Limiting Over-Diagnosis of Hepatic Incidentalomas: A Focus on Contrast Enhanced Ultrasonography

Limiting Over-Diagnosis of Hepatic Incidentalomas: A Focus on Contrast Enhanced Ultrasonography Poster No.: R-0022 Congress: 2015 ASM Type: Educational Exhibit Authors: G. Dulku, R. M. Mendelson; Perth/AU Keywords: Education and training, Imaging sequences, Health policy and practice, Diagnostic procedure, Ultrasound, MR, CT, Liver, Abdomen DOI: 10.1594/ranzcr2015/R-0022 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 38

Learning objectives 1. To emphasize the relevance of contrast enhanced ultrasound (CEUS) in characterizing incidental focal liver lesions (IFLLs). 2. An evidence-based algorithm is developed, recommending management outline for IFFLs in patients without relevant risk factors and incorporating the use of CEUS in addition to more conventional imaging modalities. Page 2 of 38

Background Advances in diagnostic imaging have led to the increased detection of hepatic incidentalomas, defined by lesions not accounting for the patient's symptoms in the absence of known risk factors for liver disease. The great majority of these lesions are benign. [1] Even in patients with known extra-hepatic primary malignancy, small liver lesions are more likely to be benign than malignant. [2] The issue with incidental lesions is the burgeoning one of over diagnosis and the potential harming of healthy people. [3] Page 3 of 38

Imaging findings OR Procedure details Materials and methods A search of PubMed, MEDLINE and the Cochrane Database of Systematic reviews identified relevant original articles, systematic reviews and evidence-based guidelines which were included. Paediatric and animal studies were excluded. Articles which were not in English, unpublished or had limited text were also excluded. Articles were graded according to Oxford Centre for Evidence-Based Medicine Levels of Evidence. [4] An evidence-based pathway was produced and reviewed by the Diagnostic Imaging Pathways expert editorial panel members and in consultation with the editor. The final algorithm provides imaging recommendations which outline the management strategy for IFLLs in the absence of known risk factors for liver disease. Imaging algorithm Page 4 of 38

Fig. 1: This pathway provides guidance on the imaging of adult patients with a focal liver lesion discovered incidentally on imaging for unrelated indications, who have no history or risk factors for malignancy. References: Diagnostic Imaging Pathways, Imaging West, Royal Perth Hospital Perth/AU Imaging findings 1. CEUS improves the characterisation of IFLLs with enhancement patterns observed during the various imaging phases similar to contrast-enhanced CT and MRI. [5-7] Page 5 of 38

Fig. 2: CEUS enhancement patterns for haemangiomas demonstrates peripheral nodular enhancement in the arterial phase, progressing in a centripetal direction to partial fill-in. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 2. The real-time nature of CEUS allows depiction of early arterial phase enhancement which is sometimes missed on CT and MRI due to their lower temporal resolution. [7] Page 6 of 38

Fig. 3: CEUS enhancement patterns for focal nodular hyperplasia demonstrates early arterial phase enhancement with a centrifugal filling pattern which is sustained in the portal-venous phase. The prominent arterial and venous supply to the lesion can be seen in the video. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 3. Enhancement dynamics of the lesions can be studied both quantitatively and qualitatively. [5, 7] Page 7 of 38

Fig. 4: CEUS enhancement patterns demonstrates peripheral nodular enhancement in the arterial phase (A), progressing in a centripetal direction (B) to partial or complete fill-in (C). Enhancement is sustained through the delayed phase with no washout, as noted in the time-intensity curve profile of haemangioma (D). References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 Page 8 of 38

Fig. 5: CEUS enhancement patterns demonstrates early arterial phase enhancement (A and B) with a centrifugal filling pattern which is sustained in the portal-venous phase (C, D and E). Time-intensity curve profile (F) of focal nodular hyperplasia shows the centre of the lesion enhancing much earlier and to a greater extent than the periphery. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 Page 9 of 38

Fig. 6: CEUS enhancement patterns demonstrating a hyperenhancing lesion in the arterial phase (A) and which is isoenhancing in the portal-venous phase (B and C). Time-intensity curve profile of hepatic adenoma (D) shows rim of enhancing occurring slightly earlier and to a greater extent than the lesion centre. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 4. Differences in late portal-venous phase due to diffusion of CT and MRI contrast agents into tumour interstitium which may conceal wash out is also overcome with the use of CEUS. [7] 5. No requirement for predefined scan time points or need to perform bolus tracking. [7] 6. Excellent tolerance and safety profiles of ultrasound contrast agents, allow for their repeated administrations in the same session when needed. They can be given in the presence of renal impairment. [7, 9] 7. In women on hormonal therapy, CEUS is a valuable alternative to distinguish atypical focal nodular hyperplasia from hepatic adenomas when the availability of MRI is limited. Page 10 of 38

8. CEUS can be performed at the same attendance as the ultrasound at which the lesion was discovered, with resultant early reassurance of the patient and his/her doctors in the majority of cases. [8, 9] 9. Disadvantages: [7, 9] Operator and body habitus dependent Specificity and sensitivity are reduced in moderately or markedly fatty livers and with deeply positioned lesions Very small focal liver lesions (<3 mm) may be overlooked If the baseline ultrasound is suboptimal, CEUS may be unreliable 10. Indications for CEUS: [7] Incidental findings on routine ultrasound Lesion(s) or suspected lesion(s) detected with ultrasound in patients with a known history of a malignancy, as an alternative to CT or MRI Need for a contrast study when CT and MRI contrast are contraindicated Inconclusive cytology/histology results Inconclusive MRI/CT Teaching points 1. The great majority of incidentally detected liver nodules are benign. [1] 2. The problem of incidental lesions, in the liver and elsewhere, is the burgeoning one of over-diagnosis and the potential harming of healthy people. [3] 3. It is important to distinguish hepatic adenomas (HA) from focal nodular hyperplasia (FNH) as the former can present acutely due to rupture and consequent haemoperitoneum in addition to the risk of malignant transformation up to 10 per cent of these tumours. [1] 4. Breath-hold T1 and fast spin-echo T2 weighted MR images are used for the evaluation of a liver nodule with gadolinium-enhanced dynamic MRI imaging improving liver lesion characteristics. [10, 11] Page 11 of 38

Fig. 7: MR imaging of a haemangioma demonstrates a hypointense lesion on axial T1weighted image (A), which is homogeneously, hyperintense on the axial T2-weighted image (arrow in B), intensity of which resembles a glowing light bulb (light bulb sign). T1-weighted contrast-enhanced axial images (C and D) demonstrates peripheral enhancement of this lesion progressing to partial fill-in. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Page 12 of 38

Fig. 8: MR imaging demonstrates a segment VIII, mildly hypointense hepatic lesion on non-contrasted T1-weighted image (arrow in A) which enhances intensely in the arterial phase (arrow in B). The lesion remains slightly hyperintense in the portal-venous phase (arrow in C) but becomes isointense to the liver in the delayed phase (arrow in D), characteristic of focal nodular hyperplasia. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2010 Page 13 of 38

Fig. 9: MR imaging demonstrates hypointense lesions on the T1-weighted imaging (A) which are hyperintense on the T2-weighted image (B). These lesions are iso- (C) and hypointense (D) in the portal-venous and delayed phases respectively. Characteristic feature of hepatic adenomas are the decrease in signal intensity (signal drop-out) in the out-of-phase T1-weighted image (E) indicating fat. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2010 5. Technetium-99m-labelled red blood cell scan (Tc-99m RBC scan) is a non-invasive test that has a high specificity and positive predictive value for hepatic haemangiomas but a negative diagnostic test result will then demand further imaging investigation. [12] 6. Tc-99m RBC scan has a limited sensitivity for the detection of small lesions and those located adjacent to the heart or major vessels. [13, 14] Page 14 of 38

7. In the absence of risk factors, biopsy has a limited role in the diagnosis of hepatic incidentalomas as the advances in dynamic imaging techniques are sensitive for diagnosing hepatocellular carcinoma (HCC) in most liver nodules. [15-17] 8. The accuracy of percutaneous needle biopsy is around 90 per cent [18] but the risk of needle track tumour implantation following a biopsy of a hepatocellular carcinoma is 2.7 per cent overall. [17] 9. Other complications include intraperitoneal haemorrhage, haemobilia, pneumothorax, infection, bile leak, parenchymal bleeding and pericardial tamponade. [18-20] 10. This underlines the importance of performing percutaneous needle biopsy only when absolutely necessary or when the information gained is likely to alter the management. [16, 19] 11. However, in individuals with risk factors for hepatocellular carcinoma (HCC): Lesions <1 cm are usually followed up by serial imaging Management should be for HCC, if the lesion(s) show characteristic intense arterial enhancement with contrast washout in delayed venous phase, on: [15] i. one imaging modality (for lesions >2 cm) or, ii. two imaging modalities (for lesions 1-2 cm) and/or, iii. the alpha-fetoprotein is raised, otherwise biopsy is recommended 12. The typical imaging appearance of commonly encountered, benign, non-cystic hepatic incidentalomas is summarised in Table 1 on page 33. [1, 7, 9, 10, 19, 21-25] Images Haemangioma Page 15 of 38

Fig. 10: Ultrasound abdomen demonstrates a well circumscribed, homogenous echogenic focal lesion (A) which exhibits posterior acoustic enhancement (arrow in B) as seen with haemangiomas. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Page 16 of 38

Fig. 11: Triphasic computed tomography demonstrates characteristic initial peripheral enhancement (A and B), followed by delayed but incomplete filling of the lesion with contrast (C) in a centripetal fashion, indicative of a haemangioma. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Focal nodular hyperplasia (FNH) Page 17 of 38

Fig. 12: Triphasic computed tomography demonstrates a slightly hypoattenuating lesion (arrow in A) which progressively enhances in the arterial phase (arrows in B and C), suggestive of a focal nodular hyperplasia. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2010 Hepatic adenoma (HA) Page 18 of 38

Fig. 13: Ultrasound abdomen demonstrates a hyperechoic segment II liver lesion with hypoechoic areas (arrow) within which may represent fat, indicative of a hepatic adenoma. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2012 Page 19 of 38

Fig. 14: Triphasic computed tomography demonstrates a large heterogeneously enhancing lesion with intra-lesional hypoattenuation (thin arrows) in the presence of other smaller enhancing left liver lobe lesions (thick arrows) suggestive of a hepatic adenoma. References: Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Page 20 of 38

Images for this section: Fig. 1: This pathway provides guidance on the imaging of adult patients with a focal liver lesion discovered incidentally on imaging for unrelated indications, who have no history or risk factors for malignancy. Diagnostic Imaging Pathways, Imaging West, Royal Perth Hospital - Perth/AU Page 21 of 38

Fig. 3: CEUS enhancement patterns for focal nodular hyperplasia demonstrates early arterial phase enhancement with a centrifugal filling pattern which is sustained in the portal-venous phase. The prominent arterial and venous supply to the lesion can be seen in the video. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 Page 23 of 38

Fig. 4: CEUS enhancement patterns demonstrates peripheral nodular enhancement in the arterial phase (A), progressing in a centripetal direction (B) to partial or complete fillin (C). Enhancement is sustained through the delayed phase with no washout, as noted in the time-intensity curve profile of haemangioma (D). Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 Page 24 of 38

Fig. 5: CEUS enhancement patterns demonstrates early arterial phase enhancement (A and B) with a centrifugal filling pattern which is sustained in the portal-venous phase (C, D and E). Time-intensity curve profile (F) of focal nodular hyperplasia shows the centre of the lesion enhancing much earlier and to a greater extent than the periphery. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 Page 25 of 38

Fig. 6: CEUS enhancement patterns demonstrating a hyperenhancing lesion in the arterial phase (A) and which is isoenhancing in the portal-venous phase (B and C). Timeintensity curve profile of hepatic adenoma (D) shows rim of enhancing occurring slightly earlier and to a greater extent than the lesion centre. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2004 Page 26 of 38

Fig. 7: MR imaging of a haemangioma demonstrates a hypointense lesion on axial T1weighted image (A), which is homogeneously, hyperintense on the axial T2-weighted image (arrow in B), intensity of which resembles a glowing light bulb (light bulb sign). T1-weighted contrast-enhanced axial images (C and D) demonstrates peripheral enhancement of this lesion progressing to partial fill-in. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Page 27 of 38

Fig. 8: MR imaging demonstrates a segment VIII, mildly hypointense hepatic lesion on non-contrasted T1-weighted image (arrow in A) which enhances intensely in the arterial phase (arrow in B). The lesion remains slightly hyperintense in the portal-venous phase (arrow in C) but becomes isointense to the liver in the delayed phase (arrow in D), characteristic of focal nodular hyperplasia. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2010 Page 28 of 38

Fig. 10: Ultrasound abdomen demonstrates a well circumscribed, homogenous echogenic focal lesion (A) which exhibits posterior acoustic enhancement (arrow in B) as seen with haemangiomas. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Page 30 of 38

Fig. 11: Triphasic computed tomography demonstrates characteristic initial peripheral enhancement (A and B), followed by delayed but incomplete filling of the lesion with contrast (C) in a centripetal fashion, indicative of a haemangioma. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Page 31 of 38

Fig. 12: Triphasic computed tomography demonstrates a slightly hypoattenuating lesion (arrow in A) which progressively enhances in the arterial phase (arrows in B and C), suggestive of a focal nodular hyperplasia. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2010 Page 32 of 38

Fig. 13: Ultrasound abdomen demonstrates a hyperechoic segment II liver lesion with hypoechoic areas (arrow) within which may represent fat, indicative of a hepatic adenoma. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2012 Fig. 14: Triphasic computed tomography demonstrates a large heterogeneously enhancing lesion with intra-lesional hypoattenuation (thin arrows) in the presence of other smaller enhancing left liver lobe lesions (thick arrows) suggestive of a hepatic adenoma. Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Western Australia 2015 Page 33 of 38

Table 1: Typical imaging appearance of commonly encountered, benign, non-cystic hepatic incidentalomas. Diagnostic Imaging Pathways, Imaging West, Royal Perth Hospital - Perth/AU Page 34 of 38

Conclusion CEUS is a technique becoming a standard procedure for the characterization of FLLs in much of Europe as it is able to overcome some of the limitations of conventional B-mode and Doppler ultrasound techniques, concurrently enabling the display of liver parenchymal microvasculature. [7, 9] Unfortunately, CEUS is underutilized in Australia, partly due to lack of expertise in its use and partly due to the lack of a Medicare rebate. The answer to this challenging issue is a more widespread use of CEUS and greater access to hepatic MRI, both of which may have to await more favourable funding mechanisms. Page 35 of 38

Personal information Dr Gurjeet Dulku Research Fellow, Diagnostic Imaging Pathways Imaging West, Royal Perth Hospital, Department Of Health Western Australia Email: Gurjeet.Dulku@health.wa.gov.au Professor Richard Mendelson Emeritus Consultant Radiologist, Royal Perth Hospital Clinical Professor, University of Western Australia Adjunct Professor, Notre Dame University, Western Australia Page 36 of 38

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