Hepatic hemangiomas are known to be the most. Contrast-Enhanced Ultrasound of Histologically Proven Liver Hemangiomas. Patients and Methods

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1 Contrast-Enhanced Ultrasound of Histologically Proven Liver Hemangiomas Christoph F. Dietrich, 1 Joachim C. Mertens, 1 Barbara Braden, 2 Gudrun Schuessler, 1 Michaela Ott, 1 and Andre Ignee 1 Differentiation of small and atypical hemangiomas from other hepatic masses using imaging methods can be difficult, especially in patients with underlying malignant disease. Therefore, contrast-enhanced ultrasound was assessed in patients with histologically confirmed hemangiomas with respect to contrast-enhancing kinetics and tumor characteristics. In 58 patients with indeterminate hepatic lesions demonstrated with at least 2 imaging methods (ultrasound/computed tomography/magnetic resonance imaging), ultrasound-guided liver biopsy revealed hemangioma. In all patients a hepatic neoplasm had been suspected because of underlying malignant disease (n 41), liver cirrhosis (n 15), or growth of the lesion (n 2). All patients underwent nonlinear, low mechanical index real-time contrast-enhanced ultrasound scanning with bolus injections of SonoVue. Peripheral nodular arterial enhancement was detected in 43 patients (74%), whereas the typical metastatic peripheral rim-like enhancement was not observed at all. Strong homogenous arterial enhancement was found in 9 of 58 (16%) patients. In 6 patients (10%), the arterial contrast enhancement pattern could not be determined because of the very small size of the lesions or fibrotic nodules. Forty-five (78%) of the hemangiomas showed homogenous centripetal filling within 180 seconds. Conclusion: Contrast-enhanced ultrasound demonstrates typical hemangioma imaging characteristics, that is, peripheral nodular contrast enhancement and iris-diaphragm sign in a high percentage of patients with undetermined lesions. This technique may therefore improve noninvasive functional characterization and differentiation of hemangiomas. (HEPATOLOGY 2007;45: ) Hepatic hemangiomas are known to be the most common benign liver tumors, with an incidence in autopsy and imaging studies of up to 7% As incidentally discovered hepatic tumors are more frequently detected with the increasing use of modern abdominal imaging techniques, reliable noninvasive characterization and differentiation of such liver tumors is highly important in the clinical routine. Although ultrasound (US) has long been considered inferior to computed tomography (CT) and magnetic resonance imaging (MRI), 10,11 new US imaging techniques, especially contrast-enhanced techniques, have changed Abbreviations: CEUS, contrast-enhanced ultrasound; CT, computed tomography; MRI, magnetic resonance imaging; US, ultrasound. From the 1 Second Department of Internal Medicine, Caritas Hospital Bad Mergentheim, Bad Mergentheim, Germany; and 2 John Radcliffe Hospital, Oxford, UK. Received September 19, 2006; accepted December 12, 2006 Address reprint requests to: Christoph F. Dietrich, M.D., 2nd Department of Internal Medicine, Caritas Hospital Bad Mergentheim, Uhlandstr. 7, D Bad Mergentheim, Germany. christoph.dietrich@ckbm.de; fax: (49) Copyright 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience ( DOI /hep Potential conflict of interest: Nothing to report. this view Contrast-enhanced US (CEUS) has been demonstrated to significantly improve the detection of liver metastases in comparison with B-mode US, including a multicenter trial study. 16 The results are within the same range as for CT. CEUS also can differentiate between most benign and malignant liver lesions by analyzing the portal venous phase in patients with normal liver parenchyma. 17,18 In addition, CEUS could differentiate between typical focal nodular hyperplasia and hepatocellular adenoma. This differentiation is essential because of different therapeutic approaches. 19 In contrast, the role of real-time CEUS in characterizing hemangiomas has not yet been determined. We examined the contrast-enhancing imaging features of atypical liver hemangiomas with inconclusive complementary imaging results to assess the accuracy of CEUS. Patients and Methods Between 2000 and 2006, 58 patients [29 female, 29 male; (24-77) years] with histologically confirmed hemangiomas were included in this prospective study. Indications for liver biopsy were indeterminate le- 1139

2 1140 DIETRICH ET AL. HEPATOLOGY, May 2007 sions shown in at least 2 imaging methods (US/CT/ MRI). Examination Techniques. All patients underwent B-mode ultrasound and color or power Doppler examination with a 3.5-MHz and 7-MHz multifrequency transducer as described. 18,20 Siemens Elegra Advanced or Acuson Sequoia (Sonoline Elegra, Siemens, Erlangen, Germany, or Acuson Sequoia, Siemens, Erlangen, Germany) were used with a low mechanical index 0.2 to 0.3 setting (no split screen imaging was used). All examinations were carried out by the same examiner (C.F.D.); however, image analysis was performed by at least 2 additional examiners. All examinations were digitally stored and documented by a commercially available system or videotapes. The images of a particular patient were always shown to the additional readers in the same sequence: baseline followed by CEUS. The patients received up to 3 bolus injections (1 bolus injection in 50 patients) of 2.4 (Acuson Sequoia) or 4.8 ml (Siemens Elegra) of the contrast agent SonoVue (Bracco, Milan, Italy). The criteria reported for this setting were peripheral nodular enhancement during the arterial phase, iris-diaphragm sign using time-analysis of contrast enhancement within seconds to analyze the arterial phase in comparison with the hepatic artery and portal venous phase in comparison with the surrounding portal vein (branches) as described. 13,19 Reference Imaging Examinations and Liver Biopsy. Reference imaging examinations (e.g., CT, MRI, and scintigraphy) were performed as part of the clinical workup of the patients in several cases outside of our institution and not for the purpose of this study. The standard practice used in our department includes 2 different imaging procedures (US: n 59/CT: n 55/ MRI: n 33) (re)evaluated by at least 2 experts. All hemangiomas were histologically confirmed because of inconclusive findings in the imaging methods and suspected malignancy. In 41 cases (41 of 58, 71%), an underlying malignant disease was found. In all cases, the diagnosis of a liver metastasis would have changed the therapeutic approach. Fifteen patients (15 of 58, 26%) had a liver lesion in a (suspected) liver cirrhosis attributable to HCV infection (10 of 15, 67%), primary biliary cirrhosis (4 of 15, 27%), or cystic fibrosis (1 of 15, 7%). In those cases, a HCC could not be excluded. In 2 cases (2/58, 3%), significant growth within a year was observed in patients with history of ovarian tumors under hormone therapy, and the former diagnosis of a hemangioma was in doubt. Liver biopsy was performed closely to and always after the US examination. The size of the lesion was stable during the interval between liver biopsy and the study in Table 1. Demographic Characteristics and Indications for Biopsy all patients. Clotting indices were considered adequate for biopsy in all patients, following the general rules. Biopsy under US guidance using a device and avoiding direct puncture of superficial lesions was performed with a Temno 1.2-mm cutting needle to allow accurate histological evaluation (with a minimum required sample size of 15 mm and in most cases 20 mm). Liver biopsy specimens were fixed in formalin and embedded in paraffin for routine staining and immunohistochemistry. In 3 of 58 patients (3 of 58, 5%) more than one biopsy was necessary to determine the correct histological nature of the lesion. No complications were recorded. Statistics. Clinical characteristics of patients were expressed as mean standard deviation (SD) and as median values with limits of 50% interquartile ranges when appropriate. Institutional Board Approval. Institutional Board approval and informed consent according to the ethical guidelines from Helsinki was obtained from all patients after informing the patient about the purpose and aim of the study before the ultrasound examination was started. Patient characteristics are summarized in Table 1. Results Characteristics Percentage Demography No. (M/F) 58 (29/29) Mean age (years) (24-77) Indication for biopsy Underlying malignant disease 41/58 (81%) Growing tumor* 2/58 (3%) (Suspected) liver cirrhosis (HCV/PBC/CF) 15/58 (19%) (10/4/1) Abbreviations: M, male; F, female; HCV, hepatitis C virus infection; PBC, primary biliary cirrhosis; CF, cystic fibrosis. *An impressive growth pattern from less than 20 mm to more than 50 mm within 2 years was seen in a patient with a malignant ovarian tumor. In contrast to other reports with female preponderance, the sex ratio (male/female ratio) was equal in this study. In all patients, adequate visualization of the respective contrast phases was possible. No adverse events were reported. In 10 patients, the histologically confirmed hemangiomas were not visualized by CT (n 6) or MRI (n 4). These patients had lesions below 15 mm. Coincidence of Hemangiomas with Malignant Tumors. A single tumor was seen in 21 patients, whereas in the remaining 38 patients two (n 15) or more tumors were observed. Coincidence of metastases (lymphoma) and hemangiomas occurred in 8 of 58 (14%), and coincidence of hepatocellular carcinoma and hemangiomas occurred in 2 of 58 (4%) patients, which means a coinci-

3 HEPATOLOGY, Vol. 45, No. 5, 2007 DIETRICH ET AL Table 2. B-Mode and Color Doppler Imaging Characteristics of 58 Histologically Proven Lesions Number of Lesions Percentage One lesion 21/58 (36%) Multiple lesions 37/58 (64%) Size [mm] (6-130) Echogenicity Hyperechoic 45/58 (78%) Isoechoic 4/58 (7%) Hypoechoic 9/58 (15%) Halo 0/58 (0%) Color Doppler imaging Feeding and draining vessels* 25/58 (43%) Homogenous hypervascularity 4/58 (7%) *Representing the color Doppler imaging (CDI) sign of peripheral nodular contrast enhancement. In patients with liver cirrhosis, the tumors were hyperechoic in 14 and isoechoic in 1. CDI was not helpful in identifying shunts in any of the patients because vascularity cannot be displayed. dence of 10 of 58 (17%) hemangiomas with malignant lesions also proven by histology. Ultrasound Findings. On conventional B-mode, we found a single lesion in 21 patients (21 of 58, 36%) and more than one lesion in 37 patients (37 of 58, 64%). Using color Doppler imaging in 25 patients (25 of 58, 43%), at least one feeding or draining vessel was found. This sign is thought to be the corresponding Doppler sign to the peripheral nodular enhancement pattern of contrast-enhanced methods. A homogenous hypervascularity was found in 4 patients (4 of 58, 7%). In all other patients (29 of 58, 50%) no vascularization inside the lesion could be demonstrated at all (Table 2). In 43 patients (43 of 58, 74%), a peripheral nodular arterial enhancement could be demonstrated. In no patients could the peripheral rim-like enhancement be visualized (0 of 58, 0%), which is typically seen in metastasis. In 6 patients (6 of 58, 10%), the pattern could not be determined because of very small size of the lesion or fibrotic nodules. A strong homogenous arterial enhancement could be seen in 9 patients (9 of 58, 16%). Complete homogenous fill-in could be seen in 45 patients (45 of 58, 78%). In most patients (27 of 45, 60%), the time to complete fill-in was between 61 and 180 seconds. In 12 patients (12 of 45, 27%), the time was equal to or faster than 30 seconds. In 6 patients (6/45, 13%), the time to complete fill-in was between 31 and 60 seconds. An incomplete (inhomogenous, incomplete iris-diaphragm sign, including 1 with complete sparing that was interpreted as a solitary necrotic nodule) was seen in 13 patients (13 of 58, 22%). Peripheral nodular arterial enhancement as well as complete portal venous fill-in was seen in 31 of 58 (54%) patients. In 12 of 58 (21%) patients, peripheral nodular arterial enhancement but no complete fill-in was seen. In 14 of 58 (24%) patients, a complete fill-in but no peripheral nodular enhancement was seen. In 1 of 58 (2%) patients, neither peripheral nodular enhancement nor complete fill-in was seen. The sensitivity for peripheral nodular arterial enhancement was 74% (95% confidence interval, 61%-85%); for complete portal venous fill-in was 78% (65%-88%); and for the combination of both, 98% (91%-100%). The results are summarized in Table 3. Discussion Up to now only a few imaging studies have investigated hepatic hemangiomas, and most of them did not confirm the diagnosis by histology. 18,21-24 To our knowledge, low mechanical index real-time CEUS has never been used to characterize atypical hemangiomas. We demonstrate that CEUS can reliably compile typical signs of hemangiomas in most patients with undetermined findings using nonenhanced US, CT, and MRI, which might be useful in avoiding biopsy. Hemangiomas show peripheral nodular enhancement with gradual centripetal filling and are regarded as having a large, slowly enhancing blood volume. Atypical features include small ( 15 mm) or huge hemangiomas [ 4-7 cm (depending on the literature published)], so-called shunt hemangiomas 25 with abundant arterio(porto-) venous shunts (functionally described as high-flow hemangiomas), sclerosing hemangiomas, and hemangiomas with regressive changes such as calcifications, thrombosis, and phlebolith. Hemangiomas below 10 mm, in particular, tend to lack the typical hemangioma contrast enhancement and are a particular challenge. The best, though most expensive, imaging method for hemangiomas is MRI with a sensitivity and specificity Table 3. Contrast-Enhancing Pattern of 58 Histologically Proven Lesions Characteristics Percentage Contrast enhancement, arterial Peripheral nodular arterial enhancement 43/58 (74%) Peripheral rimlike enhancement 0/58 (0%) Not determinable (e.g., due to size of the lesion, solitary fibrotic nodule) 6/58 (10%) Strong homogenous arterial enhancement* 9/58 (16%) Centripetal filling Complete (homogenous) fill-in 180 seconds 45/58 (78%) 30 seconds 12 (21%) 30 seconds and 60 seconds 6 (10%) 60 seconds and 180 seconds 27 (47%) Incomplete (inhomogenous, incomplete iris diaphragm sign, including one with non-enhancing solitary necrotic nodule) 13/58 (22%) Sensitivity Peripheral nodular arterial enhancement 43/58 (74%) Complete portal venous fill-in 45/58 (78%) Combination of both 57/58 (98%) *In 2 patients with liver cirrhosis, shunt-hemangiomas were found.

4 1142 DIETRICH ET AL. HEPATOLOGY, May 2007 Fig. 1. (A-F) Small peripherally located shunt-hemangioma in a patient with colorectal cancer within a hypoechoic wedge-shaped region containing less fat. The finding to note during the hepatic arterial phase is the enhancement adjacent to the hemangioma via arterioportal shunts. Because of metabolic changes, the area is hypoechoic and probably contains less fat. between 85% and 95%. Bright signal intensity on T2- weighted images, and similar enhancement pattern to enhanced CT are very specific and effective for accurate diagnosis. 26 However, atypical findings of hemangiomas such as cystic hemangiomas or small hemangiomas with immediate homogeneous enhancement are also seen. 27,28 In these cases, histological confirmation via needle biopsy is required. 26 Atypical hemangioma behavior includes the differential diagnosis of hemangiomas versus hypervascular malignancy, hemangiomas with arterioportal shunts, hemangiomas in liver cirrhosis, hemangiomas in fatty liver, small hypoattenuating hemangiomas, atypical signal on T2-weighted MR imaging, and attenuation relative to vascular pool. 28 Differentiation of hemangiomas from other benign and from malignant hypervascular tumors can be a challenge because some can mimic peripheral nodular (globular) enhancement (which is especially true in very small tumors), and not all hemangiomas show this characteristic pattern. 27,29 Neuroendocrine tumors or metastases from gastrointestinal cancer and other organs also may show strong T2 hyperintensity, 29 and a prolonged contrast enhancement may be seen in certain hypervascular malignancies. 27 It is helpful to know that hemangiomas can remain unenhanced (e.g., due to thrombosis). Therefore, image interpretation based on the combination of all imaging phases is required. Arterioportal shunts associated with a hepatic tumor have been reported primarily in patients with malignant tumors, especially in advanced hepatocellular carcinoma with portal vein thrombosis However, arterioportal shunts have been observed in hepatic hemangiomas not only through use of CEUS 25 but also through use of multiphase helical CT and MRI in a significant percentage of hemangiomas (19%-26%), which is in the range reported in our study. One possible explanation for rapidly enhancing small hemangiomas is a hyperdynamic status with large arterial inflow, rapid tumoral enhancement, and consequently, large and rapid outflow, which seems to result in early opacification of the draining portal vein via shunts 39 (Fig. 1). We and others recently pointed out the importance of hemangiomas in liver cirrhosis. 40 With progressive cirrhosis, hemangiomas are likely to decrease in size and become more fibrotic and difficult to diagnose radiologically and pathologically. 41 Conversely, HCC and dysplastic nodules often mimic hemangiomas on sonography because of hyperechogenicity resulting from factors such as necrosis, fibrosis, fatty change, or sinusoidal dilatation. In cirrhosis, any hyperechoic and hypervascular nodule should be considered a probable hepatocellular carcinoma

5 HEPATOLOGY, Vol. 45, No. 5, 2007 DIETRICH ET AL Fig. 2. (A-E) Small shunt-hemangioma next to focal fatty infiltration in a patient with colorectal cancer 3 years previously and a newly diagnosed lesion not shown by CT and MRI. Note the fill-in within 4 seconds. until proven otherwise, and therefore operation or biopsy and histological evaluation are mandatory. Severe fatty liver may alter the apparent enhancement pattern of focal hepatic lesions (Fig. 2). It is well known that originally hyperechoic hemangiomas may appear hypoechoic in fatty liver parenchyma. In severe fatty liver, the attenuation of hemangiomas may reverse even to hyperattenuation, although not greater than that of vessels, on unenhanced CT. Even hypovascular tumors such as metastases can show relatively high attenuation on CT and may mimic hemangiomas with a persistent enhancement pattern. Small hypoattenuating hemangiomas are detected more frequently with helical CT (the incidence being 8%- 16% 27,42 ), whereas they are easily overlooked on conventional CT because they tend to be isoattenuating on latephase images. 42 Small hypoattenuating hemangiomas are particularly problematic in patients with underlying malignancy. If present, the bright-dot sign tiny enhancing dots in the hemangiomas that do not progress to the classic globular enhancement because of the small size of the lesion and the propensity for very slow fill-in is helpful in diagnosing this type of hemangioma. 42 However, a number of hemangiomas have no discernible enhancement. One pathological correlative study suggested that hemangiomas with a slow fill-in pattern have relatively large vascular spaces and that those with rapid enhancement have small vascular spaces and a large interstitium. Such a tendency has no relation to the size of the tumor. 43 Therefore, hemangiomas should be included in the differential diagnoses of small hypoattenuating lesions as well as hypervascular lesions. CEUS, which has the advantage of real-time dynamic assessment, could be of help in characterizing such lesions. We could show, and this is in accordance with the literature, that approximately 10% of patients with hemangiomas cannot be reliably diagnosed using imaging methods. 44 In a series of 1011 patients who underwent hepatic resection for liver tumors, 107 (11%) of these patients were asymptomatic individuals who presented with incidental lesions. Benign pathological conditions were found in 45 (42%) patients, including focal nodular hyperplasia (n 17), hemangiomas (n 12), angiomyolipoma (n 5), cirrhotic regenerative nodule (n 4), hepatic adenoma (n 2), and others (n 5). 45 One retrospective study of percutaneous biopsies using 20- gauge needles of 38 patients ( cm, with a mean of 3 cm) with suspected hemangiomas reported that it is safe and effective for establishing the diagnosis of hemangiomas. 46 In a series of 25 consecutive patients who underwent surgery for giant hemangiomas, CT and MR images were reviewed retrospectively and revealed similar results in accordance with our findings. 47 Although hemangiomas can occur at any age, most of them grow very slowly and are rarely diagnosed during

6 1144 DIETRICH ET AL. HEPATOLOGY, May 2007 Fig. 3. Cavernous hemangioma in a woman with ovarian cancer showing the typical peripheral nodular contrast enhancement and (partial) centripetal fill-in. The lesion is displayed longitudinally in the conventional B-mode scanning (A) and transversally in the contrast images (B-E). The lesion was located next to the heart, demonstrating the advantage of a real-time method diminishing motion artefacts shown by the complementary non real-time imaging methods. childhood. We observed 2 patients with more than 50% growth in 1 year. The pathogenesis of hemangiomas and especially the growth pattern is not well understood. Growth of hemangiomas is thought to be due to ectasia rather than hypertrophy or hyperplasia. Some of these hemangiomas have estrogen receptors, and accelerated growth has been observed during estrogen influence during puberty, pregnancy, oral contraceptive use, and with androgen treatment. 26,46,48,49 Growing tumors are mainly seen in women. 49,50 In summary, for typical hemangiomas in an asymptomatic patient without risk factors for malignancy, conventional B-mode ultrasound is sufficient and no further imaging method is recommended. For atypical hemangiomas in an asymptomatic patient without risk factors for malignancy, contrast-enhanced imaging techniques (US, CT, MRI) should be additionally used. This is especially true in larger lesions, those with uncertain imaging features, or those at risk for any type of malignancy. Hemangiomas demonstrate a reproducible and apparently specific pattern of enhancement even in small lesions, echogenicity rapidly becoming equal to or greater than that of the liver through the portal venous phase and beyond because of the real-time nature of CEUS, which is an essential for confident diagnosis. Complete enhancement does not always occur, especially in large lesions, which often undergo central thrombosis with scarring (Fig. 3). In patients with suspected metastatic disease and therapeutic implications for patient management, biopsy and histological examination are still mandatory. In conclusion, CEUS can reliably detect morphological and functional features, also characterizing atypical hemangiomas in most cases. References 1. Ishak KG. Benign tumors and pseudotumors of the liver. Appl Pathol 1988;6: Ishak KG, Sesterhenn IA, Goodman ZD, Rabin L, Stromeyer FW. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases. Hum Pathol 1984;15: Luks FI, Yazbeck S, Brandt ML, Bensoussan AL, Brochu P, Blanchard H. Benign liver tumors in children: a 25-year experience. J Pediatr Surg 1991; 26: Marchal G, Baert AL, Fevery J, Kint E, Peeters S, van D, X, et al. Ultrasonography of liver haemangioma: a report of 35 patients totalizing 53 lesions. Rofo 1983;138: Ruiz GA, Martin HL, Roldan CR. Hepatic tumors in patients with cirrhosis: an autopsy study. Rev Esp Enferm Dig 1997;89: Stocker JT, Ishak KG. Mesenchymal hamartoma of the liver: report of 30 cases and review of the literature. Pediatr Pathol 1983;1: Linhart P, Bonhof JA, Baque PE, Pering C. [Ultrasound in diagnosis of benign and malignant liver tumors]. Zentralbl Chir 1998;123: Takagi H. Diagnosis and management of cavernous hemangioma of the liver. Semin Surg Oncol 1985;1:12-22.

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