AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Background

The liver provides a fertile soil in which metastases can 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.

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, involving both lobes in 77% patients, and only 10% are solitary. Multiple tumors often vary in size; this observation 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. Few tumor types, such as colonic carcinoma, carcinoid, and hepatocellular carcinoma (HCC) may present with lesions confined to the liver. Most tumors that metastasize to the liver, such as breast and lung cancers, often spread to other sites at the same time.

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.

(See also the eMedicine articles Liver Tumors [Pediatrics] and Hepatic Carcinoma, Primary [Oncology], as well as Evaluation of Liver Metastases After Radiofrequency Ablation: Utility of 18F-FDG PET and PET/CT, on Medscape.)

Pathophysiology

Common primary sites

Metastasis is the most common neoplasm in an adult liver, and 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%.^{1, 2} 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%). In their article, Gilbert et al concluded that the liver is a primary target organ of gastrointestinal (GI) cancers, some urologic cancers, neuroblastomas, some melanomas, and lung cancers.³ 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. (42,81)

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 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.

Stasis-damaged endothelium and normally fenestrated endothelium are 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,⁴ Sträuli and Weiss,⁵ and Rohrlich and Rifkin⁶ have 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 can 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 expanding 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. About 7-15% of patients have tumor thrombi that occlude the portal and/or hepatic veins. In the presence of mucin secretion, necrosis, and phosphate activity, metastases can develop calcification that is detectable radiographically.^{7, 8, 9, 10}

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 figures are based on autopsy series that reflect the end stage of a disease process. However, depending on the site of the primary tumor 30-70% of patients dying of cancer have liver metastases.^{3, 2}

International

No evidence suggests that the international frequency of liver metastases 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 can 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 of the frequent presence of extrahepatic disease at the time of diagnosis.^{7, 8, 9, 10}

Hepatic involvement of metastatic tumor and the duration of survival appear to be inversely related. Many patients die of cancer as a result of not only 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 and not due to 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 as a result 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, and they contribute to an electrolyte imbalance and subsequent demise. These syndromes also 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 (42, 81).
• The male-to-female ratio is 1:1 for Wilms tumor, neuroblastoma, pancreatic cancer, gastric cancer, and lung cancer (42, 81).

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 in the 50- to 70-year age group.^{3, 2}
• 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 aged 2.5-3 years.^{3, 2}

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, as 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 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 divides 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, which has at its core 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 flat endothelial cells, which have circular fenestrae of varying sizes, and the stellate Kupffer cells. The Kupffer cells usually anchor to the vessel walls by pseudopodia, and they almost obstruct the passage through the sinusoids. Platelets usually adhere to Kupffer cells and are designed to trap foreign material from blood passing through the sinusoid. The adherence of platelets to the Kupffer cells provide for an additional entrapment mechanism.

The space of Disse is the space immediately subjacent to the endothelial cells. Circulating tumor cells and/or emboli entering the sinusoids 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 Kupffer cells have tumoricidal activity. 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.

Clinical Details

Physical examination

Symptoms due to 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, and more than 10% of the nodules have no surface involvement.¹¹ However, with large liver metastases or with tumors 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 and/or ascites.

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 to indicate liver metastases. Of these, 5'-nucleotidase is the most sensitive predictor compared 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 they are significantly linked to specific tumor types.

Preferred Examination

Plain chest radiographs are routinely obtained in patients who are suspected of having cancer, or they are used in the staging of cancer. A plain abdominal radiograph 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 versus 84% for transabdominal US. Duplex and color flow image provide additional aids to the localization of lesions, the differentiation between ducts and blood vessels, the documentation of vascular invasion and/or occlusion, and 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.¹² The researchers 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 can demonstrate hypervascular liver metastases by showing capillary blush in involved areas, highlighting the potential response of tumors to embolization. Angiography is an essential step 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 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.

DIFFERENTIALS

Section 3 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Other Problems to Be Considered

Extramedullary hematopoiesis

RADIOGRAPH

Section 4 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

Plain radiographs have only a minor role in the diagnosis of liver metastases, and most radiographic abnormalities are an incidental finding. The chest radiograph may show an elevated right hemidiaphragm due to hepatomegaly or ascites. A primary lung parenchymal tumor may be demonstrated. Metastases may be present in the lung and mediastinum.

A plain radiograph of the abdomen may confirm hepatomegaly and show changes suggestive of ascites. Calcified metastases have been reported from a variety of primary sites but particularly from a mucin-secreting colorectal cancer.

Calcification within metastases tends to be amorphous, unlike solid calcification in granuloma. The spleen may be enlarged with or without portal hypertension. Plain radiography may also demonstrate other nonspecific features, extrinsic impression of the left lobe of liver on a gastric gas shadow, ascites, and splenomegaly, among other findings. Calcification is a more specific sign, seen in 2-3% of lesions, but it is insensitive except in children with neuroblastoma, in whom the sensitivity approaches 25%. The pattern of calcification seldom indicates whether the tumor is primary or secondary. The pattern can be variable, and it may have a stippled, flaky, amorphous, nodular, or granular appearance.

Causes of calcified liver metastases include the following:

• Ovarian serous lesion
• Mucinous adenocarcinoma of the stomach, pancreas, colon, and rectum
• Cystadenocarcinoma
• Neuroblastoma
• Leiomyosarcoma (usually of the stomach)
• Carcinoid
• Endocrine pancreatic carcinoma
• Medullary carcinoma of the thyroid
• Melanoma
• Osteogenic sarcoma
• Treated breast cancer
• Bronchogenic carcinoma
• Pleural mesothelioma
• Renal cell carcinoma
• Testicular carcinoma
• Lymphoma
• Chondrosarcoma
• Ovarian teratocarcinoma

Degree of Confidence

Chest radiographs are routinely obtained in all patients with cancer and in those with suspected cancer. Lung cancer is a frequent cause of liver metastases, and metastases to the lung from other primary sites alter the management of cancer considerably. Chest radiography remains the primary imaging modality for the detection of lung cancer. A plain abdominal radiograph plays only a minor role in the investigation of liver metastases.

False Positives/Negatives

Chest radiography lacks specificity, and an appearance similar to that of cancer can occur with a benign lung parenchymal lesion. Calcified liver lesions have been reported in granulomatous disease, hydatid cysts, old healed liver abscesses, old liver infarcts, primary benign and malignant liver tumors, porcelain gallbladder, vascular calcification, and intrahepatic biliary calculi, to name a few examples.

CT SCAN

Section 5 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

CT is the examination of choice for evaluating liver metastases. This preference is largely attributable to the affects of the dual blood supply on the enhancement characteristics of metastases compared with normal liver parenchyma. The recent advent of helical (spiral) CT techniques and, more recently, multisection CT have revolutionized the use of CT in hepatic imaging. The accuracy of CT in the detection of metastases varies with the technique used, the underlying primary lesion, and the degree of vascularity.

Metastases may appear in a multitude of ways on CT scans. The majority of liver metastases are hypovascular (hypoattenuating) compared with surrounding parenchyma; therefore, on nonenhanced CT scans, most lesions appear either hypoattenuating or isoattenuating relative to the surrounding parenchyma. Though nonenhanced scans are no longer routinely obtained in the evaluation of liver metastases, they are useful for the detection of calcified metastases, which often occur with mucinous primary tumors such as those of the colon, ovary, and breast. Nonenhanced images may also be helpful in the detection of hemorrhage.

Both calcification and hemorrhage may become obscured on contrast-enhanced scans. Hypovascular lesions are routinely detected by using contrast-enhanced techniques. The accuracy of the technique depends on the timing of the acquisition relative to the administration of contrast material. The optimal scanning time is in the portal venous phase (approximately 60 s).

Conventional CT scanners have been superseded by helical scanners and multisection scanners that allow the rapid acquisition of images and the use of smart preparation, which triggers scanning at a predetermined Hounsfield unit value in a region of interest.

During portal venous scanning, the attenuation of the normal liver parenchyma increases, revealing the relatively hypoattenuating metastases, sometimes with vague peripheral enhancement. The enhancement that occurs represents viable tumor peripherally, which appears against a necrotic center. The hypoattenuating center can be due to cystic changes, such as those in primary tumors of the ovary and pancreas. Though the margins of the lesions can vary considerably from well defined to ill defined and infiltrating, the defining characteristic of a hypoattenuating center is the most common CT presentation.

Hyperattenuating lesions due to increased tumor vascularity are uncommon. On nonenhanced scans, some metastases of vascular primary tumors, such as renal cell carcinomas, pancreatic islet cell tumors, pheochromocytomas, melanomas, and breast carcinomas, may appear as hypoattenuating lesions. When vascular metastases are suspected, a nonenhanced scan is recommended. On arterial phase (20-30 s) enhanced scans, these vascular metastases show homogeneous enhancement compared with the surrounding liver; sometimes, a hypoattenuating rim is observed. Most of these lesions become isoattenuating to normal liver in the portal phase of dual-phase CT. Dual-phase CT requires fast scanning sequences provided only by helical and multisection scanners. Triple-phase CT is routinely performed in some centers; it involves multisection scanners; and it is particularly useful in evaluating suspected hyperattenuating metastases.

CT techniques

Delayed high-dose contrast-enhanced CT is a rarely used technique; however, it is of value in equivocal lesions. This examination is performed 4-6 hours after the administration of contrast material. The iodinated contrast agent used concentrates in the normal liver hepatocytes but not in focal lesions. Therefore, focal lesions appear as regions of low attenuation. The dual-phase CT scan obtained earlier also serves as a roadmap for the normal vessels of the liver.

The most sensitive technique for detecting liver metastases is CT arteriography (CTA) and CT arterioportography (CTAP). Although these are invasive procedures, they are invaluable in accurately assessing the number and position of the lesions prior to hepatic resection. In CTA, a percutaneous catheter is placed into the hepatic artery, and CT scan is obtained through the liver. Though the technique demonstrates the most minimal of peripheral vascular enhancement in hypoattenuating lesions, CTA is most useful in evaluating hyperattenuating lesions because hepatic neoplasms receive most of their blood supply from the hepatic artery.

In CTAP, a catheter is placed percutaneously into the superior mesenteric or splenic artery so that CT can be performed during the portal venous phase of contrast enhancement. The normal liver is homogeneously enhancing, and the metastases appear as nonenhancing masses. Therefore, CTAP is the preferred technique for evaluating hypovascular metastases.

A further scanning technique that is rarely used in the evaluation of metastases is iodolipid CT. A hyperattenuating iodolipid such as lipiodol is injected directly into the hepatic artery, and CT scanning is performed through the liver in 5-7 days. The iodolipid is rapidly cleared from the normal parenchyma, but it is retained within neoplastic tissue; this feature aids in the detection of very small space-occupying lesions.

Degree of Confidence

CT is the most sensitive technique for the detection of liver metastases. Contrast-enhanced scans offer a high degree of sensitivity, as high as 80-90%. The specificity is 99%. Helical and multisection techniques have eliminated respiration-related misregistration, allowing far better detection of smaller metastases.¹²

CTA and CTAP have similar sensitivities, though whether CTAP is more sensitive in detecting small subcentimeter metastatic lesions is arguable. CTAP is less specific than CTA.

False Positives/Negatives

Metastases can look like almost any lesion that occurs in the liver. Hemangiomas can easily be mistaken for metastases when they are multiple. On nonenhanced CT, they often form well-defined hypoattenuating lesions that mimic vascular metastases. On contrast-enhanced scans, they show peripheral enhancement. However, unlike vascular metastases, hemangiomas take at least several minutes to become completely filled. The area of central low attenuation typified by hypoattenuating metastases can simulate cysts in the liver. However, with the administration of contrast material, little doubt remains because cysts show no enhancement.

FNH rarely poses a major diagnostic problem, except if the lesions do not possess a prominent central scar, in which case they may look like vascular metastases. A fatty liver can obscure metastases on both nonenhanced and enhanced scans. Focal fatty sparing in a diffusely fatty liver or foci of focal fatty infiltration can simulate metastases. However, on nonenhanced scans, these regions of fat variation tend to be nonspherical and geographic, with no mass effect or distortion of the local vessels.

Small, 0.5-cm lesions can be missed on helical and multisection CT scans. With helical CT, partial-volume artifact can compound this problem if the pitch is greater than 1.5. The rate of contrast administration and the timing of the acquisition must be precise to avoid false-negative results. It is essential to use a dynamic bolus technique. On delayed scans, hepatic vessels appear hypoattenuating, as do focal lesions; therefore, the vessels can be confused with small lesions. As long as a dynamic bolus examination has been performed earlier to identify vessels, this confusion should be limited.

Problems can arise with the invasive techniques of CTA and CTAP. CTA highlights subtle differences in the perfusion of the liver due to, for example, variations in hepatic arterial anatomy. The detection of small metastases can be difficult, and portal branches can mimic masses. Perfusion abnormalities can interfere with CTAP (eg, in the presence of portal hypertension or lobar hyperperfusion secondary to accessory or replaced hepatic arteries). The specificity of CTAP is not as good as that of CTA, because virtually all lesions appear hypoattenuating. Anomalous peripheral venous drainage, local variations in portal perfusion, and mixing from nonenhancing splenic venous blood can enable the detection of pseudolesions, as well as false-negative results.

MRI

Section 6 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

As with CT and US, liver metastases have a variety of appearances on MRI. Most liver tumors, whether benign or malignant, appear as hypointense lesions on T1-weighted images and hyperintense lesions on T2-weighted images. There are a few exceptions to this rule (eg, metastatic melanoma, which exhibits high signal intensity on T1-weighted MRIs relative to the liver).

Heavily T2-weighted images are useful in differentiating hemangiomas and cysts because the signal intensity is higher in these benign lesions than in liver metastases. However, differentiating benign lesions from malignant lesions on the basis of signal intensity characteristics on heavily T2-weighted images may not be conclusive, and combining the signal intensity changes with the morphologic changes in the lesion is more useful.

Morphologic characteristics on T2-weighted images that suggest metastatic liver disease include the following: (1) heterogeneous signal intensity with irregular and indistinct outer margins and (2) a smooth or irregular central area of high signal intensity with a surrounding ring of signal intensity lower than that of the central focus but higher than that of the adjacent normal liver. Intravenous contrast agents improve the detection of liver mass lesions.

MRI contrast agents and contrast-enhanced techniques

The contrast agents available for use in liver imaging can be classified into 4 groups according to their biologic distribution: (1) gadolinium chelates, which have an extracellular distribution; (2) macrophage-monocytic agents targeted to the phagocytic system; (3) hepatobiliary agents; and (4) blood pool agents. This classification is not strictly accurate because these agents are distributed successively or simultaneously to more than 1 site.

Dynamic gadolinium-enhanced MRI not only improves the detection of focal liver masses but also permits the differentiation of benign lesions and malignant lesions. In some instances, contrast-enhanced imaging may enable the specific diagnosis of a focal liver lesion. Metastases enhance heterogeneously and occasionally show central nonenhancing areas due to tumor necrosis. Hypervascular metastases enhance more than the surrounding liver in the arterial phase of a dynamic study, whereas hypovascular metastases enhance less than the surrounding liver.

Extracellular contrast agents, such as gadolinium-based agent, have a narrow time window during which the liver can be imaged. This limitation can be overcome by using contrast agents targeted to the liver.

An octadenatate gadolinium chelate, gadolinium benzylopropionictetraacetate (Gd-BOPTA) has been developed as an extracellular hepatobiliary contrast agent for MRI. This agent produces more-selective and more-prolonged liver enhancement. Gd-BOPTA may therefore overcome the timing restrictions encountered with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA).

Compared with Gd-DTPA, mangafodipir trisodium (Mn-DPDP) also provides a 5-fold increase in the signal-to-noise ratio and also prolonged liver enhancement, whereas liver metastases show no significant enhancement. After the intravenous injection of Mn-DPDP, maximal liver enhancement is sustained for approximately 30 minutes. Therefore, Mn-DPDP may also overcome the restrictive imaging window encountered with Gd-DTPA.

Iron oxides are cleared by the reticuloendothelial system. Two types of iron oxides are available: superparamagnetic iron oxide particles (SPIOs) and ultrasmall superparamagnetic iron oxide particles (USPIOs). Iron oxides decrease the signal intensity of the normal liver by shortening T2 as a result of magnetic susceptibility. Delayed-enhanced images obtained 60 minutes after the injection outline the phagocytic activity of the liver. However, because metastases do not usually contain Kupffer cells, they do not take up iron oxide particles. Thus, liver metastases stand out against a dark background.

Degree of Confidence

Role of MRI

MRI is seldom used as a primary tool in the diagnosis of liver metastases, but it is regarded as problem-solving technique. It is also used when alternative imaging is contraindicated. MRI has the advantage of providing high inherent contrast resolution, providing biochemical and morphologic information, offering a multiplanar capability, and possessing an intrinsic sensitivity to blood flow and blood breakdown products.

Sensitivity and specificity of MRI

Technically, MRI is as sensitive as CT in the detection of liver metastases, and the more recent use of ultrafast techniques has certainly increased the sensitivity of MRI, although it is still inferior to CTAP. In a number of instances, MRI is superior to other imaging techniques. Hemangiomas are reliably diagnosed with MRI, and more importantly, they are more easily differentiated from metastases.

MRI is said to be the best modality in the diagnosis of FNH, with a sensitivity of 70% and a specificity of 98%. The central scar is more often detected by MRI than by CT. One limiting factor of gadolinium-enhanced MRIs of the liver is that the liver must be imaged repetitively with T1-weighted gradient-echo sequences during hepatic arterial, portal venous, and delayed phase of contrast enhancement.

Gadolinium-enhanced study is always performed in the phase that shows the greatest differences in the distribution of contrast agent between normal tissues and abnormal tissues. For all practical purposes, this means the portal venous phase. Therefore, a time limit exists during which imaging can be performed with gadolinium-based and other extracellular contrast agents. The time-limiting factor can be overcome by using tissue-specific contrast agents.

Mn-DPDP not only overcomes the restrictive timing with Gd-DTPA but also potentially allows the distinction of nonenhancing hepatocellular lesions (eg, metastases) from benign and malignant hepatocellular lesions. Mn-DPDP imaging has a sensitivity of 100%, a specificity of 92%, and an accuracy of 93.6%.

SPIO and USPIO images depict more liver focal lesions than do nonenhanced MRIs obtained at all field strengths. With SPIO techniques, the size of detectable lesions is also reduced from 10 mm to 3 mm. Compared with conventional techniques, SPIO enhancement appears to be more sensitive than contrast-enhanced CT.

Limiting factors with MRI

Two major factors limit the widespread use of MRI in liver imaging: technical factors and cost. The technical factors include motion artifacts; respiratory, cardiac, and bowel movements, as well as aortic pulsation, tend to degrade the images. These problems are not insurmountable and may be overcome with the use of ultrafast imaging, phased-array surface coils, and intraluminal and organ-specific contrast agents. Regarding the cost factor, with escalating healthcare expenses, cost-effectiveness and the selection of single imaging modality that can answer the clinical question are being emphasized.

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy.

NSF/NFD has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

False Positives/Negatives

Diseases that can be confused with liver metastases include the following: hemangioma, FNH, HCC, hepatocellular adenoma, liver cyst, biliary hamartoma, biliary cystadenoma, intrahepatic cholangiocarcinoma, angiosarcoma, epithelioid hemangioendothelioma, primary hepatic lymphoma, focal fatty infiltration and focal fatty sparing, lipoma, and inflammatory pseudotumor. These diseases are described below.

In addition, Mn-DPDP enhancement has been reported in HCC, regenerative nodules, and foci of FNH. The appearances on SPIO and USPIO images are nonspecific, and metastases, primary benign tumors, malignant tumors, and cysts can give rise to similar appearances.

Hemangioma

Hemangiomas and liver metastases are often confused. Hemangiomas show low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Heavily T2-weighted images are useful in differentiating hemangiomas from other solid tumors because the signal intensity is higher in hemangiomas.

Breath-hold and fast spin-echo techniques are particularly good for distinguishing hemangiomas from metastases. Hemangiomas can also be characterized by their typical enhancement pattern after the administration of a gadolinium chelate. Typically, discrete, nodular peripheral enhancement is observed. In distinction, metastases often show transient rim enhancement. A peripheral rim of hypointensity relative to the center of the tumor on delayed-contrast images is said to be a specific sign of malignancy.

Focal nodular hyperplasia

FNH often contains a central scar. Because hepatocytes are the major components of FNH its signal intensity on MRI parallels that of the normal liver. Small areas may be difficult to detect on MRIs. FNH usually has homogeneous signal intensity except for the central scar. FNH is slightly hypointense to the liver on T1-weighted images and slightly hyperintense on T2-weighted images. The central scar appears hypointense on T1-weighted images and hyperintense on T2-weighted images. Flow-sensitive MRI may demonstrate arteries in the central scar if the arteries are large enough. These features of FNH on nonenhanced images are not encountered in all cases, and hence, contrast-enhanced MRI studies may be required for a confident diagnosis. (See also Focal Nodular Hyperplasia.)

Hepatocellular carcinoma

HCC may be solitary or multicentric, and it may mimic liver metastases. HCC has a low, intermediate, or high intensity on T1-weighted images. High signal intensity may be related to the fat content, intracellular glycogen, hemorrhage, or copper deposition. The finding of high intensity on T1-weighted images is useful because few other liver lesions have high signal intensity on these images; these lesions include fat-containing benign tumors and hemorrhagic tumors, such as hepatic adenomas.

HCC is hyperintense on T2-weighted images, and larger tumors may show a mosaic pattern. A tumor capsule, if seen, may have low signal intensity on T1-weighted images and a double-layered appearance on T2-weighted images. The outer layer is hyperintense, and the inner layer is hypointense. Associated venous thrombosis that is well depicted on MRIs suggests HCC. Regenerative nodules in a cirrhotic liver classically have low signal intensity on T1-weighted images, owing to accumulated iron.

Hepatocellular adenoma

Hepatocellular adenomas are usually solitary, and most affect young females taking oral contraceptives. However, in rare cases, the tumors may be multiple and mimic metastases. On MRI, the tumor appears hyperintense or isointense on T-1 weighted images and mildly hyperintense on T-2 weighted images. These tumors often have a fatty component (50%), which can be assessed by means of fat-suppressed or inversion recovery sequences. The appearance of hemorrhage within the liver, which is common, depends on the age of the hematoma. Signal heterogeneity within these tumors is common, owing to the wide range of pathologic changes that may occur in hepatic adenomas.

Gadolinium enhancement patterns are variable. In distinction to FNH, which are usually hypervascular, adenomas may appear as avascular lesions. However, most hepatocellular adenomas are hypervascular in the arterial phase of a dynamic contrast dynamic study. In about a third of the cases, a peripheral rim is observed; this is hypointense on T1-weighted images and of variable intensity on T2-weighted sequences. This rim shows gadolinium enhancement, which corresponds to compressed normal liver around the tumor. Some MRI features described are shared by both hepatocellular adenomas and HCCs, and therefore, a tissue diagnosis may be required.

Liver cyst

Complex and complicated liver cysts may be confused with metastases. MRI is particularly good for depicting hemorrhagic hepatic cysts. Intracystic hemorrhage remains hyperintense on T2-weighted images, but with T1-weighted images, the signal intensity is homogeneously high or heterogeneous. A hyperintense fluid-fluid level may be observed in the dependent part of the cyst, and low or intermediate signal intensity may be present in the upper part of the cyst. Infected cysts enhance with the use of a gadolinium-based contrast agent. Multiloculated or coalescent cysts may also mimic cystic tumors with intramural nodules. The walls and septa do not enhance. MRI is not usually indicated in the workup of cysts detected with US or CT. MRI is useful in differentiating complicated cysts from metastases.

Biliary hamartoma

Biliary hamartomas (Meyenberg complexes) are benign lesions that consist of a focal collection of bile ducts. They are usually multiple and predominantly located in the subcapsular region. US and CT findings are nonspecific and may mimic those of metastases. The lesions have low signal intensity on T1-weighted MRIs and homogeneously high signal intensity on T2-weighted MRIs. The homogeneous hyperintensity on T2-weighted images is crucial and indicates benign lesions. Gadolinium enhancement has been described only once.

Biliary cystadenoma

Biliary cystadenoma and cystadenocarcinoma may mimic cystic liver metastases. These tumors are similar to mucinous cystic tumors of the pancreas and ovary. Most tumors contain closely bound spindle cells below the epithelium that resemble ovarian stroma found only in women. A small number of tumors do not contain ovarian stroma, and these may be found in men and women. Grossly, the tumors are multiloculated with varying degrees of septation and nodularity. The locules contain fluid of variable consistency; this fluid may be serous, mucinous, bilious, hemorrhagic, or a combination of these. Radiologically, features such as septa and nodularity are associated with cystadenocarcinoma when they are seen together. MRI depicts the multilocular mass with septa and nodularity; the signal intensity varies with the consistency of the intralocular fluid.

Intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinomas account for 10% of all primary malignant liver tumors. MRI depicts a non-encapsulated tumor that is hypointense on T1-weighted images and hyperintense on T2-weighted images. A central hypointensity corresponding to a central scar may be seen on T2-weighted images. The depiction of a central scar on MRIs is a reliable feature for differentiating a metastatic tumor from a primary liver tumor.

Gadolinium enhancement patterns depend on the size of the tumor. Small tumors may be homogeneously enhancing, mimicking HCC. Larger tumors show minimal-to-moderate peripheral enhancement with progressive central filling. Incomplete central filling is noted on delayed images. The central scar may enhance, but it becomes isointense on delayed images, unlike FNH, which becomes hyperintense. There is controversy regarding portal and hepatic vein invasion. Some authors believe that vascular involvement is more a feature of HCC and that such involvement is exceptional with intrahepatic cholangiocarcinoma. However, most authors now believe that vascular infiltration is common with intrahepatic cholangiocarcinoma. Gradient-echo MRI is valuable in depicting vascular invasion.

Angiosarcoma

Angiosarcoma is a rare aggressive tumor of the liver that has been linked to industrial and environmental exposure to toxins. The MRI features are similar to those described in hemangiomas. Because both tumors contain abundant vascular spaces, they are usually hyperintense on T2-weighted images. However, angiosarcomas usually exhibit heterogeneous signal intensity with T2-weighted sequences. Peripheral gadolinium enhancement is often seen, but the enhancement is not as intense or globular as that in hemangiomas, and it is usually discontinuous.

Epithelioid hemangioendothelioma

Epithelioid hemangioendothelioma is a rare, vascular, primary tumor of the liver that may mimic metastases on imaging. The tumor predominantly affects women in their 40s. MRI features have been described in only 1 case. T2-weighted images depict subcapsular nodules with increased signal intensity, similar to most liver malignancies, but the signal intensity is not as intense as that of a hemangioma. The tumor shows faint peripheral enhancement with a gadolinium-based contrast agent. MRI features of malignant mesenchymal tumors (plasmocytoma, leiomyosarcoma, undifferentiated sarcoma, epithelioid hemangioendothelioma, and angiosarcoma) can be difficult to differentiate from those of other benign or malignant liver tumors.

Primary hepatic lymphoma

Primary hepatic lymphoma is a rare disease. Hepatic lymphoma deposits are seen usually in association with systemic disease. On MRI, primary hepatic lymphoma is usually well defined and isointense to homogeneously hypointense or slightly hyperintense on T1-weighted images. On T2-weighted images, they are slightly heterogeneous and hyperintense. Lobulation is better seen with T2-weighted sequences. In 1 case, the margins were ill defined, and portal vein branches were identified within the tumor, an unusual finding in liver neoplasms. One lesion was studied after the injection of gadopentetate dimeglumine, and it showed marked and heterogeneous enhancement.

Focal fatty infiltration and focal fatty sparing

Both focal fatty infiltration and focal fatty sparing can mimic malignant disease of the liver on images. The geographic configuration and typical periligamentous and periportal location should suggest the diagnosis. These lesions do not appear as a mass, and they have no mass effect. Blood vessels traverse these lesions undistorted. Chemical shift imaging can be used to determine if a suspicious area or the surrounding liver parenchyma contains microscopic fat. T2-weighted MRIs, particularly fat-suppressed images, show that the lesion has the signal intensity of normal liver and not the spleen.

Lipoma

Fatty liver tumors are rare. Lipomas are well-defined tumors that are hyperintense on T1-weighted images. The signal intensity is usually similar to that of subcutaneous and retroperitoneal fat. On fat-suppressed images, the tumor appears hypointense, and it can be differentiated from other hyperintense lesions on T1-weighted images. These lesions may be caused by copper deposition, hemorrhage, or peliosis, for example. Hepatic angiomyolipomas are usually hyperintense and heterogeneous on T1-weighted images. The hyperintensity is usually related to the fat content of the tumor and is usually suppressed with fat-suppression sequences. The hypervascularity and the aneurysmal component of the tumor may also cause hyperintensity on T1-weighted MRIs.

On T2-weighted images, the lesion again appears hyperintense and heterogeneous. The atypical angiomyolipoma is more likely to be confused with other liver tumors because they are hypointense on T1-weighted images and hyperintense on T2-weighted images. Rarely, angiomyolipomas do contain fat. These tumors are difficult to differentiate from other tumors on the basis of the imaging results. After the administration of a gadolinium-based contrast agent, these tumors enhance heterogeneously.

Inflammatory pseudotumor

Inflammatory pseudotumor of the liver is a rare disorder that usually affects infants and young men. The process is an inflammatory response to an unknown agent, and the majority of patients present with signs and laboratory evidence of an active inflammatory process. Most of these lesions are located in segment 4.¹³

Only a few case reports describe the MRI features of hepatic pseudoinflammatory tumors. These lesions are usually solitary, and they may have nonspecific increased signal intensity on T1- and T2-weighted images. However, others describe a hypointense lesion on T1-weighted images and isointensity with a hyperintense ring on T2-weighted images. Another case report describes irregular and intensely enhancing lesions on immediate postgadolinium spoiled gradient-echo images. Rapid washout was noted. Periportal involvement was also shown on T2-weighted fat-suppressed images. On the whole, the diagnosis may be difficult by using imaging, and biopsy may be required.

ULTRASOUND

Section 7 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

This section addresses general and specific findings and also imaging methods, including Doppler techniques and intraoperative US (IOUS) and laparoscopic US.

General US findings

Generally, metastases cause hepatomegaly, though this may not be evident until the disease is advanced. Intrahepatic masses may alter the shape of the liver, and its surface may appear nodular or lobular. This latter sign is nonspecific and also occurs in cystic fibrosis and liver infiltration.

In general, the US appearance of liver metastases is nonspecific, and biopsy may be required for a tissue diagnosis. However, the presence of multiple hepatic nodules of different sizes within the liver is nearly always due to metastases. Also, percutaneous biopsy should not be undertaken if curative hepatic resection may be possible.

Liver metastases may cause focal or diffuse parenchymal changes. The US appearance and the histologic findings are poorly correlated, though cauliflower masses are often from the colon, and evaluation of the abdomen may reveal a bowel mass. The echogenicity is dependent on tumor vascularity; the cellular composition; the degree of tissue invasion; and the presence or absence of necrosis, fibrosis, and fatty change. Metastases complicated by hemorrhage, necrosis, or infection may result in bizarre changes in their configuration and echo pattern.

Specific US findings

Isoechoic metastases

Isoechoic and infiltrating metastases are ill defined and difficult to identify. They occasionally have a mass effect, which is shown as a contour anomaly and a surface irregularity of the liver, as displacement or compression of the intrahepatic vasculature, or as segmental bile duct obstruction. Other signs of malignancy may be apparent; such signs include lymphadenopathy, ascites, and peritoneal metastases. Also, the primary site may be recognized; for example, a mass may be found in the pancreas.

Rarely, a sonolucent ring sign is seen. A mass in the liver adjacent to the gallbladder may demonstrate a hump sign (ie, edge sign) or a gallbladder compression sign. A hump, or edge, sign may indicate the presence of a superficial mass near the surface. These findings are nonspecific signs of space-occupying lesions in the liver, and they may be caused by benign or malignant lesions. The gallbladder compression sign has also been described as a normal variant, although this condition is exceptionally rare.

Echogenic metastases

Metastases containing multiple tortuous vessels tend to be hypervascular; their echogenicity is most probably related to the number of blood-tissue interfaces rather than the blood vessel walls themselves. Metastases from the following tumors tend to be echogenic: GI cancer, renal cell carcinoma, carcinoid, choriocarcinoma, pancreatic islet cell tumors, chloromas (leukemic), and AIDS-related Kaposi sarcoma. In children, metastases from neuroblastoma, hepatoblastoma, leukemia, hepatoma, and Wilms tumor may be densely echogenic. Tumors responding to therapy may show increased echogenicity, but more often, they show a reduction in size.

Causes of echogenic metastases

Causes of echogenic metastases include the following:

• Mucinous adenocarcinoma of the colon
• Pancreatic carcinoma (usually hypoechoic but possibly becoming echogenic as calcification occurs)
• Gastric carcinoma (usually hypoechoic)
• HCC
• Neuroblastoma
• Cholangiocarcinoma
• Treated breast carcinoma
• Renal cell carcinoma
• Carcinoid
• Choriocarcinoma
• Pancreatic islet cell tumors
• Wilms tumor (usual spread is to lung)
• Kaposi sarcoma
• Myeloma deposit
• Hepatic chloroma

Hypoechoic metastases

Hypoechoic metastases are generally hypovascular and comprise uniform tissue and/or cellularity. Any primary tumor can cause this pattern of metastases, but those particularly likely to have this pattern are lymphomas; melanomas; and carcinomas of the pancreas, lung, or cervix.

Causes of hypoechoic metastases include the following:

• Lymphoma (especially AIDS related)
• HCC
• Pancreatic carcinoma
• Lung (particularly adenocarcinoma)
• Cervical carcinoma
• Melanoma
• Nasopharyngeal carcinoma
• Kaposi sarcoma (rare, most are hyperechoic)
• Myeloma deposits
• Cystic liver metastases
• Mucinous cystadenocarcinoma colon
• Cystadenocarcinoma ovary
• Cystadenocarcinoma pancreas
• Leiomyosarcoma
• Squamous cell carcinoma
• Testicular carcinoma
• Carcinoid
• Granulosa cell ovarian tumor

Cystic metastases

Metastases that are cystic can mimic abscesses, hemorrhagic infarcts, hematomas, simple cysts, and hydatid cysts. Cystic metastases display a degree of complexity in the form of mural nodules, thickened walls and septa, and fluid/debris levels. These features are not present in simple hepatic cysts. A detailed clinical history may help exclude hematomas, hydatid cysts, and abscesses from consideration.

Two groups of patients tend to get cystic metastases: (1) patients who have a primary neoplasm with a cystic component, such as a mucinous cystadenocarcinoma of the colon, stomach, pancreas, or ovary, and (2) patients with metastases that are undergoing central necrosis, when low-level echoes and wall irregularity are seen. Squamous cell carcinoma, leiomyosarcoma, melanoma, and testicular carcinoma have a propensity to undergo extensive central necrosis.

Causes of bull's eye, or target, metastases

In bull's eye, or target, metastases the halo is most probably related to a combination of compressed normal hepatic parenchyma around the mass and a zone of cancer cell proliferation. The presence of a halo usually suggests aggressive behavior. Bronchogenic carcinoma characteristically causes target-type metastases. However, this pattern is nonspecific and can be found with metastases from the breast and colon, as well as primary malignant liver neoplasms (eg, HCC) and benign liver neoplasms (eg, adenoma in glycogen storage disease). A similar appearance has been described with liver abscesses.

Causes of calcified metastases

If calcified metastases are densely echogenic, they may shadow. The calcification and echogenicity result from intratumoral mucin, necrosis, or phosphatase activity. This pattern of metastases can occur from many primary sites, but it is particularly common with carcinoma of the colon of the mucin secreting type, pseudomucinous cystadenocarcinoma of the stomach, and (rarely) adenocarcinoma of the breast or melanoma. In children, neuroblastoma is the most common metastasis; it is usually hypoechoic, but may show calcification, and it can be echogenic.

Diffuse or infiltrative metastases

Diffuse disease may be due to the confluence of areas of focal disease, infiltrating tumors, or miliary metastatic deposits. Diffuse disease is seen less frequently than focal disease. The liver may appear moth eaten or diffusely heterogeneous, or uncommonly, the infiltrates are isoechoic.

Diffuse metastases may be difficult to detect with US, particularly on the background of fatty infiltration, which may occur as result of cirrhosis or chemotherapy. Lymphoma and leukemia are particularly prone to diffuse disease, which may appear hypoechoic, though these changes do not always reflect the presence of metastases; reactive lymphocytic infiltration secondary to disease elsewhere may give rise to the same appearance. A diffuse pattern is also commonly seen with carcinoma of the breast, lung, or melanoma.

When the liver is extensively replaced by metastases, jaundice may occur because of inadequate liver function; this sign may be due to the lack of normal liver tissue or by distortion of the hepatic architecture, particularly the bile ducts and vessels. Alternatively, Hodgkin disease may cause intrahepatic biliary obstruction at the canalicular level, while lymphadenopathy may compress the extrahepatic biliary system. Even in the absence of jaundice, liver function tests shows some abnormality in the presence of diffuse intrahepatic malignancy.

Causes of heterogeneously echogenic liver metastases

Causes of heterogeneously echogenic liver metastases include cancers from the following sites: breast, colon and/or rectum, stomach (especially anaplastic lesions), and cervix.

Other causes of heterogeneously echogenic liver metastases include the following: HCC (especially when complicated by hemorrhage), carcinoid, melanoma, and bronchogenic carcinoma.

Leukemia

Hepatomegaly is common in both lymphatic leukemia and myeloid leukemia. Chloromas are composed of granulocyte precursor cells. These are rare solid extramedullary tumors that usually have a mass effect. They may occur in intracranial, intrathoracic, and intra-abdominal sites. Most chloromas are seen in children. Chloromas within the liver are extremely rare. They may appear as hypoechoic or hyperechoic masses. The hyperechoic mass may mimic hemangiomas. Chloromas may rarely show central necrosis, which appears as echogenic centers mimicking Candida abscesses.

Lymphoma

Diffuse infiltration of liver and spleen is common in lymphoma; focal involvement is less common. The diffusely infiltrating type of liver lymphoma is difficult to image with US, as it may cause subtle architectural distortion or no US abnormality at all.

Primary lymphoma of the liver is an unusual entity, but its incidence appears to be rising. This change may reflect its appearance in the increasing numbers of immunocompromised patients, such as patients with AIDS or those undergoing organ transplantation. Primary lymphoma (confined to solitary organs) is more common with non-Hodgkin lymphoma than with other diseases. Focal hepatic lymphoma is usually hypoechoic, but target and hyperechoic patterns have been described in non-Hodgkin lymphoma but not Hodgkin lymphoma. Burkitt lymphoma can also cause hypoechoic liver masses. These masses are usually large at diagnosis.

AIDS-related liver tumors

Non-Hodgkin lymphoma and Kaposi sarcoma are common complications of HIV infection. The incidence of Kaposi sarcoma in AIDS patients is 0.5-0.9% among those aged 1-19 years, but it increases with age, and the rate is higher in males than in females. Black children and male adolescents who report having homosexual intercourse have a 3-fold increase in the incidence of Kaposi sarcoma. In children, Non-Hodgkin lymphoma is more common than Kaposi sarcoma.

Primary Non-Hodgkin lymphoma and Kaposi sarcoma affecting the liver are uncommon. However, in autopsy series in patients with Kaposi sarcoma and AIDS, 34% have liver involvement, but the incidence during imaging is lower.

Non-Hodgkin lymphoma usually appears with multiple hypoechoic masses in the liver, and it is no different from that of a primary hepatic lymphoma in patients without AIDS. However, liver abnormalities are common in patients with AIDS and may be related to the following: (1) coincidentally acquired hepatotropic viruses, (2) complications of therapy, (3) changes associated with a chronic debilitating disease, or (4) complications related to immune compromise (eg, infections, neoplasms, iatrogenic complications).

In the liver, Kaposi sarcoma manifests itself as 5- to 12-mm hyperechoic nodules, although hypoechoic masses have also been reported. Three quarters of patients with AIDS-related Kaposi sarcoma have abdominal lymphadenopathy, which cannot be differentiated from non-Hodgkin lymphoma, inflammation, or infection on imaging. Biopsy is usually required to distinguish these entities.

Hepatic myeloma

Extramedullary myeloma deposits are extremely rare; a few cases of liver involvement have been reported. US shows hepatomegaly with single or multiple hypoechoic solid masses, but target lesions and hyperechoic masses have also been reported. A fine-needle aspirate may demonstrate numerous mononuclear cells, which are characteristic of myeloma.

US imaging techniques

Doppler techniques

Some have attempted to use color and duplex Doppler arterial flow patterns around liver masses to improve the specificity of US examination. Unfortunately, Doppler results cannot always be used to differentiate metastases from other masses (eg, hemangioma) because the former are mostly hypovascular.

There has been some success in differentiating HCC from metastases, as Doppler shifts of >5kHz are reported to be specific for HCC. Moreover a basket-type pattern has been described for hepatomas on color flow Doppler images. A Doppler shift of up to 4 kHz has been described in vascular metastases. On color flow Doppler images, a hypovascular mass with venous or arterial flow meandering around the mass (detour sign) is occasionally seen around metastases; this finding reflects their mass effect in displacing such vessels.

Although color Doppler study is of limited value in adding specificity to a US diagnosis, it can be invaluable in localizing areas of vascularity to optimize the site for biopsy.

IOUS and laparoscopic US

IOUS is an important diagnostic tool in patients undergoing hepatic resection for colorectal metastases. IOUS allows careful evaluation of the normal liver segments to exclude occult metastases in the segments that will be left in situ. The high accuracy of IOUS is due to the contact scanning possible with a high-frequency transducer and color flow Doppler imaging; with this technique, the complete organ can be covered without artifact. IOUS depicts 25-35% more lesions than does preoperative US. Most significantly, 40% of the lesions detected by means of IOUS are neither visible nor palpable and would presumably have been missed with other means.⁹

IOUS has also been shown to be a sensitive means of detecting HCC, particularly if US contrast agents are used to improve Doppler images.

Operative US is also used routinely during cryotherapy, or intraoperative freezing of metastases. The tip of the cryotherapy probe is placed in the center of the metastasis, which is then frozen with liquid nitrogen. As the metastasis freezes, it becomes echogenic and is seen as an echogenic sphere forming around the tip of the probe. Cryotherapy is applied until the echogenic sphere has replaced all of the visible metastasis with a margin, which fully includes the edges of the tumor to prevent recurrence. On follow-up, the metastasis forms a lollipop-shaped defect with a cystlike hypoechoic area representing the site of the treated tumor, which becomes necrotic with a tubular stem with the attenuation of fluid; this stem represents freezing around the probe shaft.

IOUS has been used as an aid to liver resection since the end of the 1970s. This approach has been particularly useful in the resection of tumors from a cirrhotic liver in which conventional resection methods resulted in high mortality and morbidity rates. IOUS combines the needs for adequate tumor resection with sparing of the liver parenchyma.

Good background knowledge of the liver surgical anatomy and of US is vital before one embarks on IOUS for surgical resection. At laparotomy, liver mobilization by dividing the round, falciform, and triangular ligaments is an essential prerequisite before liver exploration with IOUS. When the round ligament is pulled, the liver surface is widely exposed, and by following the portal venous branches and hepatic veins, the liver can be fully examined. The use of IOUS in liver resection can be schematically divided in 2 principal phases: liver exploration for staging the disease and guidance of the surgical maneuvers.

IOUS also permits an accurate 3-dimensional reconstruction of the relationships between the tumor, the hepatic veins, and the portal branches. Moreover, the portal venous branches are used as landmarks in defining the resection line. This finding is fundamental for planning the surgical strategy.

In cirrhotic livers, the hard and irregular surface makes the detection of small nodules difficult by means of palpation. In 30-65% of patients, liver tumors smaller than 4-5 cm in diameter are not palpable. IOUS allows accurate localization of these tumors in 96-98% of patients. In the evaluation for HCC, IOUS allows the identification of 30% new hypoechoic, malignant nodules in a cirrhotic liver; this finding alters the surgical strategy.⁹

Moreover, laparoscopic US may help in preventing unnecessary laparotomy in 63% of cases with nonresectable malignancies.⁹ Tumor thrombi in the portal and hepatic veins and invasion of the biliary tree in the setting of HCC and other metastases are regarded as signs of advanced-stage disease, particularly with HCC. The tumor extension is readily seen on IOUS as hypoechoic masses occupying the vessel lumen. Liver resection for HCC may be performed in the presence of tumor thrombi in the portal vein trunk, and in this instance, IOUS allows an evaluation of the extent of the tumor thrombus, which determines the extent of liver resection. Though not completely satisfactory, IOUS remains the most accurate tool available for defining vascular tumor invasion.

Operative US can also be used to guide segmental resection by allowing visualization of portal vein branches, which can then be injected with dye. This injection leads to staining of the liver segment, which accurately demarcates its vascular boundaries on the liver surface. This technique can be further refined with the insertion of a 6F balloon catheter into the supplying portal vein under IOUS guidance. Inflation of the placed balloon creates a relatively bloodless field for surgery.

Laparoscopic US is also valuable. It has an advantage over abdominal US in that the probe can be used to palpate the surface of the liver. This ability aids in the diagnosis of hemangiomas, which can be compressed, unlike solid tumors, which cannot.

Synchronous liver metastases are frequently encountered at surgery for GI malignancy; of these, as many as 40% may not have been palpable. IOUS enables the detection of 93% of liver metastases, compared with the 51% detection rate with preoperative CT and US; 66% are palpable at surgery.⁹

By better defining the hepatic venous vasculature, IOUS allows many more surgical resections for colorectal metastases than was possible, as determined on the basis of preoperative scanning. However, IOUS may also cause the upstaging of colorectal metastases, preventing unnecessary surgery.

Degree of Confidence

The specificity of US in detecting liver metastases is poor, and its overall false-negative rate is 50%. However, these data are from older studies, and US technology has evolved considerably. Therefore, both sensitivity and specificity are expected to improve with modern techniques.

In these days of spiraling costs and limited resources, there is considerable debate regarding the choice of the ideal noninvasive imaging modality for the detection of liver metastases. The use of multiple modalities is both time-consuming and costly. One must therefore place US in the correct order within the diagnostic pathway. US is valuable, inexpensive, quick, and portable, and it can depict lesions as small as 1 cm.

The addition of Duplex, color Doppler, and tissue harmonic imaging and the use of US contrast enhancement have improved the sensitivity and specificity of US in the detection of focal liver lesions. US can also be used to guide access to focal liver lesions for biopsy.

IOUS is extremely sensitive for metastases not detected on preoperative scanning. The 90% sensitivity of IOUS approaches that of CT with the bolus injection of contrast material, and IOUS is the most sensitive test available for detecting liver focal lesions. IOUS of the liver has the highest sensitivity for the detection of focal liver abnormalities, with 96% accuracy, versus 84% for transabdominal US. At present, IOUS is more accurate than any other imaging modality and is used in the authors' unit for cases not adequately diagnosed and staged by US, CT, and MRI.

False Positives/Negatives

Hemangiomas, multicentric HCCs, multiple liver adenomas, complicated simple cysts, hydatid cysts, FNH, regenerative nodules, focal fatty sparing, and focal fatty infiltration may all mimic liver metastases.

With IOUS, a false-positive diagnosis may occur in 2-4% of cases; however, IOUS-guided biopsy that allows the examination of frozen sections may address this problem.

NUCLEAR MEDICINE

Section 8 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

The standard sulfur colloid scans for the detection of liver metastases are no longer performed. The value of nuclear medicine studies lies in the fact that they can be used to characterize several of the benign liver lesions, which may mimic solitary or multiple metastases. The distinction of these lesions is a particular problem when one is staging a known primary cancer in a patient in whom benign focal liver masses are incidentally discovered. The colloid scan can be of great help in distinguishing a number of benign conditions that may mimic metastases and include fatty infiltration, FNH, and macroregenerative nodules.

The role of nuclear medicine in liver imaging has been undergoing great changes; for example, CT has replaced radionuclide imaging as the criterion standard screening tool for liver metastatic disease. Although conventional CT has a sensitivity of 85% for detecting any metastases, it is only 60% sensitive for individual lesions. (Whether helical and multisection CT improves the sensitivity remains to be seen). The specificity of solitary lesions is also low with CT.

In a patient with a known primary malignancy, the presence of multiple liver lesions is highly suggestive of metastases. However, a solitary liver lesion in the same patient almost always needs further characterization. In this instance, imaging modalities such as MRI and radionuclide imaging are often necessary to make a specific diagnosis. Many of these lesions can be further characterized by performing scintigraphy, and a specific diagnosis may be made with focal fatty infiltration, focal fatty sparing, FNH, liver abscesses, and hemangiomas.

Nuclear medicine techniques

Hepatic arterial perfusion scintigraphy

With limited liver disease, resection of metastases is associated with a 5-year survival rate of 25-30% in patients with colorectal cancer. However 30%, of patients undergoing hepatic resection for colorectal metastases are known to have occult metastases that are not detected with CT, US, or sulfur colloid scanning. These patients may benefit from CTAP, which works on principals similar to those of hepatic artery perfusion scintigraphy (HAPS). The study involves the infusion of technetium-99m (^99mTc) macroaggregated albumin into a hepatic artery catheter. Metastases appear as areas of increased focal radionuclide uptake.

Hepatic perfusion index

The hepatic perfusion index has been used to evaluate occult or subclinical liver metastases. The technique involves dynamic hepatic scintigraphy, which provides an estimate of the ratio of the total arterial blood flow to the total liver blood flow; this ratio is known as the hepatic perfusion index. Some believe that an increased hepatic perfusion index is associated with occult liver metastases, whereas others maintain that a low index is more important. A low index suggests that the patient is at a low risk of metachronous tumors, and therefore, they can be spared from adjuvant chemotherapy.

^99mTc sulfur colloid scintigraphy

Sulfur colloid scintigraphy has largely been abandoned as an imaging test for liver metastases despite its reasonably high sensitivity for detection of metastatic disease (80-85%). The lesions appear as photon-deficient defects, which are nonspecific. Also, the sensitivity of planar imaging decreases dramatically for surface lesions smaller than 2 cm and deeper lesions smaller than 3-4 cm in diameter. A genuine liver lesion within a fatty liver may be missed or mischaracterized on other imaging studies. In this instance, sulfur colloid scanning can be useful in confirming or excluding a mass lesion in the liver.

Somatostatin receptor analogue scintigraphy

Scintigraphy may be useful in evaluating GI carcinoids and other neuroendocrine tumors. Somatostatin receptor analogue scintigraphy has had the greatest impact on the diagnosis of gastrinomas, with a sensitivity and specificity of 80-90% for detection of both primary and metastatic sites. Somatostatin receptor analogue scintigraphy can depict subcentimeter liver metastases with a high signal-to-noise ratio. Somatostatin receptor analogue scintigraphy has been reported to show uptake in insulinomas, glucagonomas, small-cell lung cancer, thyroid cancer, and carcinoids.

Somatostatin receptor analogue scintigraphy may prove useful in the treatment of patients with hypergastrinemic states who have increased incidence of gastric carcinoids. In patients with multiple endocrine neoplasia type 1 (MEN-1), localization in the upper abdomen may not be associated with a pancreatic endocrine tumor; instead, it may be caused by a gastric carcinoid.

With pancreatic carcinoid, somatostatin analogue scintigraphy has been proven to be sensitive, although findings are nonspecific because the scan also may show positive findings for islet cell tumors. Regarding small-bowel carcinoid, somatostatin receptor scintigraphy performed with indium-111 (¹¹¹In) octreotide and  ¹¹¹In pentetreotide is used to image many neuroendocrine tumors, including carcinoids that possess somatostatin-binding sites. Several studies have shown that this method is sensitive and noninvasive for imaging primary carcinoid tumors and carcinoid metastatic spread. The addition of single photon emission CT (SPECT) further refines the technique, increasing sensitivity.

Scintigraphy performed with iodine-123 (¹²³I) metaiodobenzylguanidine (MIBG) demonstrates 44-63% uptake in GI carcinoids. A higher frequency of uptake is found in midgut carcinoids and in tumors with elevated serotonin levels.

FDG PET

High rates of tumor recurrence after liver resection for colorectal metastases suggest that current imaging strategies are failing to detect occult liver and extrahepatic metastases. Although FDG PET cannot match the anatomic resolution of cross-sectional imaging, it is particularly useful in the detection and characterization of extrahepatic disease that may not be identified on cross-sectional imaging.

¹⁸F-Dopa PET has been used to image primary GI carcinoid tumors and lymph node and organ metastases, with promising results. FDG PET imaging is now more available and more widely used. In general, FDG PET is useful in poorly differentiated carcinoids and other neuroendocrine tumors, but it should not be used as a first-line imaging agent. FDG PET is primarily useful when somatostatin receptor scintigraphy results are negative.

CEA immunoscintigraphy

CEA is a tumor-associated antigen arising from the entodermally derived epithelium of the GI tract. It is expressed in a variety of adenocarcinomas, such as colorectal cancer. CEA is a self-antigen not recognized by the immune system as a foreign substance, and therefore, it does not provoke an immune response. CEA occurs on the cell membrane of colorectal carcinomas. An anti-CEA antibody der