Introduction
Background
The liver provides a fertile soil in which metastases may become established, not only because of its rich, dual blood supply but also because of humoral factors that promote cell growth. (The blood supply of the liver is exceeded only by that of the lung, in terms of blood flow per minute.) The fenestrations in the sinusoidal endothelium allow a foothold into the space of Disse for tumor emboli arriving via the blood stream.1,2,3
The liver is the second most commonly involved organ by metastatic disease, after the lymph nodes. In Europe and the United States, a focal liver lesion is more likely to represent a metastatic deposit than a primary malignancy. The liver may be the site of metastasis from virtually any primary malignant neoplasm, but the most common primary sites are the eye, colon, stomach, pancreas, breast, and lung. In children, the most common liver metastases are from a neuroblastoma, a Wilms tumor, or leukemia.
Most liver metastases are multiple. In 77% of patients with liver metastases, both lobes are involved; in only 10% of cases is metastasis solitary. Multiple tumors often vary in size; this fact suggests that tumor seeding occurs in episodes. Growing metastases compress adjacent liver parenchyma, causing atrophy and forming a connective tissue rim. Large metastases often outgrow their blood supply, causing hypoxia and necrosis at the center of the lesion.
Approximately 50% of the patients with liver metastases have clinical signs of hepatomegaly or ascites; liver function tests tend to be insensitive and nonspecific.
Several factors influence the incidence and pattern of liver metastases. These include the patient's age and sex, the primary site, the histologic type, and the duration of the tumor. In a few tumor types, such as colonic carcinoma, carcinoid, and hepatocellular carcinoma (HCC), metastasis is confined to the liver. Most tumors that metastasize to the liver, such as breast and lung cancers, spread to other sites at the same time (see Images 1-2).
Liver, metastases. The metastatic cascade in the development of liver metastases.
Liver, metastases. Diagram showing the mechanism of the local-regional spread of colorectal liver metastases.
Some focal lesions may be surgically resectable or treated by means of ablation techniques. Imaging plays a vital role in the diagnosis of liver metastases and in the assessment of the response to treatment. The recognition of a liver lesion as a metastatic focus may significantly influence the patient's treatment and prognosis.
Related eMedicine topics:
Hepatic Carcinoma, Primary
Hepatocellular Carcinoma
Pathophysiology
Common primary sites
Metastasis is the most common neoplasm in an adult liver; the liver is the second most common site for metastatic spread, after the lymph nodes. Analyzing the data from 9700 consecutive autopsies in patients with 10,736 primary cancers, Pickren et al found that liver metastases were present in 41%.4,5 They found that the primary sites most commonly metastasizing to the liver are the eye (77.8%), pancreas (75.1%), breast (60.6%), gallbladder and extrahepatic bile ducts (60.5%), colon or rectum (56.8%), and stomach (48.9%). Gilbert et al reported that the liver is a primary target organ of gastrointestinal (GI) cancers, some urologic cancers, neuroblastomas, some melanomas, and lung cancers.6 In breast cancer, the liver is less often the primary target organ. The liver may be the only organ involved in colorectal primaries, HCCs, and neuroendocrine tumors.
Contribution of the hepatic blood supply and vasculature
The dual blood supply and the microvasculature of the liver significantly contribute to the establishment of liver metastases. Tumor emboli entering the sinusoids through the liver's blood supply appear to be physically obstructed by the Kupffer cells, but if tumor emboli are large, they tend to become lodged in the portal venous branches.
The presence of stasis-damaged endothelium and normally fenestrated endothelium is conducive to the implantation of tumor emboli. By contrast, an intact endothelium prevents the adhesion of tumor emboli. Access to underlying collagen in the space of Disse provides attachment points for cancer emboli arriving at the sinusoid, but not all implanted cancer cells in the space of Disse progress to develop liver metastases. The fenestrations in the sinusoidal lining aids in cancer implantation.
The destruction of liver tissue by cancer cells and their metastases is related to the release of a variety of proteinases from the cancer cells. Tumor emboli leaving the sinusoid move immediately to a subendothelial position or between the plates of liver cells (see Anatomy). Thus, in the early stages of tumor implantation, the tumor cells lie in close proximity to the diffusible nutrients.
Dingemans and Roos,7 Strãuli and Weiss,8 and Rohrlich and Rifkin9 studied the ultrastructural aspects of liver tumor invasion. They found great variation in the patterns of liver invasion for different tumor cells, though the initial tumor implantation is similar in all types of tumor cells.
Factors in the mode of liver invasion
The main factors that dictate the mode of liver invasion by tumor cells are the following: (1) the tendency to retain a round shape, (2) the adhesiveness of different types of tumor cells and their adhesiveness to hepatocytes, (3) the inability of some tumor cells to survive and proliferate in the bloodstream for long periods, (4) the pressure on the surrounding tissues, (5) the formation of tumor cell and hepatocyte junction, (6) tumor cell locomotion, and (7) host tissue destruction by enzymes elaborated by tumor cells.
Pathologic-anatomic characteristics of metastases
The pathologic anatomy of metastases resembles that of the primary tumor. Metastases often show the same degree of vascularity as that of the primary tumor. Most metastases are hypovascular, but some primary tumors characteristically have hypervascular metastases. These include metastases from carcinoids; leiomyosarcomas; neuroendocrine tumors; renal carcinomas; thyroid carcinomas; and choriocarcinomas. Occasionally, cancers of the pancreas, ovary, or breast produce hypervascular metastases.
Blood flow is said to increase relative to the normal parenchyma in all metastases, even hypovascular tumors. Large metastases tend to displace the surrounding vessels, and they may compress or occlude the portal venous branches. However, neovascularity, vascular encasement, and arteriovenous shunting are rare. Large metastases often outgrow their blood supply, causing hypoxia and necrosis at the center of the lesion.
Metastatic tumors of liver may be expansive or infiltrative. They vary in size, shape, vascularity, and growth pattern. They vary because of differences in blood supply, hemorrhage, cellular differentiation, fibrosis, and necrosis. A weak correlation exists between the histologic type and the appearance of metastasis on imaging.
Metastatic carcinoma of the breast and pancreas incite an intense fibrous or sclerosing reaction around the tumor acini, leading to fibrous scar formation. In about 7-15% of patients, tumor thrombi occlude the portal vein, the hepatic vein, or both. In the presence of mucin secretion, necrosis, and phosphate activity, metastases may develop calcification that is detectable radiographically.10,11,12,13
The patterns of blood supply of liver metastases are of considerable clinical importance because a number of diagnostic and therapeutic approaches depend on the degree of neovascularity and the source and type of the blood supply.
Frequency
United States
The true prevalence of metastatic liver disease is unknown because most data derive from autopsy series that reflect the end stage of a disease process. Depending on the site of the primary tumor, 30-70% of patients dying of cancer have liver metastases.5,6
International
No evidence suggests that the frequency of liver metastases internationally is different from that in the United States.
Mortality/Morbidity
A large number of local or regional treatments are now available. These include hepatic resection and several minimally invasive techniques. These treatments have been successful, particularly in the treatment of colorectal cancers, for which hepatic resection may offer the potential for cure. Studies have shown a 20-40% 5-year survival rate after hepatic resection in select patients. In patients with more extensive disease, chemotherapy is now a feasible option; it may produce a response in 20% of patients. However, there has been little success in the treatment of liver metastases from the breast, lung, or pancreas because extrahepatic disease is often present at the time of diagnosis.10,11,12,13
Hepatic involvement of metastatic tumor and the duration of survival appear to be inversely related. Many patients die of cancer as a result not only of metastases but also recurrence of their primary tumor and treatment with cytotoxic drugs. In most patients with cancer, the cause of death is usually indirect; death is not the result of an overwhelming metastatic burden.
- Renal damage may occur as a result of direct renal or ureteric invasion rather than renal metastases. The most common causes of death in cancer patients are chest or urinary tract infections, usually of gram-negative organisms. The infections usually result from an impairment in drainage caused by metastases.
- Paraneoplastic syndromes occur in as many as 75% of patients at one time or another; these syndromes contribute to an electrolyte imbalance and subsequent demise. These syndromes have no direct relationship to tumor metastases. Most patients with liver metastases die with metastases rather than from metastases.
Race
Liver metastases have no known racial predilection.
Sex
- The male-to-female ratio is 3:2 for colon carcinoma.
- The male-to-female ratio is 1:1 for Wilms tumor, neuroblastoma, pancreatic cancer, gastric cancer, and lung cancer.
Age
- In children, the most common liver metastases are from a neuroblastoma, the eyes, a Wilms tumor, or leukemia.
- Metastases from primary sites in the eye, colon, stomach, pancreas, breast, or lung affect adults, usually those 50 to 70 years of age.5,6
- Mean ages for patients with various types of cancer are as follows: colon cancer, 71 years; rectal cancer, 69 years; breast cancer, 30-70 years; and neuroblastoma, 6-9 years. In males, the rate of breast cancer peaks in those aged 60-69 years. The rate of Wilms tumors peaks in those 2.5-3 years of age.5,6
Anatomy
The liver receives blood via the hepatic artery and portal vein. The hepatic artery carries arterial blood, whereas the portal vein drains venous blood from the GI tract and other parts of the splanchnic area. Just over 70% of hepatic blood flow is supplied by the portal vein, but venous blood is only 80% saturated with oxygen. The portal venous blood supplies only 50-60% of the hepatic oxygen requirement. The remaining oxygen is supplied by hepatic arterial blood, which accounts for 25% of the flow.
Venous drainage from the liver is via the hepatic veins and the small veins directly from the caudate lobe to the inferior vena cava (IVC). The hepatic veins run upward and medially through the liver to the IVC. The caliber of the hepatic veins increases toward the diaphragm, whereas the caliber of the portal veins decreases. The portal vein is an isolated vascular unit; it is separated from both arterial blood flow and the IVC by capillaries. It shows a monophasic low velocity flow, though a slight variation often occurs with respiration and pulsation of adjacent arteries. The hepatic veins drain via the IVC to the right atrium. They show triphasic flow. The hepatic arteries show a low-resistance arterial pattern.
The dual blood supply makes hepatic infarcts uncommon except in hepatic surgery, which may directly affect the hepatic vasculature. In the absence of other diseases, the hepatic artery may be occluded without major consequences. Portal and hepatic venous flow is essential for normal hepatic function. An exception that is being seen with increasing frequency is the insertion of hepatic arterial lines for chemotherapy. If the portal vein is occluded, chemotherapeutic agents given via the hepatic artery tend to concentrate within the hepatic arterial branches. These cause intense, local necrosis and eventually give rise to biliary strictures.
Shortly after entering the liver at the porta hepatis, the hepatic artery and portal vein divide into lobar branches, which in turn divide into interlobular branches. Short branches from the interlobular veins break up into hepatic sinusoids. The branches of the portal vein branches, the branches of the hepatic artery, and the bile ducts form portal triads, which run together in a collagenous sheath. The hepatic lobule consists of plates of liver parenchymal cells, usually 2-4 cells in thickness. On average, the hepatic sinusoids receive 1500 mL of blood per minute, of which approximately 900 mL is derived from the portal vein and 600 mL from the hepatic artery.
The acinus is the basic unit of function; at its core is the final division of the hepatic artery. At the area of the acinus distal to the point of entry of the mixed blood supply, the acinus acquires a starlike pattern around the central part of the classic hexagonal lobule. In its center, this lobule contains the hepatic venous tributary. The hepatic sinusoids have wide lumina and are lined by the stellate Kupffer cells and by flat endothelial cells, which have circular fenestrae of varying sizes. The Kupffer cells usually anchor to the vessel walls by pseudopodia; they almost obstruct the passage through the sinusoids. Platelets usually adhere to Kupffer cells; they are designed to trap foreign material from blood passing through the sinusoid. The adherence of platelets to the Kupffer cells provides an additional entrapment mechanism.
The space of Disse is the space immediately subjacent to the endothelial cells. Circulating tumor cells, emboli entering the sinusoids, or both appear to be physically obstructed by the Kupffer cells; if tumor emboli are large, they tend to become lodged in the portal venous branches. The Kupffer cells have tumoricidal activity. The presence of stasis-damaged endothelium and normally fenestrated endothelium is conducive to the implantation of tumor emboli. By contrast, an intact endothelium prevents the adhesion of tumor emboli. Access to the underlying collagen in the space of Disse provides attachment points for cancer emboli arriving at the sinusoid, but not all implanted cancer cells in the space of Disse progress to develop liver metastases.
Presentation
Physical examination
Symptoms of metastatic liver disease may be few, and the extent of liver involvement on images may be surprising, given the absence of clinical or laboratory evidence suggestive of hepatic functional insufficiency.
The only physical sign may be hepatomegaly, sometimes with nodularity of the free edge. About 30% of patients with liver metastases have a normal-sized liver; more than 10% of the nodules have no surface involvement.14 However, with large liver metastases or with tumors that are critically close to the bile ducts, signs of obstructive jaundice may be present, and results of liver function tests may be abnormal. The patient may have weight loss with malaise and abdominal enlargement secondary to hepatomegaly, ascites, or both.
The presence of ascites usually indicates widespread tumors in the liver, and it is regarded as a grave prognostic sign. The spleen is often enlarged, without portal hypertension. Ascites and lower limb edema is indicative of invasion or occlusion of the IVC. With carcinoid tumors that cause pulmonary stenosis, liver metastases are invariably present.
Laboratory examination
Laboratory examination reveals anemia, leukocytosis, minor elevation of bilirubin levels, and increased levels of alkaline phosphatase and transaminase. Various biochemical markers have been proposed as indicative of liver metastases. Of these, 5'-nucleotidase is the most sensitive predictor in comparison with conventional markers and imaging findings. The diagnostic accuracy of tumor markers such alpha-fetoprotein (AFP), protein induced from the absence of vitamin K (PIVKA II), carcinoembryonic antigen (CEA), and CA19-9 for differentiating focal liver lesions has not yet been defined, but these markers are significantly linked to specific tumor types.
Preferred Examination
Plain chest radiographs are routinely obtained in patients who are suspected of having cancer; they are also used in the staging of cancer. Plain abdominal radiography has a limited role in the investigation of liver metastases. Ultrasonography (US) is widely used in the investigation of suspected liver metastases.
Intraoperative US (IOUS) of the liver has the highest sensitivity for the detection of focal liver abnormalities, with 96% accuracy; by contrast, the accuracy of transabdominal US is 84%. Duplex and color-flow imaging provide additional aids in the localization of lesions; the differentiation between ducts and blood vessels; the documentation of vascular invasion, occlusion, or both; the assessment of the presence of collateral circulation; and the degree of vascularity of liver metastases. Late-phase pulse-inversion harmonic imaging is a useful technique for characterizing hepatic lesions and for demonstrating both greater numbers of liver metastases and smaller liver metastases. Contrast-enhanced US in the liver-specific phase of contrast enhancement improves the detection of hepatic metastases, relative to nonenhanced conventional US.
MRI is usually reserved for problem solving because of the cost of the procedure. However, evidence supporting the use of MRI in the evaluation of liver metastases is accumulating because MRI allows the effective localization of hepatic and vascular invasion. However, CT remains the preferred option over both MRI and US. CT permits better evaluation of the involvement of extrahepatic tissues, including the bones, bowel, lymph nodes, and mesentery.
In their meta-analysis, Kinkel et al compared US, CT, MRI, and 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG) imaging in the detection of liver metastases from colorectal, gastric, and esophageal cancers.15 They concluded that, with an equivalent specificity, FDG positron emission tomography (PET) is the most sensitive noninvasive imaging modality for the diagnosis of liver metastases. Selective hepatic angiography may demonstrate hypervascular liver metastases by showing capillary blush in involved areas, highlighting the potential response of tumors to embolization. Angiography is essential when hepatic vascular intervention is planned.
Limitations of Techniques
One major drawback of all imaging examinations is that they seldom enable a tissue diagnosis. The differentiation of granulomatous lesions of the liver from primary benign or malignant liver lesions may be difficult. Diagnostic difficulties may be encountered in the characterization of atypical hemangiomas and focal nodular hyperplasia (FNH). Hemangiomas may coexist with metastases.
In endemic regions of the world, hydatid liver disease may be a great mimic of liver metastases. Hydatid cysts may be unilocular, multilocular, complex, and solid or calcified. Occasionally, defects present after liver cryosurgery may mimic liver metastases. Certain pseudolesions, such as focal fatty infiltration or focal fatty sparing, may also pose problems. (See also the eMedicine article Hydatid Cysts.)
In general, the imaging appearances of liver metastases are nonspecific, and biopsy specimens are required for histologic diagnosis.
Differential Diagnoses
Other Problems to Be Considered
Extramedullary hematopoiesis
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Further Reading
Keywords
liver metastases, hepatic metastases, hepatic cancer, liver cancer, liver neoplasms, Kupffer cells, Kupffer's cells, space of Disse, hepatomegaly, ascites
