Thomas D. Schiano, MD and M. Isabel Fiel, MD
What is the differential diagnosis of an elevated alpha-fetoprotein (AFP) in a patient with known liver disease?
Serum AFP levels may be elevated in patients with various liver diseases, most commonly, viral hepatitis. Levels exceeding 1000 ng/mL may be seen in the presence of fulminant hepatitis, teratomas, or in yolk sac/testicular tumors. In patients with chronic hepatitis C virus (HCV), levels may be as high as 300 ng/mL in the absence of hepatocellular carcinoma (HCC). Levels > 300–500 ng/mL are almost always consistent with HCC.
True/False: Many patients with HCC may have normal AFP levels.
What variant of HCC is being demonstrated in the figure below?
The fibrolamellar variant of HCC. Tumor cells are large and contain abundant eosinophilic cytoplasm. This type of liver tumor is characterized by prominent lamellated fibrous tissue (see arrow in Figure 54-1) that dissects through the mass.
True/False: The fibrolamellar variant of HCC most commonly manifests with an elevated AFP.
False. Patients with the fibrolamellar variant of HCC are almost always young, female, and are serum AFP-negative. They do, however, have increased serum concentrations of vitamin B12 binding proteins and neurotensin.
True/False: In a female patient with cirrhosis and ascites, the presence of an elevated CA-125 level strongly suggests the presence of an ovarian tumor.
False. Although the CA-125 level is elevated in several benign and malignant neoplasms, most commonly ovarian carcinoma, it may be elevated in the presence of ascites from any cause, even in the absence of malignancy.
True/False: An elevated carcinoembryonic antigen (CEA) level in a patient with cirrhosis strongly suggests the possibility of a colonic neoplasm.
False. Minor elevations of CEA are seen in many patients with HCC and in cirrhosis, in general.
What carcinogens have been linked to the development of angiosarcoma of the liver?
Previous exposure to Thorotrast, vinyl chloride, arsenic, radium, and inorganic copper.
What are the most common modes of presentation of a hepatocellular adenoma?
• Intraabdominal catastrophe due to hemorrhage.
• Right upper quadrant abdominal pain.
• Discovery of a palpable liver mass.
• Incidental discovery of a mass on hepatic imaging performed for other reasons.
From what blood vessel does HCC receive its entire blood supply?
The hepatic artery (the vessel used in therapeutic embolization and chemoembolization) serves as the main blood supply of HCC.
What complications may occur following chemoembolization of an HCC?
Many patients experience marked right upper quadrant abdominal pain, nausea, vomiting, and high fevers. Additionally, all patients develop transient elevations of liver tests and a minority may develop liver abscess and liver failure. Portal vein thrombosis, cholecystitis, and pancreatitis may also occur.
What unique complications occur with hepatic arterial infusion of chemotherapy for colon cancer metastatic to the liver?
Gastroduodenal ulceration and inflammation may occur in up to 50% of patients and appears to be related to exposure of the gastroduodenal mucosa to high concentrations of the chemotherapeutic agents. Rarely, patients may develop sclerosing cholangitis-like biliary stricturing that leads to chronic cholestasis and secondary biliary cirrhosis.
True/False: Chemoembolization prolongs survival in HCC.
False. Chemoembolization is a form of loco-regional therapy for HCC. Gelfoam or other particles along with infusion of chemotherapy are injected into the hepatic arterial system feeding the tumor, producing a temporary reduction in blood flow and more direct exposure to the chemotherapy. Although studies have regularly shown significant reduction in the size of large tumors, there is no consistent increase in patient survival with chemoembolization.
True/False: In the setting of HCC, ascitic fluid cytology almost always reveals malignant cells.
False. Ascitic fluid cytology is rarely positive in this setting.
Why does Mozambique have the world’s highest incidence of HCC?
The population of Mozambique has a very high incidence of hepatitis B virus (HBV) infection and its soil has one of the world’s highest aflatoxin B1 contents. Aflatoxin is an environmental carcinogen and HBV and aflatoxin exposure appear to act synergistically to increase the risk of HCC.
What is the significance of portal vein thrombosis in a liver transplant candidate with known HCC?
Although portal vein thrombosis may spontaneously occur in the setting of cirrhosis, it may also be due to vascular invasion by the HCC. This would constitute extrahepatic spread of tumor and, thus, preclude liver transplantation (LT).
What nodular liver condition is being shown in the figure and what are its characteristic histologic findings?
Figure 54-2 See also color plate.
The figure demonstrates the gross appearance of focal nodular hyperplasia. The presence of a central fibrous scar with thin fibrous septa radiating outwards and enclosing nodules, ductular reaction, and abnormal thick-walled vessels embedded within the fibrous tissue are the most characteristic histologic findings.
What predisposing factors are associated with the development of cholangiocarcinoma?
Primary sclerosing cholangitis, Caroli’s disease or Caroli’s syndrome, choledochal cysts, chronic hepatolithiasis, recurrent pyogenic cholangitis, and liver fluke (Clonorchis sinensis) infection.
True/False: LT is an accepted treatment for polycystic liver disease.
True. Afflicted patients rarely, if ever, develop complications of portal hypertension and hepatic synthetic dysfunction. However, LT is sometimes needed as a definitive treatment because of the effects on quality of life due to massive hepatomegaly that causes refractory abdominal pain and distention, anorexia, malnutrition, and inanition.
Apart from kidney cysts, do patients with polycystic liver disease have other organ involvement?
Approximately 5% of patients have cysts in other viscera including the pancreas, spleen, uterus, ovaries, and seminal vesicles. There is also an increased incidence of brain aneurysms.
The most common cause of hepatic cysts worldwide is shown in the figure below. What is the diagnosis?
Echinococcosis (hydatid disease). The bottom part of the photo shows a non-staining lamellated membrane. Above it is the nucleated germinal membrane and attached to it is a protoscolex with hooklets.
What are CT scan characteristics of an echinococcal cyst?
Echinococcal cysts are intrahepatic, sharply circumscribed defects with rim enhancement, and usually have calcification within the cyst wall and daughter cysts within them.
What are the complications of hepatic hydatid disease?
Complications include biliary obstruction from compression of large intrahepatic ducts, cholangitis due to rupture into the biliary tract, secondary infection, and anaphylaxis from peritoneal, pleural, or pericardial rupture.
What is the drug of choice to treat an echinococcal infestation?
Albendazole, 400 mg BID with meals for 28 days in three successive cycles with a 2-week rest period between cycles.
What risk is associated with traumatic rupture or surgical excision of an hydatid cyst?
Anaphylaxis. Therefore, appropriate precautions need to be in place.
True/False: The presence of peri-hilar lymphadenopathy in patients with primary sclerosing cholangitis increases the suspicion for a malignancy.
False. Peri-hilar lymphadenopathy is commonly seen in patients with cirrhosis due to hepatitis C and in most forms of cholestatic liver disease even in the absence of a liver neoplasm.
How does a CT scan differentiate between HCC and a hemangioma?
HCC appears hyperdense on CT scan with preferential filling during the arterial phase of a dynamic scan, whereas a hemangioma enhances from the periphery inward with additional and persistent enhancement on delayed scans.
What is Stouffer’s syndrome?
Stouffer’s syndrome refers to the constellation of constitutional symptoms and nonspecific elevation of liver enzymes in a patient with renal cell carcinoma, even in the absence of metastatic disease to the liver.
What are the most common sites of metastatic spread in patients with HCC?
In decreasing order of frequency: lung, portal vein, hepatic vein, regional lymph nodes, bone, bone marrow, and peritoneum.
What are the most common tumors metastasizing to the liver?
Carcinomas of the lung, breast, colon, and pancreas account for the overwhelming majority of hepatic metastases in adults, whereas neuroblastoma, Wilm’s tumor, and rhabdomyosarcoma are most common in the pediatric age group.
What is a Klatskin tumor?
Also termed hilar cholangiocarcinoma, Klatskin tumor occurs at the common bile duct, the main hepatic duct, and at the bifurcation of the right and left main hepatic ducts.
What is Caroli’s disease?
Caroli’s disease (type 5 biliary cyst) is a congenital malformation characterized by multifocal intrahepatic bile duct dilation and recurrent episodes of cholangitis. When associated with congenital hepatic fibrosis, it is termed Caroli’s syndrome. Despite the absence of cirrhosis, patients may suffer from portal hypertension.
What gastrointestinal and liver complications may occur in a patient with Caroli’s disease with congenital hepatic fibrosis (ie, Caroli’s syndrome)?
Portal hypertensive complications such as ascites and variceal bleeding, with the latter occurring much more commonly. Repeated episodes of cholangitis may also occur.
What renal abnormality is associated with Caroli’s disease?
Medullary sponge kidney is present in 60%–80% of cases.
What is Kasabach–Merritt syndrome?
Thrombocytopenia related to a giant cavernous hemangioma.
The most common benign hepatic tumor is shown in the figure. What is the diagnosis?
The hemangioma, usually an incidental finding, is detected in about 1%–2% of the entire population. The majority of hemangiomas are small. When > 4 cm, they are termed cavernous hemangioma. Figure 54-4 shows cut surface of a partial hepatectomy specimen that shows a red brown spongy mass (outlined by white arrows).
What nodular liver condition is shown in the following figure?
Nodular regenerative hyperplasia (NRH) is characterized by diffuse nodularity of the liver in the absence of fibrosis. It is not a tumor but rather a condition that may be associated with a systemic medical condition such as hematologic disorders or collagen vascular disease, as well as the use of certain medications such as ddI, azathioprine, and certain chemotherapeutic agents. Patients may present with complications of portal hypertension. In addition to the nodular configuration being highlighted by the reticulin stain, there is reverse lobulation wherein the portal tract is found in the center of the nodule. This is in contrast to that of a normal lobule where the portal tracts are found at the periphery, and the terminal hepatic venule is present at the center.
Sorafenib is the treatment of far advanced unresectable HCC. What are some of its side effects?
Systolic hypertension, GI symptoms such as nausea, vomiting, diarrhea, and anorexia, and severe skin rash typically involving the extremities.
What clinical features are associated with hepatic adenomas?
These lesions tend to occur in women of reproductive age who have history of oral contraceptive use. Adenomas may also be seen in people who are using anabolic steroids and in patients with certain metabolic liver disease (eg, von Gierke’s).
True/False: PET scanning is a sensitive and specific imaging modality for the detection of HCC.
Describe the Milan criteria that are used for patients being listed for LT in the United Network for Organ Sharing (UNOS) system?
Patients who have a single HCC ≤ 5 cm or no more than three tumors with the largest diameter ≤ 3 cm with no gross vascular invasion or metastasis are prioritized to transplantation in the current model for end-stage liver disease (MELD) system. These patients receive a variance of 22 MELD points with the potential for interval increases every 3 months while on the waiting list.
True/False: Preexisting cirrhosis is a prerequisite for the development of HCC.
False. The presence of HBV infection even in the absence of cirrhosis puts a patient at high risk for the development of HCC. An increasing number of cases of HCC developing in those with hereditary hemochromatosis, nonalcoholic steatohepatitis (NASH), and HCV in the absence of cirrhosis are now being seen.
What is a von Meyenburg complex?
Von Meyenburg complexes are otherwise known as bile duct hamartomas and arise from remnants of embryonic bile ducts. They are typically discovered incidentally, have nonspecific imaging characteristics, and, when multifocal, can simulate (be confused with) metastases or abscesses.
What is the most common malignant primary hepatic tumor in children?
Hepatoblastoma. It may occur sporadically or in association with hereditary syndromes such as familial adenomatous polyposis and Beckwith–Wiedemann syndrome.
What pathological features of HCC predict a poor prognosis?
The presence of gross/macroscopic vascular invasion has a worse prognosis than microvascular invasion. With regards to microvascular invasion, the involvement of many vessels that are large, have thick walls, and are far from the main mass has worse prognosis than microvascular invasion involving small, thin-walled blood vessels present adjacent to the tumor. Poorly differentiated HCC has a worse prognosis than well- or moderately differentiated HCC.
What are some paraneoplastic syndromes associated with HCC?
Secondary polycythemia, thrombocytosis, hypoglycemia, hypercholesterolemia, and, rarely, hypercalcemia.
How common are simple hepatic cysts?
Simple hepatic cysts are thought to be congenital in nature and are present in up to 2.5% of the general population. They are almost always asymptomatic and discovered incidentally.
What is an inflammatory pseudotumor?
Inflammatory pseudotumor is a rare acquired lesion resulting from an inflammatory infectious process. Histologically, it is composed of a mixed population of inflammatory cells such as plasma cells, lymphocytes, and eosinophils in a background of fibrosis. These lesions may be solitary or multiple, are usually well circumscribed, and may spontaneously regress and disappear.
What are the presenting signs of hepatic lymphoma?
The liver is the one of the most commonly involved organs in lymphoma but primary hepatic lymphomas are rare. They may present as a mass lesion, hepatosplenomegaly, liver disease without lymphadenopathy, fulminant liver failure, or with fever and weight loss. Most are of B-cell origin.
True/False: Biliary papillomatosis may be a risk factor for cholangiocarcinoma.
True. Although most often benign, malignant transformation to cholangiocarcinoma can occur. These tumors can be solitary or multiple, occurring along the intrahepatic or extrahepatic biliary tree. They are villous and tend to secrete mucin.
True/False: Dysplastic nodules are precursor lesions for cholangiocarcinoma.
False. These lesions are found to be highly associated with the development of HCC. In particular, the presence of small cell dysplasia and in situ HCC within the dysplastic nodule is often seen in those who have clear-cut HCC elsewhere in the liver.
A patient with advanced HCC develops shortness of breath and evidence of right-sided heart failure. What is the differential diagnosis?
Patients with HCC can be at risk for the development of deep venous thrombosis and the development of pulmonary emboli. HCC may also involve the hepatic veins with thrombus extension into the right atrium leading to heart failure. A similar type of inferior vena cava thrombosis can be seen in renal cell carcinoma.
What is hepar lobatum?
Hepar lobatum is diffuse carcinomatosis of the liver from metastatic tumors and can masquerade as cirrhosis.
• • • SUGGESTED READINGS • • •
Molina EG, Schiff ER. Benign solid lesions of the liver. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s Diseases of the Liver. 8th ed. Philadelphia, PA: Lippincott-Raven; 1999:1245-1268.
Bruix J, Bru C, Llovet JM. Hepatocellular carcinoma. In: Boyer TD, Wright TL, Manns MP, eds. Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 5th ed. Philadelphia, PA: Saunders Elsevier; 2006:1109-1132.
Colombo M, Lencioni R. Benign liver tumors. In: Boyer TD, Wright TL, Manns MP, eds. Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 5th ed. Philadelphia, PA: Saunders Elsevier; 2006:1133-1168.