The same group subsequently published a larger, prospective study of liver metastases detection in 300 consecutive triple-phase helical CT examinations in breast cancer patients.² PV phase images were reviewed alone for the number and size of focal liver lesions. PV images were then reviewed in conjunction with noncontrast images, and again in conjunction with HA phase images. Little improvement in sensitivity for lesion detection was noted when comparing PV phase alone with PV phase in conjunction with noncontrast imaging (97% to 100%) or HA phase (96% to 98%), suggesting little additional benefit was derived from the addition of noncontrast or HA phases. Two to 4% of lesions were seen on HA phase imaging only. These represented either false-positive cases or were seen in conjunction with other metastases on the PV phase. The authors concluded that routine triple-phase imaging of breast cancer patients in whom liver metastases were suspected was not warranted, except at the time of initial examination when triple-phase technique is useful for characterizing focal lesions (e.g., cysts, hemangiomas, focal nodular hyperplasia) that may be encountered.

Magnetic Resonance Imaging

MRI is an excellent alternative for imaging of the liver, for initial evaluation for suspected metastases, characterization of lesions identified on other modalities, and follow-up of patients with known liver metastases. Advantages of MRI as a liver imaging modality include high intrinsic soft tissue contrast, higher sensitivity to contrast enhancement, lack of ionizing radiation, and better safety profiles of the gadolinium chelate contrast agents used in MRI compared with iodinated CT contrast agents. Reactions and allergies to gadolinium chelates are rare, and at standard doses, nephrotoxicity is generally not an issue.

Optimal liver imaging with MRI is performed on high-field strength magnets of 1 Tesla or greater, using phased array coils (for better signal-to-noise ratio than with body coil imaging), with breath-hold technique to minimize patient motion. Pulse sequences include T1-weighted gradient echo sequences (in and out of phase), fluidsensitive sequences (short tau inversion recovery [STIR] and T2-weighted), and multiphasic fat-saturated, contrast-enhanced, T1-weighted sequences (either two- or three-dimensional gradient echo). With breath-hold technique, a complete evaluation of the liver, with and without contrast enhancement, including multiphasic dynamic enhanced technique, can be completed in 30 minutes.

Breath-hold, fat-saturated, gradient echo volumetric sequences can image the entire liver in thin slices (three-dimensional) in a reasonable breath hold, and can be repeated before and after contrast enhancement to obtain a dynamic assessment of the contrast enhancement pattern of any lesions that are identified. The sequence can be run repetitively to coincide with HA dominant, PV phase, and hepatic venous or interstitial phases of enhancement. The contrast agents are extracellular gadolinium chelates, which shorten T1 relaxation time, and are analogous in distribution to iodinated contrast agents used for enhancement in CT.

The HA dominant phase occurs 15 to 30 seconds after the bolus injection of contrast. During this phase, hypervascular lesions (lesions that enhance more than the liver parenchyma) are more readily visualized against a background of the minimally enhanced liver parenchyma. The hepatic arteries should be brilliantly enhanced during this phase, and the main portal veins show early enhancement as well, but the hepatic veins will not yet be enhanced.

The PV phase occurs 45 to 75 seconds after the start of bolus contrast injection, and during this phase, the liver parenchyma is maximally enhanced, as well as the portal and hepatic veins. This phase is optimal for depiction of most hypovascular liver lesions, including most metastases.

A delayed enhanced series, performed from 90 seconds to 5 minutes, depicts the hepatic venous or interstitial phase and is useful for characterization of lesions with persistent or late enhancement, such as cavernous hemangiomas and some cholangiocarcinomas.

Positron Emission Tomography

On PET, the normal liver generally displays a diffuse, low to medium level of activity. On attenuation-corrected images particularly, the liver activity often has a diffusely mottled appearance. Reconstruction artifacts contribute to this appearance and will be most apparent in larger patients. Non-attenuation-corrected images will show a gradient of activity (increased toward the liver periphery) but can be helpful to review in such patients. In general, the expected low level of activity of the normal liver provides an excellent backdrop for ready identification of hypermetabolic liver metastases. In the untreated patient, liver metastases as small as 1 cm can be identified. However, visualization of even considerably larger liver metastases may be less reliable when patients are receiving hormonal or chemotherapy.

FINDINGS OF LIVER METASTASES

Ultrasound

Liver metastases on ultrasound may manifest as solitary or multiple lesions, which most commonly are hypoechoic compared with the normal liver (Figure 1), or as diffuse inhomogeneity of the liver parenchyma (Figure 2).

FIGURE 1 A 37-year-old woman with metastatic breast cancer to liver, thorax, and bone. Longitudinal ultrasound image of the liver shows multiple hypoechoic liver metastases scattered throughout the liver. There is a right pleural effusion as well.

FIGURE 2 Another ultrasound manifestation of liver metastatic disease is diffuse inhomogeneity of the liver parenchyma, seen here in an 83-year-old woman who had known liver metastases for 3.5 years and had been treated with a variety of therapies. The liver contour is nodular, a recognized treatment effect, simulating cirrhosis.

Computed Tomography

On CT, breast cancer liver metastases typically are hypodense relative to normal liver on noncontrast series, may display rim enhancement or be hypervascular compared with the poorly enhanced liver on the hepatic arterial phase of enhancement, and on the portal venous phase, are hypodense relative to the enhancing liver (Figure 3).

FIGURE 3 CT images of liver metastases from an 83-year-old woman (same patient as in Figure 2) who developed a malignant pleural effusion and liver metastases 20 years after undergoing mastectomy for breast cancer. At the time of this study, the patient had known metastatic breast cancer for 3 years and had been relatively asymptomatic, first on letrozole (Femara) and then on fulvestrant (Faslodex), but progressive disease was suspected based on rising tumor markers. A, Unenhanced abdominal CT scan (acquired with arms at sides during tidal respiration for attenuation correction of PET) shows liver metastases as hypodense lesions compared with rest of the liver. B, Arterial phase enhanced CT scan shows three similar-appearing metastases, with thick peripheral enhancement and central hypodensity. The large hepatic veins are not enhanced during the HA phase of enhancement. C, PV phase enhanced CT image, same level, shows the lesions as larger hypodense regions, and an additional hypovascular metastasis is now seen in the peripheral right lobe, anterior segment, which was not previously seen on unenhanced or HA phase enhanced CT scans.

Magnetic Resonance Imaging

On T1-weighted sequences, the liver normally is brighter than the spleen. Most liver lesions that are not of hepatocellular origin (including the most commonly encountered liver lesions, namely cysts, hemangiomas, and metastases), are hypointense compared with the liver parenchyma on T1-weighted sequences. Lesions that are of hepatocellular origin (such as hepatocellular carcinoma, adenomas, and focal nodular hyperplasia) are often isointense or hyperintense to liver parenchyma on T1-weighted sequences. A variety of T1-weighted sequences are available, including conventional spin echo, turbo or fast spin echo (depending on the manufacturer), and gradient echo. Gradient echo T1-weighted sequences may be acquired with the echo time (TE) varied so that fat and water protons are in or out of phase. Such acquisitions are sensitive to the presence of microscopic fat and are very useful for identifying fatty infiltration, focal areas of fat deposition or sparing, and nodular forms of steatosis (Figures 4 and 5). On in-phase imaging, water and fat signal in the same voxel are additive, whereas on out-of-phase images, water and fat signal in the same voxel are opposed, leading to a loss of signal, which identifies fat-containing regions. The same principle is applied in the use of in-phase and out-of-phase imaging to confirm the identity of lipid-rich adrenal adenomas.

FIGURE 4 A 50-year-old woman with indeterminate hyperechoic liver lesions found on abdominal ultrasound, obtained to evaluate epigastric discomfort. A, Triple-phase abdominal CT was initially obtained to characterize the lesions. Noncontrast CT shows a hypodense lesion in the left lobe, one of four similar-appearing lesions. B, Arterial phase enhanced CT scan does not show the lesion to be hypervascular. It is not well seen on this phase of enhancement. C, PV phase enhanced CT scan shows the lesion to be hypodense compared with the enhancing liver. No peripheral nodular enhancement was seen to suggest a hemangioma.

FIGURE 5 Abdominal MRI was then obtained to further assess the indeterminate liver lesions seen on CT in Figure 4. A, Axial half-Fourier acquisition single shot turbo spin echo (HASTE) (T2-weighted) shows the lesion to be brighter than the liver, similar to the spleen (arrow). B, Axial STIR does not clearly show the lesion. C, In-phase, T1-weighted axial image shows the lesion to be slightly hyperintense compared with the rest of the liver. D, Out-of-phase, T1-weighted axial image shows the pivotal observation: there is a marked loss of signal of the lesion, indicating fat content. The other lesions behaved in a similar fashion. E, Axial fat-saturated, T1-weighted, gradient echo image before contrast administration shows the lesion as hypointense. F, PV phase, enhanced, fat-saturated, T1-weighted, gradient echo image shows the lesion as hypointense compared with the liver. No vascular displacement is evident. G, Coronal HASTE (T2-weighted) image shows two of the four similar-appearing lesions in the left lobe. H, Coronal fat-saturated, T1-weighted, gradient echo image of the same two lesions. Hyperechoic ultrasound lesions most commonly represent hemangiomas, but focal fat is also in the sonographic differential diagnosis. These lesions show none of the characteristic imaging features of hemangiomas on CT or MRI. The critical observation to make is the loss of signal of the lesions between in-phase and out-of-phase, T1-weighted, gradient echo imaging, confirming mass-like accumulations of focal fat. This was biopsy-confirmed macrovesicular steatosis.

Fluid-sensitive sequences include T2-weighted and STIR sequences, which can be performed with or without fat saturation. Most liver lesions are hyperintense compared with liver parenchyma. The degree of hyperintensity is helpful in characterization of lesions, with cysts and hemangiomas more hyperintense and “fluid” in signal intensity than metastases and other more “solid” neoplasms. A good rule of thumb: the signal intensity of cysts and hemangiomas should be analogous to the cerebrospinal fluid (CSF) signal, whereas that of metastases and other neoplasms will approximate the signal intensity of the normal spleen.

Dynamic, enhanced imaging consists of repetitive performance of breath-hold, three-dimensional, fat-saturated, T1-weighted, gradient echo volumetric sequences, before, at 25 seconds, at 60 to 70 seconds, and at 2 or more minutes after bolus administration of gadolinium chelate contrast media. The presence or absence of contrast enhancement and the pattern and timing of enhancement generally enable reliable differentiation of benign cysts and hemangiomas from metastases.³

As previously noted, breast cancer metastases have been variably considered in the literature to be hypervascular metastases. Danet and associates looked at a series of liver MRIs obtained on 165 consecutive patients with untreated liver metastases, from a variety of primary tumors, including 16 patients with breast cancer.⁴ In this series, 69% of the breast cancer patients (11 of 16 patients) had metastases that were hypervascular, defined as enhancement greater than the liver on HA phase of enhancement, comparable to the pancreas. Smaller lesions (<1.5 cm) showed homogeneous hypervascular enhancement, whereas larger lesions (>3 cm) tended to show a peripheral ring of enhancement during the HA phase. In this series, 31% of the breast cancer patients (5 of 16) showed a hypovascular pattern of enhancement of liver metastases. Even for hypovascular metastases, the most common enhancement pattern seen during arterial dominant imaging was a faint peripheral ring of enhancement. The peripheral ring of enhancement was the most common enhancement pattern seen for all untreated metastases during arterial phase imaging in this series, and was seen in both hypervascular and hypovascular metastases and in 72% of the patients overall. This is considered a specific enhancement pattern for metastases. Incomplete central progression of enhancement was the most common pattern seen on delayed imaging in both hypervascular and hypovascular metastases, and was seen in 63% of the patients in this series of untreated metastases from a variety of primaries.

FREQUENCY OF LIVER INCIDENTALOMAS

On imaging of the liver for suspected metastases, a variety of benign “incidentalomas” will be encountered. These must be accurately characterized, reported, then dismissed. It is useful to gain perspective on the scope of this issue by reviewing series from the literature that address the incidence and significance of small focal liver incidentalomas. Depending on the series, small focal liver lesions have been variably defined as less than 10 or 15 mm. Jones and colleagues demonstrated that small focal liver lesions (<15 mm in this series) are common, found in 17% of 1454 consecutive outpatients undergoing contrast-enhanced abdominal CT over a 1-year period.⁵ Eighty-two percent of the patients with small focal liver lesions had a malignancy history. Of these, lesions were found to be benign in 51%. This report found that in patients with no cancer history, small focal liver lesions are almost invariably benign.

Even in patients with a malignancy history, small focal liver lesions (<10 mm in the series of 2978 cancer patients undergoing CT over a 2-year period by Schwartz and associates) were benign 80% of the time.⁶ In this series, focal liver lesions proved to be metastases in about 12% of patients overall and in 22% of patients when the malignancy history was breast cancer. However, this series did not include a control group of breast cancer patients without such lesions.

Krakora and colleagues evaluated the prognostic significance of the presence of small (<15 mm), hypoattenuating liver lesions on CT in breast cancer patients.⁷ This was a retrospective review of 153 breast cancer patients who underwent serial abdominal CT, who did not have definite liver metastases at initial CT. Of these patients, 35% (54 of 153) had one or more small hypoattenuating liver lesions on initial CT. Twenty-eight percent (43 of 153) developed definite liver metastases on subsequent CT. These included 28% of patients (15 of 54) with hypoattenuating liver lesions on initial CT and 28% (28 of 99) without such lesions. No association was demonstrated between the presence, size, or number of small hypodense liver lesions on initial CT and the subsequent development of liver metastases. The authors concluded that in breast cancer patients, the presence of small, hypoattenuating liver lesions on CT, without other evidence of hepatic metastases, was not associated with an increased risk for subsequently developing liver metastases.

Khalil and associates looked at the prevalence and significance of hepatic lesions considered to be too small to characterize (TSTC), which were identified on contrast-enhanced CT obtained in breast cancer patients.⁸ At least one hepatic lesion considered TSTC (and no definite metastasis) was identified in 29% (277 of 941) of their patients. Subsequent imaging in 69% of patients (191 of 277) showed no change in 92% (175 of 191) or lesion nonvisualization in 4% (8 of 191). Interval enlargement of a lesion previously considered TSTC was noted in 6 of 191 patients (3%). Of these 6, 3 were metastatic breast cancer, 1 was metastatic pancreatic cancer, 1 was a growing cyst, and the final lesion was indeterminate. In this series, liver lesions that were initially TSTC were benign 93% to 97% of the time.

Similar series have looked at the incidence of benign liver incidentalomas detected on liver imaging by MRI in patients with breast cancer. An interesting series was reported by Noone and associates, who looked at 34 patients referred for liver MRI evaluation for suspected metastases at the time of initial breast cancer diagnosis.⁹ The patients were referred for characterization of liver lesions noted on CT or ultrasound, or for liver function test abnormalities. A full third of the patients had benign lesions identified, including 11 (32%) with benign lesions only and an additional 2 patients with benign lesions coexisting with malignant lesions. The benign lesions were hemangiomas (7), cysts (5), adenomas (2), and one case each of focal fat deposition and focal fatty sparing. Three of 34 patients (9%) had multiple types of benign liver lesions.

In this series, liver neoplasia was identified in 62% of patients (21 of 34), of which 19 were breast cancer metastases, with one case each of metastatic carcinoid and hepatocellular carcinoma. There was one technically compromised false-negative case of sub-centimeter periportal biopsy-proven metastases, which was also false negative on ultrasound and CT. Overall results for the identification of malignant liver lesions were sensitivity of 95%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 92%.

In this same series of 34 patients, only 2 (6%) patients had no focal liver lesions identified on MRI. Even allowing for the select nature of the study population, this result attests to the common occurrence of benign liver lesions when evaluating a population of breast cancer patients suspected of liver metastases.

Even when not directly evaluating the liver, it may be partially visualized during breast MRI (depending on the coil coverage). Accordingly, even the full-time breast imager needs to be familiar with focal liver lesions (Figure 6). In this setting, the imaging information will not be as complete as with a dedicated abdominal examination. It is important to have an understanding of when there is sufficient information to characterize a liver lesion or not. Similarly, not infrequently, focal liver lesions may have to be assessed based on a single phase of CT enhancement (usually portal venous), such as in metastases screening CT in patients with new diagnoses of locally advanced breast cancer (Figure 7).

FIGURE 6 A 52-year-old woman with left breast inflammatory carcinoma, undergoing initial staging. A, PV phase, enhanced axial abdominal CT scan shows several sharply marginated, near water density, nonenhancing liver cysts. Additional cysts were noted on other slices. Lobular renal margins may be the residua of infection. B and C, Axial STIR images from staging breast MRI show diffuse skin thickening and edema of the left inflammatory carcinoma. In the liver, sharply marginated, hyperintense, fluid signal intensity, scattered lesions are seen in the liver. Based on this hyperintensity, a differential of small cysts or hemangiomas can be suggested. D and E, Fat-saturated, T1-weighted, gradient echo axial images through the same levels from the same study show no enhancement, confirming cysts.

FIGURE 7 A 51-year-old woman with ulcerated, neglected, locally advanced, poorly differentiated infiltrating ductal carcinoma (IDC), presenting with lytic bone metastases (stage IV disease). Images from PV phase, enhanced abdominal CT images over a 1-year period show a variety of similar, overall stable appearances of a small incidental liver hemangioma, which was metabolically inactive on PET. A, Staging CT scan shows a hypodense lesion at the dome (posterior segment, right lobe), with nodular foci of enhancement on the periphery. B, Repeat PV phase enhanced CT scan, 3 months later, shows a similar appearance of nodular and globular peripheral enhancement of a small hemangioma at the dome. C, Repeat PV phase, enhanced CT scan, 2 months later, shows stable findings. D, PV phase, enhanced abdominal CT scan, 7 months later (1 year after study in A) shows no change.

Given the high likelihood of encountering liver incidentalomas in the imaging evaluation of breast cancer patients, a thorough review of their features is in order.

IMAGING FEATURES OF COMMONLY ENCOUNTERED BENIGN LIVER INCIDENTALOMAS

Cysts

Liver cysts are common, seen in 5% to 14% of the general population. They are thought to arise from bile duct epithelium. On ultrasound, cysts in the liver are anechoic, with sharp margins and enhanced through-transmission, analogous to breast cysts. On both CT and MRI, they are homogeneous, are near-water in density or signal intensity, have circumscribed margins and an imperceptible wall, and do not enhance (see Figures 6, 11B, and 11C). On CT, the density should be less than 20 HU, with the caveat that very small cysts may be volume-averaged with adjacent tissue and will have density greater than 20 HU. Readily visualizing a small, hypodense lesion on CT suggests it is cystic, because of the greater attenuation difference between a fluid density cyst and liver parenchyma than between a small metastasis and liver. On MRI, cyst signal intensity will approximate CSF on all sequences.

FIGURE 11 Enhanced abdominal CT images from a 59-year-old woman with recurrent breast cancer, metastatic to mediastinal lymph nodes and bone. A, Localized region of hypodensity, consistent with focal fatty infiltration, is characteristic in location at the falciform ligament level. B and C, Additional sections from this patient show sub-centimeter, circumscribed, nonenhancing, near-water density cysts in the left lobe of the liver. Benign incidentalomas are not infrequently multiple, and multiple types of benign lesions can be seen in the same patient, as in this case.

Rarely, cysts may be difficult to differentiate from cystic metastases. Identification of thick or irregular walls, internal septations, and any enhancement or density greater than 20 HU on CT usually allows cystic neoplasms to be distinguished from simple cysts.

Hemangiomas

Hemangiomas are the most commonly encountered benign liver tumor, seen in 7% of the normal adult population and 20% of autopsy specimens. Composed of communicating endothelium-lined vascular channels within a loose fibroblastic stroma, they are supplied by HA branches but have slow internal circulation. This structure is reflected in their characteristic enhancement pattern, with peripheral nodular or globular puddling enhancement, progressing centripetally to partially or completely fill in on delayed imaging. Larger lesions in particular may not fill in entirely, and complete fill-in is not necessary to confirm the diagnosis. The enhancement intensity should follow the aorta throughout all phases of imaging. Small hemangiomas may be completely opacified by the time of initial enhanced imaging, so-called flash filling. Hemangiomas are sharply marginated and may have internal septa that can be visualized, especially on MRI. On noncontrast CT, hemangiomas are hypodense to normal liver and isodense to the blood pool. On unenhanced MRI, hemangiomas are hypointense to liver on T1-weighted sequences and markedly hyperintense to liver (similar to CSF) on fluid-sensitive sequences (T2-weighted and STIR). On ultrasound, small hemangiomas are generally uniformly hyperechoic. Echogenicity of larger hemangiomas is more variable. For examples of the imaging features of hemangiomas, see Figures 7, 8, 12C and 12D, and Case 1 in this chapter.

FIGURE 8 A 44-year-old woman with recurrent breast cancer, presenting 2 years after treatment of the primary with a malignant pleural effusion. Restaging CT shows in the abdomen a small hypodensity at the liver dome, with a nodular focus of associated enhancement, of similar density to other enhanced vessels. This focus was negative on PET and is compatible with a small hemangioma.

FIGURE 12 The difficulty of characterizing small, indeterminate liver lesions found on CT with ultrasound is demonstrated in this 49-year-old woman with newly diagnosed, node-positive (5 of 8, largest 1.9 cm, with extracapsular extension), 1.8-cm left breast IDC. Staging studies with PET and enhanced PV phase CT showed a variety of small, indeterminate, PET-negative liver lesions. Ultrasound or triple-phase CT was recommended for further characterization, and ultrasound was obtained. A, Enhanced abdominal CT, PV phase, at the dome of the liver, shows a sharply marginated, 1.5-cm, low-density (but not clearly fluid density by HU) lesion. No ultrasound correlate was identified, despite its size, probably because of its location. B, No ultrasound correlates were found for these two tiny lucencies at the liver dome, probably because of their small size and location at the dome. C, A vague hypodensity at the periphery of the right lobe of the liver appears to have a globule of associated peripheral enhancement (arrow), suggesting it may be a hemangioma. D, Ultrasound through the right lobe of the liver shows a corresponding, uniformly hyperechoic, peripheral lesion, compatible with a hemangioma.

Fatty Change of the Liver

Fatty infiltration of the liver can be diffuse, geographic, focal or multifocal, and nodular, termed nodular steatosis.¹⁰ Fatty liver is commonly associated with alcoholic liver disease, metabolic syndrome (insulin resistance, obesity, and hyperlipidemia), viral infections or hepatitis, and drug exposure to steroids or prior chemotherapy. On ultrasound, fatty change is generally recognized by increased liver parenchymal echogenicity compared with normal renal cortex (Figure 9). The normal liver approximates or is minimally more echogenic than the normal kidney. The liver may be enlarged. With increasing degrees of fatty change, intrahepatic vessel visualization is hampered, as well as visualization of the diaphragm.

FIGURE 9 A 50-year-old woman with stage IV breast cancer metastatic to bone, diagnosed at presentation 2.5 years before, now has elevated liver function tests and rising tumor markers. The patient had been on exemestane (Aromasin) and zoledronic acid (Zometa) since her diagnosis, but had initiated chemotherapy recently and had undergone one cycle of capecitabine (Xeloda). Longitudinal abdominal ultrasound image shows diffuse hyperechogenicity of the liver, compared with the right kidney. There is loss of detail of intrahepatic vessels. Ultrasound findings are compatible with fatty change of the liver. This appeared to be new compared with CT performed 3 months before.

On CT, fatty change of the liver is recognized best on noncontrast images as reduced liver attenuation compared with the spleen (Figure 10). With marked degrees of fatty change, conspicuity of vessels and lesions is increased in comparison with the hypodense liver parenchyma, with the fatty change serving as a form of natural contrast. The liver density is normally 8 HU higher than the spleen. The diagnosis of fatty liver can be confirmed when the attenuation of the liver is at least 10 HU less than the spleen on unenhanced CT, or if the liver attenuation is less than 40 HU on enhanced CT.

FIGURE 10 A 35-year-old woman with stage IV breast cancer (metastatic to bone) at presentation 7 months prior, treated with tamoxifen and Zometa until 1 month before, when chemotherapy with docetaxel (Taxotere) was begun and tamoxifen discontinued, for progression on bone scan of bone metastases. A, Unenhanced abdominal CT scan shows the liver to be markedly hypodense compared with the spleen. The liver fatty change serves as a natural contrast agent, delineating a new left lobe metastasis. B, HA phase, enhanced CT from the same study. Enhancement in the lesion is more difficult to discern visually. C, PV phase, enhanced CT, from the same study, shows the same lesion. Enhancement is difficult to assess visually. Measurement of density confirms enhancement, increasing from 25 HU on the noncontrast study to 72 HU on this PV phase. D, Comparison study (PV phase, enhanced), 7 months earlier, at initial diagnosis of stage IV breast cancer, shows normal liver density.

Focal fat deposition is recognized as geographic or non-mass-like reduced attenuation and is commonly noted adjacent to the ligamentum teres (Figure 11A), as well as the porta hepatis and the gallbladder fossa. The location and appearance are usually sufficiently characteristic to enable recognition. Occasionally, focal fat deposition may be mass-like and will require further workup. If further characterization is needed, in-phase and out-of-phase T1-weighted, gradient echo MRI will show loss of signal in fat-containing regions on the out-of-phase images (see Figure 5).

CHARACTERIZING SMALL FOCAL LESIONS

Given that most routine liver imaging is with CT and that small, hypodense, difficult to characterize lesions will be regularly encountered, is there utility in additional imaging, with either ultrasound or MRI, to characterize indeterminate small lesions? We have seen that statistically, such too small to characterize (TSTC) lesions found on CT are most often benign.

Ultrasound is very operator dependent, and its sensitivity for identification of small liver lesions is greatly affected by a patient’s body habitus. Eberhardt and colleagues looked retrospectively at the performance of sonography in evaluating small, indeterminate liver lesions found on CT in cancer patients.¹¹ In their series of 76 patients with 124 indeterminate, CT-identified, small (<1.5 cm) liver lesions, less than half (48%) of the lesions were found on ultrasound. The detection rate was influenced both by the size of the lesions and whether the sonographer was aware of the CT result and specifically sought an ultrasound correlate. Two thirds (66%) of lesions were found when the CT data were referenced, compared with only about one third (32%) when it was not. Lesion size was the other major factor influencing detection, with 67% of lesions measuring 0.6 to 1.5 cm found, compared with 19% of lesions smaller than 0.5 cm. Patient body habitus was also a significant factor affecting lesion detection with ultrasound. The lesions ultrasound did find were successfully characterized in most cases (93%).

The authors concluded that ultrasound may be useful to characterize 0.6- to 1.5-cm indeterminate liver lesions found on CT in cancer patients of average body habitus. The opposite conclusion could be drawn in reference to the same material: that ultrasound is too operator and patient body habitus dependent, as well as too limited for evaluation of very small (<0.5 cm) lesions to be routinely advocated to characterize small, indeterminate, CT-identified lesions, which are statistically highly likely to be benign (Figure 12).

Such a conclusion was drawn by Patterson and associates, who looked at evaluating small (TSTC) CT liver lesions in breast cancer patients with MRI.¹² Their study population consisted of 38 women with breast cancer who underwent abdominal MRI at or after initial diagnosis of breast cancer and who had at least one TSTC liver lesion previously identified on CT. In 11 patients (30%), indeterminate lesions on CT remained indeterminate on MRI. Follow-up imaging, biopsy, or both in 8 of these 11 patients confirmed benignity of the indeterminate lesions. In 8 patients (21%), no lesion was confirmed on MRI at the site questioned on CT. Metastatic lesions were identified in 2 patients, and benign diagnoses were confirmed by MRI in 22. The authors concluded that only marginal benefit was derived from using MRI to characterize TSTC liver lesions found on CT in newly diagnosed breast cancer patients, if their initial CT did not show definite liver metastases. In this series, only about 5% of such TSTC lesions on CT proved on MRI to be metastases.

TREATMENT EFFECTS: IMAGING MANIFESTATIONS

A variety of morphologic changes can be seen in the liver after treatment with chemotherapy. These changes can be diffuse, such as fatty change (see Figure 10), or local changes may be seen at the site of treated liver metastases. Liver metastases may shrink, or largely resolve, in response to successful systemic therapy. A hypodense, scar-like residual may remain at the site of a treated lesion, and either growth or shrinkage of breast cancer metastases has been shown to induce changes in the overlying liver contour, resulting either from capsular retraction or nodular regeneration of uninvolved areas. The end result can on occasion mimic cirrhosis, with lobularity of the liver contour, atrophy of heavily involved lobes, enlargement of the caudate lobe, and even development of ascites on occasion (Figures 13 and 14). This appearance developing in response to chemotherapy for breast liver metastases has been termed pseudocirrhosis and is illustrated in Case 3 in this chapter.

FIGURE 13 A 63-year-old woman with metastatic breast cancer to bone and liver. Liver metastases were biopsy proven, with three separate sites sampled. A and B, PV phase, enhanced abdominal CT images show multiple rim-enhancing necrotic metastases. C and D, PV phase, enhanced abdominal CT images, 1 year later, showing comparable levels. The patient had been receiving weekly chemotherapy. Liver metastases show marked improvement. Some lesions have resolved, whereas others have shrunk. Hypodense residual lesions, many with capsular contraction, remain where the larger metastases were and produce a pseudocirrhosis appearance of the liver. Concurrent PET scan showed extensive osseous metastases, but no foci of uptake in the liver.

FIGURE 14 A 50-year-old woman, treated the previous year with breast conservation for a high-risk left breast cancer, estrogen receptor positive, with angiolymphatic invasion and 10 of 11 lymph nodes involved. She had been treated with chemotherapy with doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), and paclitaxel (Taxol), completed 3 months before, and started tamoxifen. Radiation therapy concluded 2 months before the patient presented with node-positive, inflammatory right breast cancer (IDC). There was no evidence of visceral metastatic disease by CT or PET, and the patient was treated with four cycles of chemotherapy using Taxotere and Xeloda. A, Restaging enhanced abdominal CT (PV phase) showed two new hypodense liver lesions. The larger of the two is shown, in the posterior segment of the right lobe, and measures 11 mm. PET/CT was negative at this time in the liver. B, Repeat CT scan, 3 months later, after two cycles of Taxol and bevacizumab (Avastin). The index lesion has grown, and there are multiple, additional, smaller, less well-defined hypovascular lesions seen throughout the liver. Note developing left lobe deformity, with surface nodularity due to capsular contraction. C, Concurrent PET scan shows multiple metabolically active liver metastases, new from a study 3 months prior. D, Repeat CT scan, 3 months later, after a trial of gemcitabine. An increasingly nodular appearance of the left lobe is seen. The liver is diffusely heterogeneous, with multiple rim-enhancing metastases. E, Concurrent PET scan shows progressive bone, right chest wall soft tissue, and liver metastases. F, Abdominal ultrasound, later the same month as D, shows diffuse parenchymal heterogeneity and macronodular liver contour. Individual liver metastases are difficult to define. Ascites has developed, and the patient was now jaundiced.

Rarely, treated metastases may regress to leave cyst-like residuals (see Case 6 in this chapter).

REFERENCES

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12 Patterson SA, Khalil HI, Panicek DM. MRI evaluation of small hepatic lesions in women with breast cancer. Am J Roentgenol. 2006;187:307-312.

CASE 1 Workup of indeterminate liver lesion with MRI (hemangioma)

A 57-year-old woman with a remote history of treated breast cancer developed mild liver function test elevations while on statin therapy for elevated low-density lipoprotein cholesterol. Her breast cancer history was 17 years before at age 40 years, and was an early-stage, T1N0M0, 1.1-cm infiltrating ductal carcinoma, with negative lymph nodes and margins. She had been treated with lumpectomy, radiation therapy, and 5 years of tamoxifen. A triple-phase liver CT scan was obtained to further evaluate the liver. A hypovascular mass was identified, with rim enhancement, with subtle suggestion of rim nodularity (Figure 1). No delayed images were obtained. The findings were regarded as indeterminate and not diagnostic of a hemangioma. MRI was recommended for additional characterization, and confirmed signal intensity and enhancement characteristics of a hemangioma (Figures 2, 3, 4, 5, 6, 7, 8, 9, and 10).

FIGURE 1 Enhanced abdominal CT image during the portal venous (PV) phase of imaging shows a lobular, hypovascular focal liver lesion in the periphery of the anterior segment right lobe. There is subtle rim enhancement, which is mildly nodular. No delayed images were obtained. Findings were regarded as indeterminate.

FIGURE 2 Axial T1-weighted MRI scan shows the lesion to have a lobular margin and to be hypointense to the liver parenchyma.

FIGURE 3 Axial T2-weighted MR image (HASTE) shows the lesion to be hyperintense, with thin septa within.

FIGURE 4 Axial STIR image of the lesion again shows a lobular contour, hyperintense signal, and internal septa.

FIGURE 5 Coronal single-shot, T2-weighted, breath-hold image (HASTE) shows the lesion in question to be hyperintense, with faint internal septa. A second small, hyperintense lesion is seen in the left lobe medial segment, which proved to be a cyst.

FIGURE 6 Fat-saturated, T1-weighted, three-dimensional, gradient echo, enhanced image obtained during the hepatic arterial (HA) phase of enhancement shows nodular peripheral enhancement of the lesion. As is normal for HA phase imaging, the hepatic veins and liver parenchyma are minimally enhanced, the kidneys are in the corticomedullary phase of enhancement, and there is heterogeneous enhancement of the spleen.

FIGURE 7 Fat-saturated, T1-weighted, three-dimensional, gradient echo, enhanced image obtained during the PV phase of enhancement shows progression of the nodular peripheral enhancement of the liver lesion. As expected during the PV phase of enhancement, there is maximal parenchymal enhancement of the liver, spleen, and kidneys compared with the HA phase.

FIGURE 8 Repeat of the same sequence, about 2 minutes after injection of the gadolinium-based contrast agent, shows slow progression of the peripheral enhancement. The nodular enhancement seen earlier has coalesced to a thicker peripheral rim.

FIGURE 9 Repeat sequence, 5 minutes after injection, shows centripetal progression of the enhancement. The lesion is partly filled in.

FIGURE 10 Coronal fat-saturated, enhanced, T1-weighted, gradient echo, three-dimensional image shows the lesion to be nearly completely filled in. Breast implants are noted.

TEACHING POINTS

Imaging of the liver in patients with a history of breast cancer will frequently identify benign focal liver lesions, which will need to be accurately characterized in order to exclude liver metastatic disease. Most commonly encountered are liver cysts and hemangiomas. This case is an example of the most common benign liver tumor, the cavernous hemangioma, which can be seen in up to 7% of the normal adult population and in up to 20% of autopsy specimens. The lesion consists of interconnected, endothelium-lined, vascular channels within a loose fibroblastic stroma. Fed by branches of the hepatic artery, the lesion has slow internal circulation, leading to its characteristic enhancement pattern, which enables these lesions to be recognized and confidently characterized on CT and MRI. Early enhancement consists of peripheral puddling, with nodular or globular enhancement on the rim of the lesion. This progresses centripetally until most or all of the lesion is enhanced. On all phases of enhancement, the intensity of contrast enhancement should approximate that of the aorta. The lesions are sharply marginated. On MRI, the lesions are quite hyperintense or fluid in signal intensity on fluid-sensitive sequences, such as T2-weighted and STIR sequences, similar in intensity to cerebrospinal fluid. Internal septations can be seen, as in this case, and larger hemangiomas may not completely fill in. Small hemangiomas may completely fill in early in enhancement, termed flash filling.

CASE 2 Progression of liver metastases on CT and PET

A 37-year-old woman with extensive bony metastatic breast cancer known for 1 year developed increased aching, weight loss, depressed appetite, and rising tumor markers while on goserelin acetate (Zoladex), zoledronic acid (Zometa), and exemestane (Aromasin). Positron emission tomography (PET)/CT and enhanced body CT scans showed new liver metastases (Figures 1 and 2). Chemotherapy was recommended but declined by the patient. She was started on fulvestrant (Faslodex) and restaged 2 months later, at which time fatigue, shortness of breath, and rising tumor markers were noted. Repeat PET/CT and enhanced body CT scans showed progression of liver metastases (Figures 3 and 4), as well as new lung involvement (see Case 13 in Chapter 10). One month later, the patient was admitted with mental confusion, thought to be hepatic encephalopathy due to the progressive and extensive liver metastases. Workup for alternative etiologies, including abdominal ultrasound and head CT, showed only the known disease, with no additional abnormality.

FIGURE 1 Contrast-enhanced abdominal CT scan, portal venous phase, showed multiple hypovascular new metastases in the liver, one of which is shown here, in the medial segment of the left lobe (segment IV).

FIGURE 2 Representative concurrent PET/CT fused images (left to right: coronal, sagittal, axial, coronal projection volume image) shows hypermetabolic foci in the liver, corresponding to the CT findings. The coronal projection image on the right shows diffuse abnormal marrow hypermetabolism due to bone metastases, which is patchy and inhomogeneous. This is best seen in the spine and extremities. Although chemotherapy-related marrow activation could be considered in the scintigraphic differential of diffuse increased marrow activity, it could be dismissed in this case because the patient was not receiving chemotherapy and the activity was not uniform.

FIGURE 3 Repeat CT scan, 2 months later. Chemotherapy was declined by the patient, and 2 months of treatment with Faslodex was given instead. Marked progression of liver metastases is seen. The index left lobe lesion pictured in Figure 1 has grown, and innumerable additional metastases are seen.

FIGURE 4 Repeat PET/CT, 2 months after study in Figure 2 and concurrent with CT in Figure 3. Fused PET/CT images show marked progression of liver metastases. Many more hypermetabolic liver foci are identifiable and correlate with the progressive CT findings.

Her original tumor was diagnosed 5 years before and was an estrogen receptor– and progesterone receptor–positive, T1cN1b(4) infiltrating ductal carcinoma. It was treated with breast conservation and axillary dissection, with 4 of 20 lymph nodes positive. Additional treatment included chemotherapy (four cycles of doxorubicin [Adriamycin] plus cyclophosphamide [Cytoxan] [AC] and four of paclitaxel [Taxol]); right breast, supraclavicular, and axillary radiation therapy; and tamoxifen. One year before liver metastases were discovered, diffuse bone metastases were found when the patient sought orthopedic advice for low back and right leg pain. See Case 3 in Chapter 8 for discussion of the imaging manifestations of this patient’s bone metastases.

TEACHING POINTS

This patient is typical in that liver metastases developed in the setting of widely metastatic disease, which in this case was in bone. More than half of patients with metastatic breast cancer develop liver metastases, which can be the cause of death in the 20% of patients who develop liver failure due to metastases. This patient’s terminal presentation was notable for mental confusion, with multiple biochemical abnormalities, including elevated prothrombin time and liver function tests. Clinically, she was thought to have hepatic encephalopathy due to the extensive and progressive liver metastases. Workup for other etiologies did not yield an alternative explanation.

CASE 3 Pseudocirrhotic appearance of treated breast cancer liver metastases; mislocalization of right liver metastases into right lung base on PET/CT

A 39-year-old woman developed abdominal distention and increased fatigue a year after being treated for a high-risk breast cancer. This was a right breast estrogen receptor– and progesterone receptor–positive, HER-2/neu-positive, 2.7-cm infiltrating ductal carcinoma with an extensive intraductal component. There were 10 of 12 lymph nodes with metastatic carcinoma, including a 3-cm lymph node with focal extracapsular extension. She was treated with a mastectomy, four cycles of doxorubicin and cyclophosphamide, followed by four cycles of paclitaxel, as well as chest wall, supraclavicular, and axillary radiation.

When the patient developed constitutional symptoms, she was restaged with CT scans, showing extensive hepatic metastases. Chemotherapy with carboplatin, docetaxel (Taxotere), and trastuzumab (Herceptin) was initiated, with good response. Follow-up surveillance CT scans showed resolution of the bulk of the liver metastases, with development of a progressively scarred liver, which has been termed pseudocirrhosis. Her disease status was periodically assessed while on vinorelbine tartrate (Navelbine) with enhanced abdominal CT scans and positron emission tomography (PET)/CT (Figures 1, 2, 3, 4, and 5).

FIGURE 1 A and B, Portal venous (PV) phase enhanced images from abdominal CT scan show pseudocirrhosis treatment changes. The patient had previously been treated with chemotherapy for liver metastases. Linear, scar-like lucencies extend through the liver parenchyma, some extending to the liver surface where there is capsular retraction (arrowheads). A small, isodense residual lesion, outlined by surrounding lucency, is seen at the posterior right liver dome, best seen in B (arrow).

FIGURE 2 A and B, Repeat PV phase enhanced abdominal CT scan images at comparable levels, 3 months later, show interval growth of the hypodense liver metastasis in the posterior segment of the right lobe, adjacent to the inferior vena cava, best seen in B (arrow). The pseudocirrhosis changes impart a nodular contour to the liver surfaces.

FIGURE 3 Fused PET/CT images (left to right: coronal, sagittal, axial, and coronal projection PET volume image), concurrent with CT scans in Figure 2, show the growing posterior segment right lobe liver metastasis at the dome to be intensely hypermetabolic. The coronal projection image shows a separate focus of activity in the right hemithorax, which proved to be a rib fracture. See Case 8 in Chapter 8 for a discussion of bone findings in this same patient.

FIGURE 4 Repeat PET/CT scan, 6 months later, including CT with lung windows, PET, and fused PET/CT images, shows a small hypermetabolic focus (cursors), which projects in the right lung base. However, the lung windows show no corresponding abnormality. Note the abnormal step-off and abrupt change in contour of the right hemidiaphragm in the sagittal projection, a clue that respiratory variation produced this artifact.

FIGURE 5 Concurrent enhanced chest and abdominal CT scans showed no lesion at the right lung base, but confirmed recurrent growth of the previously recognized waxing and waning metastasis in the posterior right liver dome (arrow). Pseudocirrhosis changes of the rest of the liver are again seen, with linear fibrosis in the right lobe, extending to the surface with capsular retraction, and macronodularity of the left lobe. The patient’s therapy was changed from Navelbine to doxorubicin HCl (Doxil) in response.

TEACHING POINTS

This patient had known, previously treated, extensive liver metastases, originally diagnosed 14 months before the earliest of these studies. She had had an excellent response to chemotherapy. Her particular healing response created pseudocirrhosis. These findings, described by Young and colleagues, included capsular surface retraction of the liver at the site of subjacent metastases, imparting a lobular contour to the liver, simulating cirrhosis. Volume loss in involved lobes was noted, with caudate lobe enlargement in the diffusely involved livers. In this series of 22 patients, pathologic correlation was available for 7 patients. All had residual tumor, and 6 of 7 showed nodular regenerative hyperplasia. No patients showed bridging portal fibrosis or pathologic evidence of true cirrhosis.

This case also illustrates a recognized misregistration artifact seen in PET/CT. In a series of 300 patients reported by Osman and colleagues, 2% of cases had mislocalization of liver dome lesions into the right lung base when CT was used for attenuation correction of PET. This occurs presumably because of respiratory variation between PET and CT. PET images, requiring several minutes of acquisition per position, are averaged over many respiratory cycles, as opposed to the more rapid CT acquisition. When such misregistration is suspected, review of the non-attenuation-corrected images (Figure 6) can be helpful in confirming this artifact.

FIGURE 6 Coronal (A) and sagittal (B) PET/CT images (from left to right: CT, CT attenuation-corrected [AC] PET, fused PET/CT, non-attenuation-corrected [NAC] PET) allow comparison of the apparent position of the lesion between AC and NAC PET. On AC PET, the hypermetabolic bilobed lesion projects in an artifactual “clear zone” created by respiratory variation at the border between the lung base and liver dome, whereas on NAC PET, the lesion projects in the liver.

CASE 4 Progressive liver metastases on CT and PET

A 64-year-old woman, 3 years after right mastectomy, chest wall and supraclavicular radiation, and chemotherapy for breast cancer, was found to have an abnormally elevated tumor marker (CA 27.29). Her tumor was a 2.8-cm infiltrating ductal carcinoma, estrogen receptor and progesterone receptor positive, HER-2/neu positive, with 1 of 15 lymph nodes involved.

Evaluation with positron emission tomography (PET) and CT showed two liver metastases, one in each lobe, confirmed by biopsy of a left lobe lesion. The patient was evaluated for possible surgical or radiofrequency ablation therapy, but the presence of lesions in both lobes of the liver and lack of clinical data documenting benefit of resection in this setting resulted in the patient being treated instead with letrozole (Femara).

Periodic PET and CT evaluations were obtained over the next 3 years, to assess treatment responses, especially when tumor progression was suggested by rising tumor markers and liver function abnormalities (Figures 1 and 2). These showed a waxing and waning CT response of the liver metastases to adjustments in therapy, but there was an overall progression of her liver metastases. Her treatment regimen was adjusted numerous times, with multiple regimens utilized, including trastuzumab (Herceptin) and exemestane (Aromasin), Herceptin and vinorelbine tartrate (Navelbine), then capecitabine (Xeloda), followed by fulvestrant (Faslodex), and ultimately, bevacizumab (Avastin) and paclitaxel (Taxol). Over this time period, the patient remained relatively asymptomatic.

FIGURE 1 Enhanced abdominal CT images (displayed with liver windows, portal venous phase), obtained over a period of 14 months, showing a waxing and waning change in appearance of multiple metastatic breast cancer lesions, as this patient’s therapy is adjusted. A, Vague, poorly defined hypodensities are seen in the liver. The corresponding PET scan showed five discrete foci of liver hypermetabolism. These findings were improved compared with 6 months before. B, Comparable repeat, enhanced abdominal CT at the same level, 5 months later, shows clear progression by CT. Five discrete individual liver metastases are now clearly defined, with low-density central necrosis and thick, enhancing tumor margins. The patient’s therapy was changed from Herceptin and Navelbine to Xeloda. C, Repeat enhanced abdominal CT scan at the same level, 5 months later, shows the same number of liver metastases. Their size is similar, but there has been interval change in the appearance of the lesions, with less well-defined margins. D, Repeat enhanced abdominal CT scan at the same level, 4 months later (14 months after A) shows worsening. The metastases have grown, becoming nearly confluent in the posterior right lobe. Thick, enhancing tumor margins again show relatively well-defined edges. The patient’s therapy was changed from Faslodex to Avastin and Taxol.

FIGURE 2 Three plane PET/CT fused images. A, This study is concurrent with Figure 1C. Multiple hypermetabolic liver lesions are seen, which were not clearly changed by PET compared with 5 months earlier. The patient had been on Xeloda during this time interval. On CT, the lesions were more ill-defined. B, Repeat study, 4 months later, concurrent with CT in Figure 1D. Clear progression of liver metastases is demonstrated by PET, correlating with the change in size and appearance of the liver lesions on CT. The patient’s therapy was changed from Faslodex to Avastin and Taxol.

TEACHING POINTS

This patient was relatively asymptomatic while undergoing treatment for liver metastatic breast cancer. She was treated over a period of years with a variety of regimens, with initial responses, but ultimately progression. This was heralded by rising liver function tests and tumor markers, and confirmed by imaging with CT and PET scans. As shown here, sometimes the anatomic imaging responses to treatment can be ambiguous. These liver metastases seemed to wax and wane in conspicuity, becoming ill defined and less measurable when responding to treatment, and showing more aggressive characteristics when progressing. Supplementing the CT anatomic information with functional information from PET allows a higher confidence level in interpreting the significance of such changes in appearance.

CASE 5 Liver metastases arising in fatty liver, better seen on CT than PET

A 38-year-old woman with known metastatic breast cancer to bone on fulvestrant (Faslodex) was evaluated with PET and CT for increased aches and pains, and rising tumor markers.

Her breast cancer was diagnosed 3 years earlier when she presented with a left palpable estrogen receptor–positive, HER-2/neu-negative tumor and was treated with mastectomy. Bone metastases were identified at the time of her initial diagnosis, and the patient was treated with six cycles of doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) chemotherapy. She also received radiation therapy for lumbar spine epidural disease and a left proximal femoral metastasis.

PET/CT and contrast-enhanced body CT scans obtained to restage the patient showed new liver metastases. These were readily seen on CT as relatively hyperdense lesions against a background of a markedly fatty liver (Figure 1). The corresponding PET/CT scan, although abnormal and changed from a prior study, showed only subtle corresponding abnormalities, manifested as increased liver inhomogeneity (Figure 2).

FIGURE 1 Contrast-enhanced abdominal CT scan (displayed with liver windows, portal venous enhancement) shows the liver to be fatty, with diffusely decreased density relative to spleen. Multiple, relatively hyperdense, focal liver lesions can be seen against this background in the right lobe of the liver.

FIGURE 2 Concurrent coronal PET/CT scan shows subtle corresponding findings, with heterogeneity of the liver activity.

The patient’s therapy was changed to docetaxel (Taxotere) and capecitabine (Xeloda). She improved clinically and her tumor markers declined.

Repeat staging studies, 2 months later, confirmed the clinical and biochemical improvement (Figures 3 and 4).

FIGURE 3 Repeat contrast-enhanced abdominal CT scan (displayed with liver windows, portal venous enhancement) shows the focal liver lesions to be hypodense relative to liver parenchyma, which does not appear as fatty as before.

FIGURE 4 Repeat coronal PET/CT scan, concurrent with CT in Figure 3, shows improved homogeneity of liver activity compared with the prior study. The patient’s symptoms had improved, and her previously rising tumor markers had stabilized.