TUMORS LIVER AND TUMOR-LIKE CONDITIONS David N. Lewin, MD Robbins Basic Pathology (7th edition): pp 625 - 627 OBJECTIVES: I. Know the benign tumors and proliferations and their association with birth control pills/steroid use. Be intimately familiar with the etiology, epidemiology, pathogenesis, pathology, and natural history of hepatocellular carcinoma. Know the various microscopic features seen in hepatocellular carcinoma. Know the pathology of cholangiocarcinoma with an eye on its comparison to hepatocellular carcinoma. Know the pathology of hepatoblastoma, angiosarcoma, and metastatic tumors to the liver. BENIGN PROLIFERATIONS AND TUMORS: There are several types of benign tumors or tumor-like conditions that occur in the liver. Years ago, these were usually incidental findings at autopsy. Now, CT and MRI imaging techniques routinely find these masses. As such, these masses require differentiation from malignant tumors. A. Cavernous Hemangiomas: Most common benign tumor. Predominately seen in females less than 40 years of age. Usually discrete red to dark blue nodules located beneath the capsular surface. Microscopically composed of endothelial-lined blood-filled spaces. B. Nodular Hyperplasias a. Focal Nodular Hyperplasia (FNH): Yellow-tan, discrete but poorly encapsulated nodules up to several centimeters in diameter. On section, there is usually a central scar with fibrous strands radiating to the periphery. Within these strands are numerous bile ducts with a dense lymphocytic infiltrate. The remaining cells making up the hyperplastic nodules are hepatocytes which may be lipid or glycogenrich or otherwise normal. Thought to be associated with arteriovenous malformation. Usually found more often in women and there is a reported, but controversial association with oral contraceptives or other steroid use. b. Nodular Regenerative Hyperplasia: Affects the entire liver with roughly spherical nodules, in the absence of fibrosis. The architecture of the liver is abnormal and this is associated with portal hypertension. Similar to FNH, the underlying cause is thought to be vascular (i.e. Vasculitis). C. Liver Cell Adenoma: Yellow-tan, discrete but poorly encapsulated nodules up to several centimeters in diameter (sound familiar?). Microscopically composed mostly of normal-appearing hepatocytes which occasionally vary in both cell and nuclear size. Of note is the presence of abnormal, dilated sinusoids as well as the absence of bile ducts. Usually found more often in young women on oral contraceptives. Tumor may even regress after cessation of pill use. Besides being confused occasionally with hepatocellular carcinoma, subcapsular adenomas may
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David N. Lewin, MD Liver Tumors rupture, especially during pregnancy, causing massive intraperitoneal hemorrhage. These are not the precursor lesion of hepatocellular carcinoma. DIFFERENTIATING FEATURES Focal Nodular Hyperplasia Central scar with radiating fibrous septae Bile ducts and lymphocytic infiltrate in septae Sinusoids inconspicuous Usually clinically silent Questionable association with oral contraceptives II. Liver Cell Adenoma No scar or septae No bile ducts or infiltrate Abnormally dilated sinusoids May rupture Strong association with oral contraceptives
MALIGNANT LIVER TUMORS Five types of cancers found in liver will be discussed although many more exist: A. Hepatocellular Carcinoma (HCC, Liver Cell Carcinoma, Hepatoma): Makes up 90-95% of all primary liver cancers. 1. Epidemiology, Etiology, and Pathogenesis a. The global distribution is closely and rather intimately linked to the distribution of hepatitis B (HBV) infection. 1) This relationship is directly related to chronic states such as chronic active hepatitis and carrier states. This allows for the incorporation of the HBV genome into the hepatocyte with subsequent transformation to hepatocellular carcinoma. 2) In Third World nations (Africa and Southeast Asia), the incidence of HBV is extremely high. As such, hepatocellular carcinomas account for up to 40% of all cancers! 3) Also in these high incident areas, HBV infection usually occurs at a much younger age due to maternal-fetal transmission. Therefore, people in this area develop HCC at a much younger age. There is typically at least a 20 year latency to develop carcinoma. Up to 50% of these patients are not cirrhotic. b. Hepatocellular carcinoma is also closely associated with cirrhosis, especially post-necrotic type, which in turn is associated with HBV infection. However, in areas where HBV infection is low such as in the US, the association with cirrhosis is strong. In areas where HBV is high, the association between HCC and cirrhosis is still there, but not as strong.
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Liver Tumors c. Other factors such as aflatoxin B1, produced by Aspergillus flavus, and oral contraceptives have been implicated in the development of HCC. It should be stressed that the association with oral contraceptives is rather slim. d. Pathogenesis: i. Increased cell division ii. Clonal viral DNA integration iii. Integration causes increased genomic instability iv. HBV X protein is a transactivator of cellular and viral proteins v. Aflotoxin activated in the hepatocyte and integrates into the DNA. P53 is a susceptible site. Pathology: a. Gross: May be either unifocal, multifocal, or diffuse. The tumor may be green from bile staining. There may be massive liver enlargement and there is a strong tendency for vascular invasion. b. Micro: Histologic patterns run the spectrum from well differentiated tumors which look like hepatocytes to highly anaplastic forms with wild-looking cells to spindle forms which may be confused with a sarcoma. Other features may be present: 1) Mallory's alcoholic hyaline by routine histology 2)* Bile pigment within the tumor cells 3) Hepatitis B surface antigen by immunohistochemistry 4) Alpha-1-antitrypsin by immunohistochemistry in 75% of cases 5) Alpha-fetoprotein (AFP) by immunohistochemistry in 60-80% of cases 6)* Bile canaliculi formation by electron *Most microscopy. reliable features c. Fibrolamellar Carcinoma: A distinctive variant of HCC with a much better prognosis. Grossly, tumor is usually a solitary mass that on section resembles to some degree focal nodular hyperplasia. Microscopically composed of large plump cells separated into nests and cords by fibrous strands (scirrhous tumor). Hyalin globules and PAS-positive material may be found in the cytoplasm. Clinical Course: a. Patients may have symptoms and signs of not only a liver mass but also of hepatitis and cirrhosis. These include vague abdominal pain, malaise, fatigue, weight loss, jaundice, fever and GI bleeding. b. Serum AFP levels are elevated in 60-75% of cases. Causes of false positives include: Yolk sac tumors Cirrhosis Massive liver necrosis Chronic hepatitis Pregnancy Fetal distress/death Fetal neural tube defects page 105
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Liver Tumors c. Natural history: Death usually within six months from cachexia, massive GI bleeding or liver failure. d. Vaccinating at-risk population for hepatitis B will hopefully reduce HCC worldwide. Cholangiocarcinoma: A cancer comprised of malignant bile duct epithelium. Virtually makes up remainder of primary liver cancers. None of the risk factors for the development of HCC apply to cholangiocarcinoma. Known risk factors include exposure to thorotrast, primary sclerosing cholangitis (PSC) and invasion of the bile ducts by liver flukes--Opisthorchis sinensis. 1. Gross: Similar to HCC, but tumor is never bile-stained (bile duct epithelium does not synthesize bile). Also, there may be a dense desmoplasia resulting in a gritty texture. 2. Micro: Usually well differentiated tumors forming glands and tubules. As mentioned earlier, often there is a dense desmoplasia. Mucus, but not bile, may be found in individual cells as well as in the lumina of glands. Hepatoblastoma: "Liver cancer of infants" Most common hepatic tumor of infants, however one of the least common tumors in infancy (1-5%). Presents with an abdominal mass and usually has an elevated AFP (8090%) Two variants: 1. Epithelial type composed of small hyperchromatic fetal hepatocytes 2. Mixed type made up of more mature-appearing liver cells mixed with the fetal-appearing cells. Mixed in with all of this are mesenchymal elements consisting of skeletal muscle and/or cartilage and/or bone. Unless surgically corrected, both types are uniformly fatal in a few years. Angiosarcoma: Similar to angiosarcomas found elsewhere. Highly aggressive cancers of endothelial cells that usually kill within one year. Associated with exposure to thorotrast, vinyl chloride and arsenic with a long (decades) latency. Metastatic Tumors: By far the most common cancer found in the liver is a metastatic tumor. Any cancer may metastasize to liver, but favored primary sites include breast, lung, and colon. There are usually multiple nodules with a tendency towards central ischemic necrosis as the implant outgrows its blood supply. Of note is the often massive involvement of the liver by tumor before any clinical signs are noted.
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David N. Lewin, MD REVIEW QUESTIONS
Liver Tumors
_____1. Exposure to which of the below will increase the risk of developing angiosarcoma? A. B. C. D. Vinyl chloride Thorotrast Arsenic All of the above
_____2. The development of hepatocellular carcinoma: A. B. C. D. Is associated with hepatitis B infection Is associated with aflatoxin B1 exposure Is associated with cirrhosis All of the above
_____3. Focal nodular hyperplasia: A. B. C. D. May rupture and cause a severe hemoperitoneum Has a strong association with ste...