyperplasia is benign, and no treatment is necessary but often biopsy is required to differentiate FNH from adenoma in women at risk for both lesions. Hemangioma Cavernous hemangiomas are focal collections of dilated vascular channels and are the most common benign space-occupying lesion of the liver, with an estimated prevalence of 5% to 10%. Most are asymptomatic and are detected incidentally, but large hemangiomas can produce symptoms such as abdominal pain. The main clinical importance of this lesion lies in differentiating it from more serious disorders. Radiologic procedures play a primary role in diagnosis of hemangioma. Hemangiomas are typically hyperechoic on ultrasound and retain

14 contrast for prolonged periods on CT scanning. MRI is the most sensitive and specific means of diagnosing hemangioma. Percutaneous biopsy is rarely required and carries some risk of hemorrhage Surgical excision is necessary only for large, symptomatic lesions.