Hepatocellular carcinoma


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Hepatocellular carcinoma

  1. 1. Hepatocellular CarcinomaEpidemi olog yHepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and oneof the most common malignancies worldwide, accounting for more than 1 million deathsannually. The geographic distribution of HCC is clearly related to the incidence of hepatitis Bvirus (HBV) infection. The highest incidence of disease (>10-20 per 100,000) is found inSoutheast Asia and tropical Africa, and the lowest incidence (1-3 per 100,000) is found inAustralia, North America, and Europe. In high incidence areas, rates are variable. For example,Taiwan has an incidence of 150 per 100,000, whereas Singapore has an incidence of 28 per100,000. Epidemiologic evidence strongly suggests that HCC is largely related to environmentalfactors, with incidence in immigrants eventually taking on that of the local population afterseveral generations. An exception to this observation is that whites living in high prevalenceareas tend to have a low incidence of HCC. This is likely related to the continuation of thelifestyle and environment of their home country. It is probable that the variation in incidencerates among immigrants is related to HBV carrier rates. Recent publications have noted asignificant rise in the incidence of HCC in the United States and other Western countries duringthe past 30 years. The explanation of this rising incidence is not understood, but emergence ofhepatitis C virus (HCV) infection and immigration patterns have been suggested. [47] [48]HCC is two to eight times more common in males than in females in low and high incidenceareas. Although sex hormones may play a minor role in the development of HCC, the higherincidence in males is probably related to higher rates of associated risk factors such as HBVinfection, cirrhosis, smoking, alcohol abuse, and higher hepatic DNA synthesis in cirrhosis. Ingeneral, the incidence of HCC increases with age, but a tendency to develop HCC earlier in highincidence areas has been noted. For example, in Mozambique, 50% of patients with HCC areyounger than 30 years of age. This may be related to the differing age at infection and naturalhistories of HBV and HCV infections. [47] [48]EtiologyA large number of associations between hepatic viral infections, environmental exposures,alcohol use, smoking, genetic metabolic diseases, cirrhosis, OCPs, and the development of HCChave been recognized. Overall, 75% to 80% of HCC cases are related to HBV (50%-55%) orHCV (25%-30%) infection. What is also clear from research is that the development of HCC is acomplex and multistep process that involves any number of these risk factors.Many years of research have documented a clear association between persistent HBV infectionand the development of HCC. Studies estimate relative risks of 5 to 100 for the development ofHCC in HBV-infected individuals compared with noninfected individuals. Other evidenceincludes the following observations: geographic areas high in HBV infection have high rates ofHCC; HBV infection precedes the development of HCC; the sequence of HBV infection tocirrhosis to HCC is well documented; and the HBV genome is found in the HCC genome. HBVhas no known oncogenes, but insertional mutagenesis into hepatocytes may be a contributingfactor to the development of HCC. Another proposed mechanism is related to cirrhosis andchronic hepatic inflammation, which is present in 60% to 90% of patients with HBV infectionand HCC. Cirrhosis, however, is not a prerequisite for the development of HBV-related HCC. It
  2. 2. is important to note that the risk for HCC is not simply related to HBV exposure but requireschronic infection (i.e., chronically positive hepatitis B surface antigen). There is a higher risk forpersistent infection (carrier state) when the infection is acquired at birth or during earlychildhood. Familial clustering of HCC is probably related to early vertical transmission of thevirus and establishment of the chronic carrier state.HCV has recently been discovered to be a major cause of chronic liver disease in Japan, Europe,and the United States, where there is a relatively low rate of HBV infection. Antibodies to HCVare found in 76% of patients with HCC in Japan and Europe and in 36% of patients in the UnitedStates. HBV and HCV infection are both independent risk factors for the development of HCCbut probably act synergistically when an individual is infected with both viruses. Although thenatural history of HCV infection is not completely understood, it appears to be one of chronicinfection with a benign early course but with ultimate development of cirrhosis and HCC.Studies on the rates of progression to cirrhosis estimate a median time of 30 years, but differingprogression rates yield a range of less than 20 years to more than 50 years. Factors associatedwith a more rapid progression include male gender, chronic alcohol use, and older age atinfection. HCV is an RNA virus that does not integrate into the host genome, and therefore, thepathogenesis of HCV-related HCC may be more related to chronic inflammation and cirrhosisrather than direct carcinogenesis. [47] [48]The true relationship of cirrhosis and HCC is difficult to ascertain, and suggestions of causationremain speculative. Cirrhosis is not required for the development of HCC, and HCC is not aninevitable result of cirrhosis. The relationship of cirrhosis and HCC is further complicated by thefact that they share common associations. Furthermore, some associations (e.g., HBV infection,hemochromatosis) are associated with higher risk for HCC, whereas others (e.g., alcohol,primary biliary cirrhosis) are associated with a lower risk for HCC. Research has demonstratedthat cirrhotic livers with higher DNA replication rates are associated with the development ofHCC.Chronic alcohol abuse has been associated with an increased risk for HCC, and there may be asynergistic effect with HBV and HCV infection. Alcohol causes cirrhosis but has never beenshown to be directly carcinogenic to hepatocytes and likely acts as a cocarcinogen. Cigarettesmoking has been linked to the development of HCC, but the evidence is not consistent, and thecontributing risk independent of viral hepatitis is likely small. Aflatoxin, produced byAspergillus species, is a powerful hepatotoxin. With chronic exposure, aflatoxin acts as acarcinogen and increases the risk for HCC. The offending fungi grow on grains, peanuts, andfood products in tropical and subtropical regions, and intake of contaminated foods results inaflatoxin exposure. Levels of aflatoxin in implicated foods are regulated in the United States. Avariety of chemicals have been implicated as carcinogens related to HCC and include nitrites,hydrocarbons, solvents, pesticides, and vinyl chloride. Thorotrast (colloidal thorium dioxide) isan angiographic medium that was used in the 1930s that emits high levels of long-lastingradiation and has been associated with hepatic fibrosis, angiosarcoma, cholangiosarcoma, andHCC. Associations with inherited metabolic liver diseases, such as hereditary hemochromatosis,a1 -antitrypsin deficiency, and Wilsons disease, have also been implicated as risk factors forHCC. Associations with hormonal manipulations, such as the use of OCPs and anabolic steroids,have been suggested but are weak and are probably specifically better linked to adenoma and
  3. 3. well-differentiated HCC. Current research is focusing on relationships of HCC with diabetes,obesity, and nonalcoholic fatty liver disease. [38]Clinical PresentationMost commonly, patients presenting with HCC are men 50 to 60 years of age who complain ofright upper quadrant abdominal pain and weight loss and have a palpable mass. In countriesendemic for HBV, presentation at a young age is common and probably related to childhoodinfection. Unfortunately, in unscreened populations, HCC tends to present at a late stage becauseof the lack of symptoms in early stages. Presentation at this advanced stage is often with a vagueright upper quadrant abdominal pain that sometimes radiates to the right shoulder. Nonspecificsymptoms of advanced malignancy such as anorexia, nausea, lethargy, and weight loss arecommon. Another common presentation of HCC is hepatic decompensation in a patient withknown mild cirrhosis or even in patients without previously recognized cirrhosis.On rare occasions, HCC can present as a rupture with the sudden onset of abdominal painfollowed by hypovolemic shock secondary to intraperitoneal bleeding. Other rare presentationsinclude hepatic vein occlusion (Budd-Chiari syndrome), obstructive jaundice, hemobilia, or feverof unknown origin. Less than 1% of cases of HCC present with a paraneoplastic syndrome, mostcommonly hypercalcemia, hypoglycemia, and erythrocytosis. Small, incidentally noted tumorsare becoming a more common presentation because of the knowledge of specific risk factors,screening programs for diagnosed HBV or HCV infection, and the increasing use of high-qualityabdominal imaging. [47] [48]DiagnosisRadiologic investigation is a critical part of the diagnosis of HCC. In the past, liver radioisotopescans and angiography were common methods of diagnosis, but ultrasound, CT, and MRI havereplaced these studies. Ultrasound plays a significant role in screening and early detection ofHCC, but definitive diagnosis and treatment planning rely on CT and MRI. Contrast-enhancedCT and MRI protocols aimed at diagnosing HCC take advantage of the hypervascularity of thesetumors, and arterial phase images are critical to adequately assess the extent of disease. CT andMRI also evaluate the extent of disease in terms of peritoneal metastases, nodal metastases, andextent of vascular and biliary involvement. Detection of bland or tumor thrombus in the portalvenous system is also very important and can be done with any of the above modalitiesAFP measurements can be very helpful in the diagnosis of HCC. An AFP level greater than20ng/mL is noted in about three fourths of documented cases of HCC. False-positive elevationsof serum AFP can be seen in inflammatory disorders of the liver, such as chronic active viralhepatitis. Specificity and positive predictive values of AFP improve with higher cutoff levels(e.g., 400ng/mL), but at the cost of sensitivity. With the improvements in imaging technologyand the ability to detect smaller tumors, AFP is largely used as an adjunctive test in patients withliver masses. In fact, a hypervascular mass consistent with HCC combined with an AFP higherthan 400ng/mL is diagnostic. AFP levels are particularly useful in monitoring treated patients forrecurrence after normalization of levels. [37]
  4. 4. Percutaneous needle biopsies of liver lesions suspected of being HCC are only necessary inpatients who are being considered for nonoperative therapies. Patients with appropriate riskfactors and suggestive radiology (with or without an elevated AFP) who are candidates forpotentially curative surgical therapy do not require preoperative biopsy. Percutaneous fine-needle aspiration of HCC does run a small risk of tumor cell spillage (estimated to be ∼1%) andrupture or bleeding (especially in cirrhotic livers and subcapsular tumors).After the diagnosis of HCC has been made, the patient must be staged in order to develop anappropriate treatment plan. Most patients with HCC have two diseases, and survival is as muchrelated to the tumor as it is to cirrhosis. Staging, therefore, includes an extent of disease workupas well as an extent of cirrhosis workup.In assessing the extent of disease, the common sites of metastases must be considered. HCClargely metastasizes to the lung, bone, and peritoneum, and the preoperative history focuses onsymptoms referable to these areas. Extent of disease in the liver, including macrovascularinvasion and the presence of multiple liver masses, must also be considered. Cross-sectionalabdominal imaging, including arterial-phase images (discussed earlier), yields information onextent of disease in the liver as well as on peritoneal disease. A preoperative chest x-ray ismandatory and is followed with CT if any abnormalities are present. Routine bone scans are notperformed unless there are suggestive symptoms or signs.Assessment of liver function is absolutely critical in considering treatment options for a patientwith HCC. Liver resection is considered the treatment of choice for HCC, and the risk forpostoperative liver failure and death must be considered. This risk is related to the degree ofcirrhosis, the amount of liver resected (functional liver reserve), and the regenerative response.Other successful treatments are available for HCC, such as ablative techniques, embolizationtechniques, and liver transplantation, and therefore, a complete assessment of tumor and liverfunction must ensue. A number of assessments of liver function are available and are describedin an earlier section. Generally, they are divided into a clinical assessment and functional tests.Many clinical assessment schemes are described (see earlier), but most commonly, Childs status(as modified by Pugh) is used. Childs C patients are not candidates for resectional therapy,whereas Childs A patients can usually tolerate some extent of liver resection. Many considerChilds B patients candidates for operation, but they are generally borderline, and therapy mustbe individualized. Outside of scoring systems, it has been recently demonstrated that significantportal hypertension regardless of biochemical assessments is highly predictive of postoperativeliver failure and death. Portal hypertension can be assessed directly through hepatic vein wedgepressures but is usually obvious on high-quality imaging in the form of splenomegaly, cirrhotic-appearing liver, and varices. Blood work usually demonstrates marked cytopenias, typicallythrombocytopenia. Functional tests of liver function are well described (see earlier) but are notroutinely used in most Western centers because the results of studies evaluating predictive valuehave been mixed.Staging laparoscopy has recently been employed as a staging tool in HCC and spares about onein five patients a nontherapeutic laparotomy. Laparoscopy yields additional information aboutextent of disease in the liver, extrahepatic disease, and cirrhosis. The yield of laparoscopy isdictated by the extent of disease and is only selectively employed. The presence of clinically
  5. 5. apparent cirrhosis, radiologic evidence of vascular invasion, or bilobar tumors increased the yieldto 30%, whereas without these factors, the yield is 5%.A number of staging systems for HCC exist, but none has ever been shown to be particularlysuperior, and they probably depend on the specific population being staged and the etiology ofHCC in that particular population. The TNM staging system is not routinely used for HCC; itdoes not accurately predict survival because it does not take liver function into account. TheOkuda staging system is an older but simple and effective system that takes into account liverfunction and tumor-related factors. It adds up a single point for the presence of tumor involvingmore than 50% of the liver, presence of ascites, albumin less than 3 g/dL, and bilirubin morethan 3 mg/dL and reliably distinguishes patients with a prohibitively poor prognosis from thosewith potential for long-term survival. The most well-validated staging system is the Cancer ofthe Liver Italian Program (CLIP), which was rigorously developed and has been prospectivelyvalidated ( Table 52-7 ). An example of a scoring system that is probably population specific isthe Chinese University Prognostic Index (CUPI), which takes into account TNM stage,symptoms, ascites, and AFP, bilirubin, and alkaline phosphatase levels and appears to largelyapply to HBV-related HCC in ChinaPathologyHistologically, HCC is graded as well, moderately, or poorly differentiated. The grade of HCC,however, has never been shown to accurately predict outcome. Grossly, the growth patterns ofHCC have been classified in a number of ways. The most useful scheme divides HCC into threedistinct growth patterns that have a distinct relationship to outcome. This type of HCC isconnected to the liver by a small vascular stalk and is easily resected without sacrifice of asignificant amount of non-neoplastic liver tissue. The hanging type of HCC can grow tosubstantial size without involving much normal liver tissue. The pushing type of HCC is welldemarcated and often contains a fibrous capsule. It is characterized by growth that displacesvascular structures rather than invading them. The pushing type of HCC is usually resectable.The last type is called the infiltrative type of HCC and tends to invade vascular structures even ata small size. Resecting the infiltrative type is often possible, but positive histologic margins arecommon. Small tumors less than 5 cm in size usually do not fall into any of these groups and areoften discussed as a separate entity. Lastly, HCC can present in a multifocal manner. Most HCCsprobably start as a single tumor, but ultimately multiple satellite lesions can develop secondaryto portal vein invasion and metastases. Multifocal tumors throughout the liver probably representthe end stage of HCC with multiple metastases and multiple primary tumors. [34]TreatmentThere are a large number of treatment options for patients with HCC, reflecting the heterogeneityof this disease as well as the lack of a proven superior treatment except for complete resection (Table 52-8 ). Deciding on a treatment regimen for any one patient must take into considerationthe stage of malignancy, the condition of the patient, the condition of the liver, and theexperience of the treating physicians.Complete excision of HCC either by partial hepatectomy or by total hepatectomy andtransplantation is the treatment of choice when possible because it has the highest chance of
  6. 6. long-term survival. In general, however, only 10% to 20% of patients are considered to haveresectable disease. Historically, mortality rates for partial hepatectomy ranged from 1% to 20%,but if performed in healthy patients without advanced cirrhosis, most modern series have amortality rate less than 5%. Advances in surgical technique have allowed the development oflimited segmental resections when appropriate, which preserves functional liver and improvesearly postoperative recovery. Selection of the appropriate patient for resection is critical andmust take into account the condition of the liver as well as the extent of disease. Patients withChilds B or C cirrhosis or portal hypertension do not tolerate resection. The volume of the futureliver remnant (FLR) is also an important consideration and is associated with postoperativecomplications and mortality. Preoperative portal vein embolization is an effective strategy toincrease the volume and function of the FLR and is used liberally in patients with Childs Acirrhosis being considered for a major resection with a small FLR. The overall postresectionsurvival rates for HCC are 58% to 100% at 1 year, 28% to 88% at 3 years, 11% to 75% at 5years, and 19% to 26% at 10 years. These results obviously depend on the stage of the tumor aswell as the degree of cirrhosis in particular series, but give a sense of the possibilities. A varietyof prognostic factors predictive of survival after resection have been identified, but none areuniversally agreed on. The most commonly cited negative prognostic factors are tumor size,cirrhosis, infiltrative growth pattern, vascular invasion, intrahepatic metastases, multifocaltumors, lymph node metastases, margin less than 1 cm, and lack of a capsule. The best outcomesare found in patients with single small tumors, but size alone does not contraindicate resection.Multifocal tumors and major vascular invasion are generally associated with a poor outcome, butsome groups advocate resection in highly selected patients. [47] [49] [50]Theoretically, liver transplantation is the ideal treatment for HCC because it addresses both theliver dysfunction and the HCC. The limitations of transplantation are the need for chronicimmunosuppression as well as the lack of organ donors. There is a growing interest in the use ofpartial hepatectomy from live donors, which addresses the latter point but remains a somewhatcontroversial approach. Early series of transplantation for HCC had high recurrence rates andrelatively poor long-term survival. This has largely been attributed to the fact that most of thesepatients were being transplanted for advanced disease. Refinements in patient selection, namely,patients with single tumors less than 5 cm or multiple tumors no more than three in number and 3cm in size have resulted in improved outcomes. Long-term survival rates in recent years withmore stringent selection criteria have ranged from 50% to 85%. Recent studies have begun toexpand the indications for liver transplantation without a major effect on long-term survival butlikely with an increase in overall recurrence rates. Comparing results of resection totransplantation is difficult, and the two are viewed as complementary rather than competitive.Patients with advanced cirrhosis (Childs B and C) and early-stage HCC are considered fortransplantation, whereas those with Childs A cirrhosis have similar results with transplantationand resection and should probably undergo resection. [40]A number of nonsurgical local ablative therapies are available for the treatment of small tumors.Percutaneous ethanol injection (PEI) is a useful technique for ablating small tumors. The tumoris killed by a combination of cellular dehydration, coagulative necrosis, and vascular thrombosis.Most tumors less than 2 cm in size can be ablated with a single application of PEI, but largertumors may require multiple injections. Long-term survival after PEI for tumors less than 5 cmhas been reported to range from 24% to 40%, but no randomized trials have compared PEI to
  7. 7. resection. Percutaneous injection of acetic acid is a technique similar to PEI but has strongernecrotizing abilities, making it more useful in septated tumors. [41]Thermal ablative techniques that freeze or heat tumors to destroy them have become verypopular in recent years. Cryotherapy uses a specialized cryoprobe to freeze and thaw tumor andsurrounding liver tissue with resulting necrosis. Cryotherapy is usually performed at laparotomyor laparoscopically but has recently been performed with percutaneous techniques. Oneadvantage is that the ice ball formed is easily monitored with ultrasound. Disadvantages includea heat-sink effect, limiting the utility of freezing near major blood vessels and a relatively highcomplication rate of 8% to 41%. Reported 2-year survival rates for cryoablation of HCC rangefrom 30% to 60%, but no studies comparative to resection exist. Radiofrequency ablation (RFA)uses high-frequency alternating current to create heat around an inserted probe, resulting intemperatures greater than 60°C and immediate cell death. Although initially limited to smallertumors, improvements in technology have created RFA probes reportedly able to ablate tumorsas large as 7 cm. Nonetheless, the efficacy of RFA for HCCs larger than 3 to 5 cm is limited.RFA is also limited by the protective effect of blood vessels and does not ablate well in theseareas. RFA can easily be performed percutaneously with low complication rates, and optimalguidance systems are being developed. Recent trials have suggested that RFA is superior to PEIfor limited HCC for local tumor control but not survival. No long-term data for RFA of HCCexist.[41]Transarterial therapy for HCC is based on the fact that most of the tumors blood supply is fromthe hepatic artery. Hepatic arterial infusion (HAI) chemotherapy using 5-fluorouracil (5-FU)-based compounds, cisplatin, and doxorubicin has been studied in limited numbers. Responserates of 25% to 60% have been reported, but the requirement of a laparotomy to place the pumpand associated hepatic toxicity limits the applicability of this approach to highly selectedpatients.[17] Percutaneous transarterial embolization can induce ischemic necrosis in HCC,resulting in response rates as high as 50% ( Fig. 52-28 ). Attempts to improve the efficacy ofarterial embolization have included adding chemotherapeutic agents (chemoembolization) to theembolization particles and oils such as lipiodol that are selectively taken up by HCC.Randomized trials have not shown chemoembolization to be superior to embolization alone.Seven randomized trials have compared embolization or chemoembolization with conservativemanagement. Two of these trials and a meta-analysis have confirmed an overall survivaladvantage to embolization strategies. The selection of appropriate candidates for embolization isimportant, and treatment is generally limited to patients with preserved liver function andasymptomatic multinodular tumors without vascular invasion. Poor selection will result in ahigher incidence of treatment-induced liver failure, offsetting the potential benefits.External-beam radiation therapy (EBRT) has a limited role in the treatment of HCC, althoughoccasional dramatic responses are seen. EBRT is limited by damage to normal liver parenchymaand to surrounding organs, but newer methods of conformal radiotherapy and breath-gatedtechniques are improving the utility of this treatment modality. Intra-arterial injections of iodine-131 with lipiodol or yttrium-90 in glass microspheres have been used to deliver localizedradiation to HCC with reports of dramatic response rates. Transarterial radiotherapy ispotentially promising for HCC as primary therapy or as adjuvant therapy.
  8. 8. Systemic chemotherapy with a variety of agents has been ineffective for the treatment of HCCand has a minimal role in the treatment of HCC. Response rates are generally less than 20% andof short duration. Systemic immunotherapy and hormonal therapy have been used in smallnumbers of patients with HCC with some early promising results, but to date have notdemonstrated superiority to standard regimens.With the bewildering number of available treatment strategies for HCC, it is no surprise thatcombinations of therapies and adjuvant or neoadjuvant strategies in conjunction with resectionhave been attempted. Two randomized trials have demonstrated a survival benefit to specificadjuvant strategies after resection of HCC. The first is the use of the retinoid polyprenoic acid,and the second is transarterial iodine-131 lipiodol treatment. Further studies and larger trials areawaited to confirm these promising strategies.Distinct Variants of HCCFibrolamellar HCC (FHCC) is a variant of HCC with remarkably different clinical features thatare summarized in Table 52-9 . This tumor generally occurs in younger patients without a historyof cirrhosis. The tumor is usually well demarcated and encapsulated and may have a centralfibrotic area. The central scar can make distinguishing this tumor from FNH difficult.Histologically, FHCC is composed of large polygonal tumor cells embedded in a fibrous stromaforming lamellar structures ( Fig. 52-29 ). FHCC does not produce AFP, but is associated withelevated neurotensin levels. In general, FHCC has a better prognosis than HCC. This is likelyrelated to high resectability rates, lack of chronic liver disease, and a more indolent course.Long-term survival can be expected in about 50% to 75% of patients after complete resection,but recurrence is common and occurs in at least 80% of patients. The presence of lymph nodemetastases predicts a worse outcome. Resection of lymph node metastases and recurrent diseasehas been advocated because of a lack of alternative therapy and the possibility of long-termsurvival.[37]Rarely, HCC can present as a mixed hepatocellular-cholangiocellular tumor, with cellulardifferentiation of both types present. Whether this is two separate tumors growing into each otheror mixed differentiation of the same tumor is not known. These mixed tumors tend to take on aworse prognosis than standard HCC. A clear cell variant of HCC exists where the cells contain aclear cytoplasm. These tumors can resemble renal cell neoplasms. The clear cell variant mayhave a better prognosis than standard HCC, but this is a subject of debate. A pleomorphic orgiant cell variant of HCC has been reported. Cells in this type are multinucleated, pleomorphic,and large and likely originate from primary hepatic cells. Some HCCs show evidence ofsarcomatoid differentiation and are referred to as a sarcomatoid variant or carcinosarcoma.These tumors tend not to produce AFP and have a higher incidence of metastases at presentation.[44] [47]Childhood HCC is a distinct entity that comprises almost one fourth of pediatric liver tumors, butrarely occurs in infancy. Viral hepatitis is associated with childhood HCC in Asia, but less so inthe United States. Inherited metabolic liver diseases (discussed earlier) are often associated withchildhood HCC. As in adult HCC, complete resection is the only potentially curative treatment.
  9. 9. There is a high incidence of multifocality, vascular invasion, and extrahepatic metastasesresulting in relatively poor long-term survival rates of 10% to 20%.[36]Intrahepatic CholangiocarcinomaCholangiocarcinoma is an uncommon neoplasm with an incidence of 1 to 2 per 100,000 in theUnited States and can develop anywhere along the biliary tree from the ampulla of Vater to theperipheral intrahepatic bile ducts. Most (40%-60%) of these tumors involve the biliaryconfluence (Klatskins tumor), but about 10% emanate from intrahepatic ducts, presenting as aliver mass. Intrahepatic cholangiocarcinoma (IHC) is the second most common primary hepaticneoplasm and has also been referred to as peripheral cholangiocarcinoma or cholangiolarcarcinoma. Studies on the incidence and natural history of IHC have been confused by the factthat many series include mixed hepatocellular-cholangiocarcinoma (discussed previously).Additionally, it is likely that, in the past, many of these tumors were mistaken for metastaticadenocarcinoma because biopsy is unable to differentiate the two. Historically, the most commonrisk factors for the development of cholangiocarcinoma (all types) were primary sclerosingcholangitis, choledochal cyst disease, and recurrent pyogenic cholangitis. Recent epidemiologicevidence has now linked IHC to HCV infection, HIV infection, cirrhosis, and diabetes. Recentincreases in the diagnosis of IHC in the United States are likely related to better recognition ofthe disease and perhaps the rise in HCV infections in the 1960s and 1970s.The clinical presentation of IHC is similar to HCC. The most common symptoms are right upperabdominal pain and weight loss. Jaundice occurs in about one fourth of patients. In recent years,patients are more often presenting with incidentally found liver masses on cross-sectionalimaging. Unlike HCC, the AFP level will be normal, although CEA levels can be elevated insome cases. Most often, a search for a primary tumor with endoscopy and imaging of the chestwill ensue and will not yield any information. If a biopsy has been performed, it is often read asadenocarcinoma. On CT and MRI, IHC is seen as a focal hepatic mass that may be associatedwith peripheral biliary dilation. The mass typically has peripheral or central enhancement oncontrast-enhanced scans. Intrahepatic metastases, lymph node metastases, and growth along thebiliary tree are commonly encountered.Complete resection is the treatment of choice for IHC. Resectability rates generally range from60% to 90%, and long-term survival in unresected patients is rare. If completely resected, 3-yearsurvival rates range from 16% to 61%, and 5-year survival rates range from 24% to 44%. Factorsassociated with a poor outcome include intrahepatic metastases, lymph node metastases, vascularinvasion, and positive margins. There is little known about the utility of radiation andchemotherapy for IHC due to the rarity of the disease, and their use is not routine. Chemotherapyis largely considered ineffective for IHC, but improvements in chemotherapy for othergastrointestinal tumors will hopefully translate into improved outcomes. Regional hepatic arterychemotherapy is under study and may be a promising approach. [42]Other Primary Malignant NeoplasmsHepatoblastoma is the most common primary hepatic tumor of childhood. There are about 50 to70 new cases per year in the United States. Rare cases of adult hepatoblastoma have beenreported, but overall, the median age of presentation is 18 months, and almost all cases occur
  10. 10. before the age of 3 years. Recently, hepatoblastoma has been associated with the familialpolyposis syndrome. There are a number of histologic subtypes, but in general, the tumor isderived from fetal or embryonic hepatocytes, and there are often mesenchymal elements present.Most often, this tumor presents as an asymptomatic mass. Mild anemia and thrombocytosis arecommonly found at presentation. Serum AFP levels are elevated in 85% to 90% of patients andcan serve as a useful marker for therapeutic response. Most studies support the use ofchemotherapy followed by resection, and survival appears to be dependent on completeresection. Chemotherapy can serve to downstage tumors, facilitating resection. In patientswithout metastatic disease or the anaplastic variant, long-term survival rates of 60% to 70% canbe expected with complete resection. Interestingly, 50% of patients with pulmonary metastasescan be cured with resection of the hepatic tumor and chemotherapy or resection of the pulmonarymetastases. [44] [46]A variety of sarcomas can rarely present as primary liver tumors but must always be consideredmetastatic lesions until proven otherwise. Angiosarcoma is probably the best described primaryhepatic sarcoma because of its well-known association with vinyl chloride or Thorotrastexposure. Angiosarcoma typically presents as multiple hepatic masses and can present inchildhood. Long-term survival is uncommon with primary hepatic angiosarcoma. A variety ofother sarcomas, including leiomyosarcoma, malignant fibrous histiocytoma, embryonic sarcoma,and primary hepatic rhabdoid tumor, have been described but are rare. The latter two lesions aretypically seen in children.Non-Hodgkins lymphoma can present primarily in the liver with or without extrahepatic disease.Primary hepatic lymphoma is treated like lymphoma elsewhere in the body if the diagnosis canbe made before a liver resection. Primary hepatic neuroendocrine tumors or carcinoid tumorshave been described but are probably extremely rare. Distinguishing the rare primary hepaticneuroendocrine tumor from a metastatic lesion can be difficult because the extrahepatic primarytumor can be radiologically occult for many years, and the liver is the most common site ofmetastases. Malignant germ cell tumors of the liver, including teratomas, choriocarcinomas, andyolk sac tumors, are very rare and are principally described in children. Epithelioidhemangioendothelioma of the liver is a rare malignant vascular tumor that presents with multiplebilateral hepatic masses. Extrahepatic metastases occur in about one fourth of patients, andclinical behavior is unpredictable. Most patients ultimately die of liver failure, but cases ofsuccessful transplantation have been reported.