Journal of Medical Imaging and Radiation Oncology 58 (2014) 38–45 bs_bs_banner
RADIOLO GY —O R I G I N AL A R T I C L E
Hepatic contrast-enhanced ultrasound: Impact of its introduction in the Australian context So Yeun Won,1 Neha Singh,2 Beng Ghee Lim,3 Damien Stella3 and Robert Gibson3 1 Radiology Department, Concord Repatriation Hospital, Sydney, 2Radiology Department, Regional Imaging Riverina, Wagga Wagga, New South Wales, and 3Radiology Department, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Abstract
SY Won MBBS, FRANZCR; N Singh MBBS (Hons), FRANZCR; BG Lim MBBS, FRANZCR; D Stella MBBS, FRANZCR; R Gibson MBBS, FRANZCR. Correspondence Dr So Yeun Won, Radiology Department, Concord Repatriation Hospital, Hospital Road, Concord, New South Wales 2139, Australia. Email: [email protected] Conflict of interest: None. Submitted 16 April 2013; accepted 3 June 2013. doi:10.1111/1754-9485.12093
Introduction: Contrast-enhanced ultrasound (CEUS) is a relatively new imaging modality in Australia. We discuss our early experience with CEUS at Royal Melbourne Hospital in assessment of focal liver lesions and its clinical impact. Method: Radiology department and hospital computerised information systems were used to identify and collate information regarding the indication, previous and follow-up imaging, CEUS findings and subsequent final diagnoses of patients who underwent hepatic CEUS from 12/12/2007 to 20/4/2012. Results: A total of 388 hepatic CEUS were performed, examining 409 lesions. The cases were grouped as either ‘initial study’ or ‘follow-up’ group, with main focus on the former group. Of the 367 lesions in the ‘initial study’ group, CEUS was able to distinguish benign from malignant pathology in 344 cases (93.8%). This was especially beneficial in setting of known malignancy with indeterminate liver lesions found on CT to confidently exclude metastatic disease. For 124 of 162 patients who had an incidentally detected indeterminate liver lesion, CEUS was the final imaging investigation required to make a diagnosis. Conclusion: CEUS is a valuable tool in assessment of focal liver lesions in conjunction with other conventional modalities in a variety of clinical settings. In particular, it provided definitive diagnosis in a significant proportion of incidentally identified liver lesions many of which are benign, saving patient anxiety and further unnecessary follow-up. Key words: contrast enhanced ultrasound; liver lesions.
Introduction Contrast-enhanced ultrasound (CEUS) using second generation contrast agents has been in use in several countries for many years but is a relatively new imaging modality in Australia. It utilises microbubble contrast agents injected intravenously to enhance the ultrasound (US) signal and give information about dynamic enhancement and washout characteristics. In abdominal US, it has primarily been used in liver and, to a less degree, kidneys, with most experience in Europe and Asia.1 Second generation CEUS was introduced into Australia in 2007 when Definity® (Definity®, Lantheus, N. Bill-
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erica, MA, USA), which is a perflutren lipid microsphere agent, was approved for hepatic, renal and cardiac use. This audit-style article aims to describe the impact of the introduction in hepatic CEUS using Definity® in an Australian radiology tertiary referral hospital setting at Royal Melbourne Hospital and in doing so provide some perspective on how a more broad use of hepatic CEUS would be of benefit in the Australian radiology setting.
Method Using the Radiology Department information system, all hepatic CEUS studies were identified from 12/12/2007 to
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
20/4/2012 and data collated from referring information, external and internal imaging, and reports. The information provided on the scanned request forms or in the ‘clinical notes’ section of the report was used to determine the indication for CEUS. Information regarding prior imaging was derived from imaging available on the Synapse Picture Archiving and Communication System (both internal examinations and incorporated external films) and also from referring clinical notes. CEUS-based diagnosis was made after review of the available clinical information, prior imaging, grayscale and Doppler US appearances and finally the enhancement/washout characteristics on CEUS based on accepted CEUS guidelines.2,3 CEUS was performed and reported by one of two abdominal radiologists with experience in US. Philips iU22 (Philips Healthcare, Bothell, WA, USA) and Toshiba Aplio XG (Toshiba, Otawara-Shi, Japan) were the two US systems used. Each patient was injected with boluses of 0.3–0.6 mL of Definity®. The final diagnosis was based on either tissue histology (percutaneous biopsy or operative specimen), or behaviour on subsequent imaging. If no follow-up had been performed, the CEUS diagnosis was presumed correct or diagnosis deemed unknown depending on the level of certainty as indicated on the CEUS report.
Results A total of 388 hepatic CEUS examinations were performed during this time period, examining 409 liver lesions. Of the 388 liver examinations, 26 patients had multiple examinations (two to five examinations each), totalling 63 examinations.
Previous imaging In most of the cases, the patients had had imaging prior to CEUS. One hundred seventy-seven had previous conventional USs (67 performed externally, 110 in our department), 290 had CT scans (121 externally, 169 in our department) and 53 had MRI scans (32 externally, 21 in our department).
Indications Indications for CEUS could be divided into two distinct categories: the first (‘Group A’) is the diagnostic arm where this was the patient’s first CEUS and second group (‘Group B’) where a lesion or abnormality seen on prior CEUS was followed-up with another CEUS. Much of the following discussion centres around Group A. Group A was subdivided into four distinct groups. Group A1 includes patients with a known primary malignancy who had indeterminate lesions seen on other modality (usually CT) and who required exclusion or
confirmation of hepatic metastatic disease. This group also included a minority of cases where no known primary malignancy was present; however, the liver lesions were thought suggestive of metastases on imaging appearances. Group A2 comprised patients who were at risk of hepatocellular carcinoma (HCC) and who had an abnormality or lesion identified on surveillance scans (mostly patients with cirrhosis and chronic hepatitis B). The largest group Group A3 was patients with no known liver disease or primary malignancy elsewhere and in whom a liver lesion was discovered by imaging and required further diagnostic work up. The lesion was often incidentally discovered on scans performed for unrelated issues. Group A4 patients had a lesion causing biliary obstruction, often with a background of primary sclerosing cholangitis and specific question of cholangiocarcinoma (CCa) raised on referral. This included lesions down to the hilar level. Group B was subdivided into two categories, namely benign or indeterminate and malignant at initial diagnoses. These follow-up examinations were performed either for reassurance (to ensure benignity) or in the case of malignant lesions to assess response to local therapy such as ethanol or radiofrequency ablation for HCC (Table 1).
Diagnoses The following describes the breakdown of diagnoses on CEUS (‘CEUS diagnosis’) and final diagnosis of Group A alone. Table 2 summarises the CEUS diagnosis breakdown by groups, whereas Table 3 compares the CEUS diagnoses to the final diagnoses and how those final diagnoses were established, namely by biopsy, behaviour on subsequent imaging or neither. The cases of false positive and false negative for malignant diagnoses are discussed separately below (Tables 6 and 7).
Group A1 The most prevalent CEUS diagnosis in this group was haemangioma (35 cases), followed by malignant conditions (31), which encompassed metastases, or a differential given either as ‘metastasis or HCC’ or ‘metastasis or CCa’ depending on the enhancement characteristics. Several other benign entities comprised 32 cases including six cases where no lesion was identified in the area of interest. Eight cases were reported as equivocal. Interestingly, two of the CEUS-malignant lesions were biopsy proven as not being metastases but rather HCC and epithelioid haemangioendothelioma, respectively.
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
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Table 1. Indications for CEUS Indication Group A (Initial study)
Number 1 2 3 4
Group B (Follow-up)
1 2
Exclusion/confirmation of metastases in setting of known primary malignancy or imaging features strongly suspicious for metastases Abnormality/lesion found on HCC surveillance in setting of chronic liver disease – cirrhosis or chronic viral hepatitis Confirmation/further assessment of a focal liver lesion found on other imaging in low risk patients Exclusion/confirmation of CCa in the liver in setting of PSC or localised intrahepatic biliary dilation Follow-up of malignant lesion ⫾ post-treatment (HCC or metastases) Follow-up of benign or indeterminate lesions previously examined with CEUS
106 lesions in 100 studies 76 studies 173 lesions in 162 studies 12 studies 23 studies 19 lesions in 15 studies
CCa, cholangiocarcinoma; CEUS, Contrast-enhanced ultrasound; HCC, hepatocellular carcinoma; PSC, primary sclerosing cholangitis.
Group A2
Group A4
As expected from this subset of high-risk patients, the most prevalent CEUS diagnosis was HCC with 31 patients. Four cases were categorised as dysplastic nodules (DNs); two were reported specifically as DN, whereas the other two were reported as ‘DN or well differentiated HCC’ given that these two disease processes can show overlapping enhancement features. Of these latter two lesions, one was biopsy proven as HCC. Of the benign diagnoses, again haemangioma was the most common diagnosis (16 cases). Four were reported as equivocal cases. Of note is a case that was first reported as equivocal, then on subsequent follow-up developed enhancement characteristics typical for HCC that were absent on initial CEUS. A further interesting case was a lesion that was initially reported as an adenoma on CEUS and on follow-up MRI with gadoxetate had classic appearances of a flash filling haemangioma. The sonographic diagnosis was probably made on the basis of seeing readily visible internal flow, which is not typical appearance of a haemangioma.
Of the 12 cases in this group, five cases were reported on CEUS as CCa and seven cases as no tumour. There were no equivocal cases in this group. Combining all four subgroups in Group A, a total of 367 lesions were examined. Of these, 262 were benign, 82 malignant and 23 equivocal on CEUS. Of the benign diagnoses, haemangioma was the commonest CEUS diagnosis (109 lesions), followed by FNH (64 lesions) (Table 4).
Group A3 Group A3 was the largest subgroup of patients with a total of 173 lesions. A large majority of CEUS diagnoses were benign (147), with 15 malignant and 11 equivocal. The most common diagnosis was again haemangioma with 58 cases, followed by focal nodular hyperplasia (FNH). In seven of the cases, a differential diagnosis of haemangioma, FNH or adenoma was given. The remainder of the benign diagnoses included cyst, infection/inflammation, regenerative or dysplastic nodule, arteriovenous fistula, perfusion anomalies, focal fat sparing or infiltration. Two of the 11 equivocal cases were revealed on biopsy to be malignant.
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Group B1 Of the 23 studies examining known malignant lesions, 14 showed residual/recurrent malignancy, whereas eight showed no residual/recurrent tumour. One case of previously ablated neuroendocrine metastases was reported as equivocal.
Group B2 Twelve of 14 cases in this group showed stable findings, reassuring likely benignity. Two lesions remained equivocal – of these, one was lost to follow-up, whereas the other patient went on to have a liver resection finally revealing an HCC.
Potential impact on management We were interested in exploring how CEUS was able to influence the patient management and the role of CEUS in diagnostic algorithm in different clinical scenarios.
Group A CEUS was able to clarify benign versus malignant nature in 98 of the 106 focal liver lesions in Group A1 and 70 of the 76 lesions examined in Group A2.
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
Table 2. CEUS diagnosis breakdown by groups Group Group A1
Group A2
Group A3
Group A4
CEUS diagnosis
Number of lesions
Malignant
31
Haemangioma FNH Adenoma Cyst No lesion Equivocal Other
35 12 1 9 6 8 4
HCC DN
31 4
Benign nodule/RN Haemangioma FNH Adenoma Cyst No lesion Equivocal Other
8 16 4 1 2 4 4 2
Haemangioma FNH Adenoma Differential of haemangioma/FNH/Adenoma Malignant Cyst Equivocal Benign, other
58 48 1 7 15 8 11 21
Inflammation/infection CCa No tumour
Comments Metastasis 24 Metastasis or HCC 3 Metastasis or CCa 4
Perforated cholecystitis with surrounding liver inflammatory change 1 Scarring 1 Focal fat infiltration (FFI) 1 Perfusion anomaly 1 ‘DN or well differentiated HCC’ 2 DN 2
Focal fat sparing (FFS) 1 Shunt 1
RN 2, DN 1, Fistula 1, Perfusion anomaly 2 No lesion 1 FFI 10, FFS 1 Benign not otherwise specified 3
4 5 7
CCa, cholangiocarcinoma; CEUS, Contrast-enhanced ultrasound; DN, dysplastic nodule; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; RN, regenerative nodule.
In Group A3, of the 173 lesions examined, CEUS confirmed pre-CEUS suspected diagnoses in 87 cases. In 13 cases within this group, the diagnosis was changed from benign to malignant (six of the cases) or conversely malignant to benign (in seven cases) based on CEUS findings (Table 5). The cases where pre-CEUS diagnosis of benign pathology was changed to malignant were most significant. Of the six cases, three were initially reported as most likely haemangiomas, one FNH, one either haemangioma or FNH and one as abscesses. In the reverse scenario where pre-CEUS diagnosis of malignant pathology was changed to benign, most
were cases where the pre-CEUS imaging report concluded with a list of differential diagnoses including malignancies and other benign entities in the setting of a hypervascular (that is, arterially enhancing) lesion. Most of these did not demonstrate significant washout on subsequent phases (although some were not dedicated mutltiphasic studies) on CT. This subset reflects in part initial misinterpretation of CT enhancement patterns of focal liver lesions by the initial reporting radiologist. In Group A4 patients, all 12 of 12 cases CEUS was able to provide clarification as to whether there was a malignant lesion.
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
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Table 3. CEUS diagnosis breakdown by groups, diagnoses confirmed by, and final diagnoses Groups
Group A1
Group A2
Group A3
Group A4
CEUS diagnosis
Diagnosis confirmed by
Final diagnosis (based on)
Biopsy (Bx)
Follow-up imaging
Neither
20
6
5
Haemangioma (35)
2
8
25
FNH (12)
2
7
3
Adenoma (1) Cyst (9) No lesion (6) Equivocal (8)
1 0 0 2
0 3 5 3
0 6 1 3
Other (4) HCC (31)
0 8
2 18
2 5
DN (4)
1
2
1
Benign (regenerative nodules) (8) Haemangioma (16) FNH (4) Adenoma (1) Cyst (2) No lesion (4) Equivocal (4)
0 1 0 0 1 0 0
4 8 2 1 1 4 4
4 7 2 0 0 0 0
Other (2)
0
2
0
Malignant (15)
9
3
3
Haemangioma (58) FNH (48) Adenoma (1) DDx FNH or adenoma or haemangioma (7) Benign other (including RN, DN, THAD, fistula, FFI/FFS, no lesion, NOS) (21) Cyst (8)
0 1 0 0
15 9 1 2
43 38 0 5
0
4
17
2
3
3
Inflammation/infection (4) Equivocal (11)
1 3
2 4
1 4
CCa (5) No tumour (7)
2 3
1 0
2 4
Malignant (31)
Metastases 18 (Bx 14, imaging 4) Benign 6 (Bx 3, imaging 3) Uncertain† 6 Other 2‡ (Bx) Haemangioma 34 (presumed 25, imaging 8, Bx 1) GIST metastasis 1 (Bx) FNH 10 (presumed 3, imaging 7) Haemangioma 1 (Bx) HCC 1 (Bx) HCC 1 (Bx) Cyst 9 (presumed 6, imaging 3) No lesion 6 (imaging 5, presumed 1) Uncertain 3 (no follow up) Likely benign (stable imaging 1) Metastasis 1 (Bx) Benign (presumed 2, imaging stable 2) HCC 29 (Bx 8, imaging 16, presumed 5) Haemangioma 1 (imaging) Benign 1 (imaging) HCC 1 (Bx) DN 3 (imaging 2, presumed 1) Benign (imaging 4, presumed 4) Haemangioma 16 (Bx 1, imaging 8, presumed 7) FNH 4 (imaging 2, presumed 2) Haemangioma 1 (MRI) Cyst (Bx 1, imaging 1) No lesion 4 (imaging) Benign 3 (imaging stable/disappeared) HCC 1 (eventual development of HCC enhancement on imaging) Shunt 1 (stable imaging) Focal fat sparing 1 (imaging) HCC 4 (Bx 2, imaging 2) Cholangiocarcinoma 4 (Bx) Met 3 (Bx) Malignant, non specific 3 (presumed) Benign 1 (imaging) Haemangioma 58 (stable/concordant imaging 15, presumed 43) FNH 48 (Bx 1, stable imaging 9, presumed 38) Adenoma 1 (stable imaging) No follow up 5 Stable imaging 2 Benign (presumed 17, stable imaging 4) Benign cyst (presumed 3, stable imaging 3, Bx 1) Bile duct hamartoma 1 (Bx) Inflammation/infection 4 (Bx 1, imaging 2, presumed 1) CCa 1 (Bx) Necrotic tumour 1 (Bx) Likely benign 4 (on further imaging 4) Unclear 5 (no follow-up 4, resection but no pathology results available 1) CCa 5 (presumed 2, concordant imaging 1, Bx 2) No tumour 6 (presumed 4, Bx 2) CCa 1 (Bx)
†No imaging or biopsy to determine final diagnosis. ‡Biopsy proven HCC and epithelioid haemangioendothelioma. CCa, cholangiocarcinoma; CEUS, contrastenhanced ultrasound; DN, dysplastic nodule; FFI, focal fat infiltration; FFS, focal fat sparing; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; NOS, not otherwise specified; RN, regenerative nodule; THAD, transient hepatic attenuation difference.
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© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
Table 4. CEUS Diagnosis – benign diagnoses breakdown CEUS diagnosis
Number
Haemangioma FNH Adenoma Haemangioma vs. FNH vs. adenoma Cyst Dysplastic nodule Other
109 64 3 7 19 4 56
CEUS, contrast-enhanced ultrasound; FNH, focal nodular hyperplasia.
Group B In follow-up CEUS of 22 of 23 malignant lesions, CEUS was able to clarify presence/absence of viable tumour. In the one equivocal case, there was a history of previous ablation of neuroendocrine metastases, which were shown to be metabolically active on positron emission tomography scan. Enhancement pattern on CEUS
was equivocal and lowered the clinician’s suspicions sufficiently that the patient did not go on to receive further local ablation therapy.
Morbidity Only two adverse reactions were recorded. One patient reported erythematous changes in the sun exposed areas of skin days after the contrast injection, which did not require hospitalisation. Another patient reported back pain minutes after the injection, which subsided spontaneously. It should be noted that routine post-procedure follow-up was not done. The case of the skin erythema was only discovered due to the referring physician conveying this complication back to the radiology department.
Follow-up Of the 350 in Group A, 57 had a definitive diagnosis made on biopsy – either percutaneous or with an opera-
Table 5. Group 3 cases where pre-CEUS diagnosis was changed from benign to malignant or vice versa Patient
MB SS SB FF PL FL DS PS JS HM ADQ BH KW
Pre-CEUS diagnosis/differentials
CEUS diagnosis
Benign to malignant/malignant to benign
Final diagnosis
Atypical haemangioma vs. HCC/hypervascular metastasis Haemangioma Haemangioma Abscesses Haemangioma/FNH Atypical FNH HCC vs. AVM HCC vs. haemangioma HCC vs. FNH FNH/adenoma vs. hypervascular metastasis FNH/adenoma vs. metastasis Haemangioma vs. metastasis Haemangioma vs. HCC vs. FNH
HCC/hypervascular metastasis Metastasis HCC Metastases Malignancy Malignancy FNH Haemangioma FNH Haemangioma Haemangioma Haemangioma Haemangioma
B to M
Presumed HCC/hypervascular metastasis CCa HCC Metastases CCa Presumed malignant Presumed FNH Presumed haemangioma FNH Presumed haemangioma Presumed haemangioma Presumed haemangioma Haemangioma
B to M B to M B to M B to M B to M M to B M to B M to B M to B M to B M to B M to B
AVM, arteriovenous malformation; CCa, cholangiocarcinoma; CEUS, contrast-enhanced ultrasound; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma.
Table 6. False positives for malignancy Patient MM SL RR VM SM MG MI MW
Indication
CEUS diagnosis
Outcome
?Renal cell cancer metastasis ?Colorectal cancer metastasis ?Lung cancer metastasis ?Neuroendocrine metastases ?Metastasis vs. haemangioma Cirrhosis with known ‘haemangioma’ enlarging Hepatitis B, new lesion Possible liver lesion on CT ?haematoma vs. tumour
Suspicious for metastasis Suspicious for metastasis Suspicious for metastasis Suspicious for metastasis Suspicious for metastasis Suspicious for HCC Suspicious for HCC Suspicious for malignancy
PET negative. behaved like a non aggressive lesion Remained stable over 3 years on CT 2 negative biopsies. Biopsy negative. MRI favours adenoma. Stable on imaging. Biopsy negative. Stable on imaging Stable on multiple follow up scans Stable for 2 years prior to CEUS Stable on imaging, clinically well and not behaving like tumour
CEUS, contrast-enhanced ultrasound; HCC, hepatocellular carcinoma; PET, positron emission tomography. © 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
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Table 7. False negatives for malignancy Patient LS DP SS AW DM
Indication
CEUS diagnosis
Outcome
?Breast cancer metastasis ?Colorectal cancer metastasis ?GIST metastasis ?Breast cancer metastasis Right sectoral duct dilation on CT ?tumour
Unusual; not typical for metastasis FNH Haemangioma Adenoma No abnormal enhancement
Biopsy – breast carcinoma metastasis HCC on resection Grew in size on serial scans – GIST met on resection HCC on resection CT and resection adenocarcinoma
CEUS, contrast-enhanced ultrasound; GIST, gastrointestinal stromal tumour; HCC, hepatocellular carcinoma.
tive specimen. One hundred twenty-one had imaging follow-up, whereas 172 did not go on to have either of these.
False positives and false negatives for malignancy The diagnoses were considered falsely positive for malignancy if a suspected malignancy on CEUS remained stable on imaging or was proven benign on tissue biopsy (Table 6). Conversely, false negatives were those cases where the CEUS diagnosis was thought definite or very likely benign but either on clinical, imaging follow-up or eventual histologic grounds the final diagnosis was considered to be malignant pathology (Table 7). From Group A1, six cases were initially reported as suspicious for metastases but were ultimately thought to be benign, with negative biopsy for malignancy in three cases and in three cases behaving on subsequent scans in an indolent fashion thought unlikely for metastatic disease. From Group A2, two cases initially reported as HCC were eventually thought to be benign based on stable appearances on subsequent imaging in one patient, and in the second patient subsequently discovered imaging from 2 years prior to the CEUS had shown that the lesion had been stable. One lesion from Group A3 was initially reported as suspicious for either a metastasis or a CCa with abnormal early enhancement and washout, with locally obstructed ducts. The follow-up US 1 year later however did not identify a mass while there was progressive atrophy of the involved liver lobe. Clinically, the patient had not developed jaundice, and it was considered, although not proven, that the patient did not have a malignancy. Four lesions from Group A1 initially were proven on subsequent histology to be malignant. One case was initially reported as a haemangioma however subsequently increased in size on serial scans and biopsy revealed a gastrointestinal stromal tumour metastasis. The two lesions that were biopsy proven to be HCC were initially reported as FNH and adenoma, respectively. In one case, unusual linear echotexture change in the liver
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was seen (rather than discrete focal masses), thought atypical for metastasis but considered unusual enough to warrant a biopsy that showed a breast cancer metastasis. There was a case of a false negative from Group A4. Prior to the CEUS, CT had shown isolated right posterior sectoral biliary dilation with possible mass lesion seen on MR. The CEUS did not demonstrate any abnormal enhancement and was reported as no tumour. A follow-up CT was performed that showed an obvious mass. The surgical specimen confirmed adenocarcinoma.
Discussion CEUS was useful in all groups studied, including indeterminate liver lesions often found incidentally on other modality, indeterminate liver lesions in setting of a known malignancy and lesions identified on HCC surveillance. Overall, CEUS was able to categorise a focal liver lesion as either benign or malignant with confidence in 342 of 367 (93.8%) in Group A. CEUS gave definitive diagnosis in 314 of 367 cases (85.6%). This is in keeping with current published data on accuracy of CEUS in evaluation of liver lesions.4,5 In particular, in 124 of the 162 patients (76.5%) with indeterminate liver lesions (Group A3), CEUS was the final imaging thought to be required for establishing the diagnosis with a high level of confidence. This is very important as most of these patients have benign pathology and do not need multiple imaging tests or biopsy. CEUS was able to provide the definitive diagnosis in a substantial number of these patients. CEUS changed the diagnosis from benign to malignant in six patients and malignant to benign in seven patients, radically changing patient management especially in the former group. Perhaps the most significant limitation of our experience is the lack of diagnostic histopathology obtained for all focal liver lesions examined with CEUS. This lack of a ‘gold standard’ prevents this study from making conclusions about accuracy but based on accepted CEUS interpretation guidelines, and substantial corroboration by other modalities or by follow-up, it is reasonable to conclude that CEUS made a substantially positive impact on patient investigation in a majority of patients. In
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
many cases, CEUS provided a sufficient level of confidence not to warrant any further diagnostic work-up, which is significant in terms of cost and possibly safety. The patients were not routinely assessed for side effects from the contrast agent. As a result, not all possible side effects would have been recorded, especially if they were minor. This was not designed as an accuracy study but the small number of false negatives and positives for malignancy that were recognised highlight that this is, as with all modalities, an imperfect test. There were no consistent characteristics leading to the false diagnoses.
Conclusion Our early experience with CEUS has shown that it is a valuable adjunct in hepatic imaging. In addition to conventional US, CT and MRI, it provides added confidence to the radiologist and clinician of the nature of focal liver lesions, frequently obviating the need for further imaging of biopsy of indeterminate lesions. We found that CEUS is especially useful for confirming benign pathology in incidentally identified liver lesions. This experience in a tertiary centre could equally be expected to apply in broader radiology practice in Australia where there is generally a high level of US scanning skills. Contrastenhanced liver US should become part of the radiologist ‘toolkit’ as soon as possible, and this would clearly be
aided by government funding of this non-invasive modality. Occasional false negative and false positive results, however, do highlight the importance of interpreting CEUS results carefully and in context of the clinical features and other imaging findings.
Acknowledgements We have no financial links or affiliations to declare.
References 1. Ong YY, Gibson RN. Contrast-enhanced ultrasound: emerging modality for liver lesion characterization. J Gastroenterol Hepatol 2008; 23: 1465–6. 2. Claudon M, Cosgrove D, Albrecht T et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) – update 2008. Ultraschall Med 2008; 29: 28–44. 3. Wilson SR, Burns PN. An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography. Am J Roentgenol 2006; 186: 1401–12. 4. Wilson SR, Jang H-J, Kim TK, Burns PN. Diagnosis of focal iver masses on ultrasonography. J Ultrasound Med 2007; 26: 775–87. 5. Sporea I, Badea R, Martie A et al. Contrast enhanced ultrasound for the evaluation of focal liver lesions in daily practice. Med Ultrason 2012; 14: 95–100.
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
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RADIOLO GY —O R I G I N AL A R T I C L E
Hepatic contrast-enhanced ultrasound: Impact of its introduction in the Australian context So Yeun Won,1 Neha Singh,2 Beng Ghee Lim,3 Damien Stella3 and Robert Gibson3 1 Radiology Department, Concord Repatriation Hospital, Sydney, 2Radiology Department, Regional Imaging Riverina, Wagga Wagga, New South Wales, and 3Radiology Department, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Abstract
SY Won MBBS, FRANZCR; N Singh MBBS (Hons), FRANZCR; BG Lim MBBS, FRANZCR; D Stella MBBS, FRANZCR; R Gibson MBBS, FRANZCR. Correspondence Dr So Yeun Won, Radiology Department, Concord Repatriation Hospital, Hospital Road, Concord, New South Wales 2139, Australia. Email: [email protected] Conflict of interest: None. Submitted 16 April 2013; accepted 3 June 2013. doi:10.1111/1754-9485.12093
Introduction: Contrast-enhanced ultrasound (CEUS) is a relatively new imaging modality in Australia. We discuss our early experience with CEUS at Royal Melbourne Hospital in assessment of focal liver lesions and its clinical impact. Method: Radiology department and hospital computerised information systems were used to identify and collate information regarding the indication, previous and follow-up imaging, CEUS findings and subsequent final diagnoses of patients who underwent hepatic CEUS from 12/12/2007 to 20/4/2012. Results: A total of 388 hepatic CEUS were performed, examining 409 lesions. The cases were grouped as either ‘initial study’ or ‘follow-up’ group, with main focus on the former group. Of the 367 lesions in the ‘initial study’ group, CEUS was able to distinguish benign from malignant pathology in 344 cases (93.8%). This was especially beneficial in setting of known malignancy with indeterminate liver lesions found on CT to confidently exclude metastatic disease. For 124 of 162 patients who had an incidentally detected indeterminate liver lesion, CEUS was the final imaging investigation required to make a diagnosis. Conclusion: CEUS is a valuable tool in assessment of focal liver lesions in conjunction with other conventional modalities in a variety of clinical settings. In particular, it provided definitive diagnosis in a significant proportion of incidentally identified liver lesions many of which are benign, saving patient anxiety and further unnecessary follow-up. Key words: contrast enhanced ultrasound; liver lesions.
Introduction Contrast-enhanced ultrasound (CEUS) using second generation contrast agents has been in use in several countries for many years but is a relatively new imaging modality in Australia. It utilises microbubble contrast agents injected intravenously to enhance the ultrasound (US) signal and give information about dynamic enhancement and washout characteristics. In abdominal US, it has primarily been used in liver and, to a less degree, kidneys, with most experience in Europe and Asia.1 Second generation CEUS was introduced into Australia in 2007 when Definity® (Definity®, Lantheus, N. Bill-
38
erica, MA, USA), which is a perflutren lipid microsphere agent, was approved for hepatic, renal and cardiac use. This audit-style article aims to describe the impact of the introduction in hepatic CEUS using Definity® in an Australian radiology tertiary referral hospital setting at Royal Melbourne Hospital and in doing so provide some perspective on how a more broad use of hepatic CEUS would be of benefit in the Australian radiology setting.
Method Using the Radiology Department information system, all hepatic CEUS studies were identified from 12/12/2007 to
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
20/4/2012 and data collated from referring information, external and internal imaging, and reports. The information provided on the scanned request forms or in the ‘clinical notes’ section of the report was used to determine the indication for CEUS. Information regarding prior imaging was derived from imaging available on the Synapse Picture Archiving and Communication System (both internal examinations and incorporated external films) and also from referring clinical notes. CEUS-based diagnosis was made after review of the available clinical information, prior imaging, grayscale and Doppler US appearances and finally the enhancement/washout characteristics on CEUS based on accepted CEUS guidelines.2,3 CEUS was performed and reported by one of two abdominal radiologists with experience in US. Philips iU22 (Philips Healthcare, Bothell, WA, USA) and Toshiba Aplio XG (Toshiba, Otawara-Shi, Japan) were the two US systems used. Each patient was injected with boluses of 0.3–0.6 mL of Definity®. The final diagnosis was based on either tissue histology (percutaneous biopsy or operative specimen), or behaviour on subsequent imaging. If no follow-up had been performed, the CEUS diagnosis was presumed correct or diagnosis deemed unknown depending on the level of certainty as indicated on the CEUS report.
Results A total of 388 hepatic CEUS examinations were performed during this time period, examining 409 liver lesions. Of the 388 liver examinations, 26 patients had multiple examinations (two to five examinations each), totalling 63 examinations.
Previous imaging In most of the cases, the patients had had imaging prior to CEUS. One hundred seventy-seven had previous conventional USs (67 performed externally, 110 in our department), 290 had CT scans (121 externally, 169 in our department) and 53 had MRI scans (32 externally, 21 in our department).
Indications Indications for CEUS could be divided into two distinct categories: the first (‘Group A’) is the diagnostic arm where this was the patient’s first CEUS and second group (‘Group B’) where a lesion or abnormality seen on prior CEUS was followed-up with another CEUS. Much of the following discussion centres around Group A. Group A was subdivided into four distinct groups. Group A1 includes patients with a known primary malignancy who had indeterminate lesions seen on other modality (usually CT) and who required exclusion or
confirmation of hepatic metastatic disease. This group also included a minority of cases where no known primary malignancy was present; however, the liver lesions were thought suggestive of metastases on imaging appearances. Group A2 comprised patients who were at risk of hepatocellular carcinoma (HCC) and who had an abnormality or lesion identified on surveillance scans (mostly patients with cirrhosis and chronic hepatitis B). The largest group Group A3 was patients with no known liver disease or primary malignancy elsewhere and in whom a liver lesion was discovered by imaging and required further diagnostic work up. The lesion was often incidentally discovered on scans performed for unrelated issues. Group A4 patients had a lesion causing biliary obstruction, often with a background of primary sclerosing cholangitis and specific question of cholangiocarcinoma (CCa) raised on referral. This included lesions down to the hilar level. Group B was subdivided into two categories, namely benign or indeterminate and malignant at initial diagnoses. These follow-up examinations were performed either for reassurance (to ensure benignity) or in the case of malignant lesions to assess response to local therapy such as ethanol or radiofrequency ablation for HCC (Table 1).
Diagnoses The following describes the breakdown of diagnoses on CEUS (‘CEUS diagnosis’) and final diagnosis of Group A alone. Table 2 summarises the CEUS diagnosis breakdown by groups, whereas Table 3 compares the CEUS diagnoses to the final diagnoses and how those final diagnoses were established, namely by biopsy, behaviour on subsequent imaging or neither. The cases of false positive and false negative for malignant diagnoses are discussed separately below (Tables 6 and 7).
Group A1 The most prevalent CEUS diagnosis in this group was haemangioma (35 cases), followed by malignant conditions (31), which encompassed metastases, or a differential given either as ‘metastasis or HCC’ or ‘metastasis or CCa’ depending on the enhancement characteristics. Several other benign entities comprised 32 cases including six cases where no lesion was identified in the area of interest. Eight cases were reported as equivocal. Interestingly, two of the CEUS-malignant lesions were biopsy proven as not being metastases but rather HCC and epithelioid haemangioendothelioma, respectively.
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
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Table 1. Indications for CEUS Indication Group A (Initial study)
Number 1 2 3 4
Group B (Follow-up)
1 2
Exclusion/confirmation of metastases in setting of known primary malignancy or imaging features strongly suspicious for metastases Abnormality/lesion found on HCC surveillance in setting of chronic liver disease – cirrhosis or chronic viral hepatitis Confirmation/further assessment of a focal liver lesion found on other imaging in low risk patients Exclusion/confirmation of CCa in the liver in setting of PSC or localised intrahepatic biliary dilation Follow-up of malignant lesion ⫾ post-treatment (HCC or metastases) Follow-up of benign or indeterminate lesions previously examined with CEUS
106 lesions in 100 studies 76 studies 173 lesions in 162 studies 12 studies 23 studies 19 lesions in 15 studies
CCa, cholangiocarcinoma; CEUS, Contrast-enhanced ultrasound; HCC, hepatocellular carcinoma; PSC, primary sclerosing cholangitis.
Group A2
Group A4
As expected from this subset of high-risk patients, the most prevalent CEUS diagnosis was HCC with 31 patients. Four cases were categorised as dysplastic nodules (DNs); two were reported specifically as DN, whereas the other two were reported as ‘DN or well differentiated HCC’ given that these two disease processes can show overlapping enhancement features. Of these latter two lesions, one was biopsy proven as HCC. Of the benign diagnoses, again haemangioma was the most common diagnosis (16 cases). Four were reported as equivocal cases. Of note is a case that was first reported as equivocal, then on subsequent follow-up developed enhancement characteristics typical for HCC that were absent on initial CEUS. A further interesting case was a lesion that was initially reported as an adenoma on CEUS and on follow-up MRI with gadoxetate had classic appearances of a flash filling haemangioma. The sonographic diagnosis was probably made on the basis of seeing readily visible internal flow, which is not typical appearance of a haemangioma.
Of the 12 cases in this group, five cases were reported on CEUS as CCa and seven cases as no tumour. There were no equivocal cases in this group. Combining all four subgroups in Group A, a total of 367 lesions were examined. Of these, 262 were benign, 82 malignant and 23 equivocal on CEUS. Of the benign diagnoses, haemangioma was the commonest CEUS diagnosis (109 lesions), followed by FNH (64 lesions) (Table 4).
Group A3 Group A3 was the largest subgroup of patients with a total of 173 lesions. A large majority of CEUS diagnoses were benign (147), with 15 malignant and 11 equivocal. The most common diagnosis was again haemangioma with 58 cases, followed by focal nodular hyperplasia (FNH). In seven of the cases, a differential diagnosis of haemangioma, FNH or adenoma was given. The remainder of the benign diagnoses included cyst, infection/inflammation, regenerative or dysplastic nodule, arteriovenous fistula, perfusion anomalies, focal fat sparing or infiltration. Two of the 11 equivocal cases were revealed on biopsy to be malignant.
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Group B1 Of the 23 studies examining known malignant lesions, 14 showed residual/recurrent malignancy, whereas eight showed no residual/recurrent tumour. One case of previously ablated neuroendocrine metastases was reported as equivocal.
Group B2 Twelve of 14 cases in this group showed stable findings, reassuring likely benignity. Two lesions remained equivocal – of these, one was lost to follow-up, whereas the other patient went on to have a liver resection finally revealing an HCC.
Potential impact on management We were interested in exploring how CEUS was able to influence the patient management and the role of CEUS in diagnostic algorithm in different clinical scenarios.
Group A CEUS was able to clarify benign versus malignant nature in 98 of the 106 focal liver lesions in Group A1 and 70 of the 76 lesions examined in Group A2.
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
Table 2. CEUS diagnosis breakdown by groups Group Group A1
Group A2
Group A3
Group A4
CEUS diagnosis
Number of lesions
Malignant
31
Haemangioma FNH Adenoma Cyst No lesion Equivocal Other
35 12 1 9 6 8 4
HCC DN
31 4
Benign nodule/RN Haemangioma FNH Adenoma Cyst No lesion Equivocal Other
8 16 4 1 2 4 4 2
Haemangioma FNH Adenoma Differential of haemangioma/FNH/Adenoma Malignant Cyst Equivocal Benign, other
58 48 1 7 15 8 11 21
Inflammation/infection CCa No tumour
Comments Metastasis 24 Metastasis or HCC 3 Metastasis or CCa 4
Perforated cholecystitis with surrounding liver inflammatory change 1 Scarring 1 Focal fat infiltration (FFI) 1 Perfusion anomaly 1 ‘DN or well differentiated HCC’ 2 DN 2
Focal fat sparing (FFS) 1 Shunt 1
RN 2, DN 1, Fistula 1, Perfusion anomaly 2 No lesion 1 FFI 10, FFS 1 Benign not otherwise specified 3
4 5 7
CCa, cholangiocarcinoma; CEUS, Contrast-enhanced ultrasound; DN, dysplastic nodule; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; RN, regenerative nodule.
In Group A3, of the 173 lesions examined, CEUS confirmed pre-CEUS suspected diagnoses in 87 cases. In 13 cases within this group, the diagnosis was changed from benign to malignant (six of the cases) or conversely malignant to benign (in seven cases) based on CEUS findings (Table 5). The cases where pre-CEUS diagnosis of benign pathology was changed to malignant were most significant. Of the six cases, three were initially reported as most likely haemangiomas, one FNH, one either haemangioma or FNH and one as abscesses. In the reverse scenario where pre-CEUS diagnosis of malignant pathology was changed to benign, most
were cases where the pre-CEUS imaging report concluded with a list of differential diagnoses including malignancies and other benign entities in the setting of a hypervascular (that is, arterially enhancing) lesion. Most of these did not demonstrate significant washout on subsequent phases (although some were not dedicated mutltiphasic studies) on CT. This subset reflects in part initial misinterpretation of CT enhancement patterns of focal liver lesions by the initial reporting radiologist. In Group A4 patients, all 12 of 12 cases CEUS was able to provide clarification as to whether there was a malignant lesion.
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
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Table 3. CEUS diagnosis breakdown by groups, diagnoses confirmed by, and final diagnoses Groups
Group A1
Group A2
Group A3
Group A4
CEUS diagnosis
Diagnosis confirmed by
Final diagnosis (based on)
Biopsy (Bx)
Follow-up imaging
Neither
20
6
5
Haemangioma (35)
2
8
25
FNH (12)
2
7
3
Adenoma (1) Cyst (9) No lesion (6) Equivocal (8)
1 0 0 2
0 3 5 3
0 6 1 3
Other (4) HCC (31)
0 8
2 18
2 5
DN (4)
1
2
1
Benign (regenerative nodules) (8) Haemangioma (16) FNH (4) Adenoma (1) Cyst (2) No lesion (4) Equivocal (4)
0 1 0 0 1 0 0
4 8 2 1 1 4 4
4 7 2 0 0 0 0
Other (2)
0
2
0
Malignant (15)
9
3
3
Haemangioma (58) FNH (48) Adenoma (1) DDx FNH or adenoma or haemangioma (7) Benign other (including RN, DN, THAD, fistula, FFI/FFS, no lesion, NOS) (21) Cyst (8)
0 1 0 0
15 9 1 2
43 38 0 5
0
4
17
2
3
3
Inflammation/infection (4) Equivocal (11)
1 3
2 4
1 4
CCa (5) No tumour (7)
2 3
1 0
2 4
Malignant (31)
Metastases 18 (Bx 14, imaging 4) Benign 6 (Bx 3, imaging 3) Uncertain† 6 Other 2‡ (Bx) Haemangioma 34 (presumed 25, imaging 8, Bx 1) GIST metastasis 1 (Bx) FNH 10 (presumed 3, imaging 7) Haemangioma 1 (Bx) HCC 1 (Bx) HCC 1 (Bx) Cyst 9 (presumed 6, imaging 3) No lesion 6 (imaging 5, presumed 1) Uncertain 3 (no follow up) Likely benign (stable imaging 1) Metastasis 1 (Bx) Benign (presumed 2, imaging stable 2) HCC 29 (Bx 8, imaging 16, presumed 5) Haemangioma 1 (imaging) Benign 1 (imaging) HCC 1 (Bx) DN 3 (imaging 2, presumed 1) Benign (imaging 4, presumed 4) Haemangioma 16 (Bx 1, imaging 8, presumed 7) FNH 4 (imaging 2, presumed 2) Haemangioma 1 (MRI) Cyst (Bx 1, imaging 1) No lesion 4 (imaging) Benign 3 (imaging stable/disappeared) HCC 1 (eventual development of HCC enhancement on imaging) Shunt 1 (stable imaging) Focal fat sparing 1 (imaging) HCC 4 (Bx 2, imaging 2) Cholangiocarcinoma 4 (Bx) Met 3 (Bx) Malignant, non specific 3 (presumed) Benign 1 (imaging) Haemangioma 58 (stable/concordant imaging 15, presumed 43) FNH 48 (Bx 1, stable imaging 9, presumed 38) Adenoma 1 (stable imaging) No follow up 5 Stable imaging 2 Benign (presumed 17, stable imaging 4) Benign cyst (presumed 3, stable imaging 3, Bx 1) Bile duct hamartoma 1 (Bx) Inflammation/infection 4 (Bx 1, imaging 2, presumed 1) CCa 1 (Bx) Necrotic tumour 1 (Bx) Likely benign 4 (on further imaging 4) Unclear 5 (no follow-up 4, resection but no pathology results available 1) CCa 5 (presumed 2, concordant imaging 1, Bx 2) No tumour 6 (presumed 4, Bx 2) CCa 1 (Bx)
†No imaging or biopsy to determine final diagnosis. ‡Biopsy proven HCC and epithelioid haemangioendothelioma. CCa, cholangiocarcinoma; CEUS, contrastenhanced ultrasound; DN, dysplastic nodule; FFI, focal fat infiltration; FFS, focal fat sparing; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; NOS, not otherwise specified; RN, regenerative nodule; THAD, transient hepatic attenuation difference.
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© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
Table 4. CEUS Diagnosis – benign diagnoses breakdown CEUS diagnosis
Number
Haemangioma FNH Adenoma Haemangioma vs. FNH vs. adenoma Cyst Dysplastic nodule Other
109 64 3 7 19 4 56
CEUS, contrast-enhanced ultrasound; FNH, focal nodular hyperplasia.
Group B In follow-up CEUS of 22 of 23 malignant lesions, CEUS was able to clarify presence/absence of viable tumour. In the one equivocal case, there was a history of previous ablation of neuroendocrine metastases, which were shown to be metabolically active on positron emission tomography scan. Enhancement pattern on CEUS
was equivocal and lowered the clinician’s suspicions sufficiently that the patient did not go on to receive further local ablation therapy.
Morbidity Only two adverse reactions were recorded. One patient reported erythematous changes in the sun exposed areas of skin days after the contrast injection, which did not require hospitalisation. Another patient reported back pain minutes after the injection, which subsided spontaneously. It should be noted that routine post-procedure follow-up was not done. The case of the skin erythema was only discovered due to the referring physician conveying this complication back to the radiology department.
Follow-up Of the 350 in Group A, 57 had a definitive diagnosis made on biopsy – either percutaneous or with an opera-
Table 5. Group 3 cases where pre-CEUS diagnosis was changed from benign to malignant or vice versa Patient
MB SS SB FF PL FL DS PS JS HM ADQ BH KW
Pre-CEUS diagnosis/differentials
CEUS diagnosis
Benign to malignant/malignant to benign
Final diagnosis
Atypical haemangioma vs. HCC/hypervascular metastasis Haemangioma Haemangioma Abscesses Haemangioma/FNH Atypical FNH HCC vs. AVM HCC vs. haemangioma HCC vs. FNH FNH/adenoma vs. hypervascular metastasis FNH/adenoma vs. metastasis Haemangioma vs. metastasis Haemangioma vs. HCC vs. FNH
HCC/hypervascular metastasis Metastasis HCC Metastases Malignancy Malignancy FNH Haemangioma FNH Haemangioma Haemangioma Haemangioma Haemangioma
B to M
Presumed HCC/hypervascular metastasis CCa HCC Metastases CCa Presumed malignant Presumed FNH Presumed haemangioma FNH Presumed haemangioma Presumed haemangioma Presumed haemangioma Haemangioma
B to M B to M B to M B to M B to M M to B M to B M to B M to B M to B M to B M to B
AVM, arteriovenous malformation; CCa, cholangiocarcinoma; CEUS, contrast-enhanced ultrasound; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma.
Table 6. False positives for malignancy Patient MM SL RR VM SM MG MI MW
Indication
CEUS diagnosis
Outcome
?Renal cell cancer metastasis ?Colorectal cancer metastasis ?Lung cancer metastasis ?Neuroendocrine metastases ?Metastasis vs. haemangioma Cirrhosis with known ‘haemangioma’ enlarging Hepatitis B, new lesion Possible liver lesion on CT ?haematoma vs. tumour
Suspicious for metastasis Suspicious for metastasis Suspicious for metastasis Suspicious for metastasis Suspicious for metastasis Suspicious for HCC Suspicious for HCC Suspicious for malignancy
PET negative. behaved like a non aggressive lesion Remained stable over 3 years on CT 2 negative biopsies. Biopsy negative. MRI favours adenoma. Stable on imaging. Biopsy negative. Stable on imaging Stable on multiple follow up scans Stable for 2 years prior to CEUS Stable on imaging, clinically well and not behaving like tumour
CEUS, contrast-enhanced ultrasound; HCC, hepatocellular carcinoma; PET, positron emission tomography. © 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
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Table 7. False negatives for malignancy Patient LS DP SS AW DM
Indication
CEUS diagnosis
Outcome
?Breast cancer metastasis ?Colorectal cancer metastasis ?GIST metastasis ?Breast cancer metastasis Right sectoral duct dilation on CT ?tumour
Unusual; not typical for metastasis FNH Haemangioma Adenoma No abnormal enhancement
Biopsy – breast carcinoma metastasis HCC on resection Grew in size on serial scans – GIST met on resection HCC on resection CT and resection adenocarcinoma
CEUS, contrast-enhanced ultrasound; GIST, gastrointestinal stromal tumour; HCC, hepatocellular carcinoma.
tive specimen. One hundred twenty-one had imaging follow-up, whereas 172 did not go on to have either of these.
False positives and false negatives for malignancy The diagnoses were considered falsely positive for malignancy if a suspected malignancy on CEUS remained stable on imaging or was proven benign on tissue biopsy (Table 6). Conversely, false negatives were those cases where the CEUS diagnosis was thought definite or very likely benign but either on clinical, imaging follow-up or eventual histologic grounds the final diagnosis was considered to be malignant pathology (Table 7). From Group A1, six cases were initially reported as suspicious for metastases but were ultimately thought to be benign, with negative biopsy for malignancy in three cases and in three cases behaving on subsequent scans in an indolent fashion thought unlikely for metastatic disease. From Group A2, two cases initially reported as HCC were eventually thought to be benign based on stable appearances on subsequent imaging in one patient, and in the second patient subsequently discovered imaging from 2 years prior to the CEUS had shown that the lesion had been stable. One lesion from Group A3 was initially reported as suspicious for either a metastasis or a CCa with abnormal early enhancement and washout, with locally obstructed ducts. The follow-up US 1 year later however did not identify a mass while there was progressive atrophy of the involved liver lobe. Clinically, the patient had not developed jaundice, and it was considered, although not proven, that the patient did not have a malignancy. Four lesions from Group A1 initially were proven on subsequent histology to be malignant. One case was initially reported as a haemangioma however subsequently increased in size on serial scans and biopsy revealed a gastrointestinal stromal tumour metastasis. The two lesions that were biopsy proven to be HCC were initially reported as FNH and adenoma, respectively. In one case, unusual linear echotexture change in the liver
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was seen (rather than discrete focal masses), thought atypical for metastasis but considered unusual enough to warrant a biopsy that showed a breast cancer metastasis. There was a case of a false negative from Group A4. Prior to the CEUS, CT had shown isolated right posterior sectoral biliary dilation with possible mass lesion seen on MR. The CEUS did not demonstrate any abnormal enhancement and was reported as no tumour. A follow-up CT was performed that showed an obvious mass. The surgical specimen confirmed adenocarcinoma.
Discussion CEUS was useful in all groups studied, including indeterminate liver lesions often found incidentally on other modality, indeterminate liver lesions in setting of a known malignancy and lesions identified on HCC surveillance. Overall, CEUS was able to categorise a focal liver lesion as either benign or malignant with confidence in 342 of 367 (93.8%) in Group A. CEUS gave definitive diagnosis in 314 of 367 cases (85.6%). This is in keeping with current published data on accuracy of CEUS in evaluation of liver lesions.4,5 In particular, in 124 of the 162 patients (76.5%) with indeterminate liver lesions (Group A3), CEUS was the final imaging thought to be required for establishing the diagnosis with a high level of confidence. This is very important as most of these patients have benign pathology and do not need multiple imaging tests or biopsy. CEUS was able to provide the definitive diagnosis in a substantial number of these patients. CEUS changed the diagnosis from benign to malignant in six patients and malignant to benign in seven patients, radically changing patient management especially in the former group. Perhaps the most significant limitation of our experience is the lack of diagnostic histopathology obtained for all focal liver lesions examined with CEUS. This lack of a ‘gold standard’ prevents this study from making conclusions about accuracy but based on accepted CEUS interpretation guidelines, and substantial corroboration by other modalities or by follow-up, it is reasonable to conclude that CEUS made a substantially positive impact on patient investigation in a majority of patients. In
© 2013 The Authors Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists
Hepatic CEUS: Introduction
many cases, CEUS provided a sufficient level of confidence not to warrant any further diagnostic work-up, which is significant in terms of cost and possibly safety. The patients were not routinely assessed for side effects from the contrast agent. As a result, not all possible side effects would have been recorded, especially if they were minor. This was not designed as an accuracy study but the small number of false negatives and positives for malignancy that were recognised highlight that this is, as with all modalities, an imperfect test. There were no consistent characteristics leading to the false diagnoses.
Conclusion Our early experience with CEUS has shown that it is a valuable adjunct in hepatic imaging. In addition to conventional US, CT and MRI, it provides added confidence to the radiologist and clinician of the nature of focal liver lesions, frequently obviating the need for further imaging of biopsy of indeterminate lesions. We found that CEUS is especially useful for confirming benign pathology in incidentally identified liver lesions. This experience in a tertiary centre could equally be expected to apply in broader radiology practice in Australia where there is generally a high level of US scanning skills. Contrastenhanced liver US should become part of the radiologist ‘toolkit’ as soon as possible, and this would clearly be
aided by government funding of this non-invasive modality. Occasional false negative and false positive results, however, do highlight the importance of interpreting CEUS results carefully and in context of the clinical features and other imaging findings.
Acknowledgements We have no financial links or affiliations to declare.
References 1. Ong YY, Gibson RN. Contrast-enhanced ultrasound: emerging modality for liver lesion characterization. J Gastroenterol Hepatol 2008; 23: 1465–6. 2. Claudon M, Cosgrove D, Albrecht T et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) – update 2008. Ultraschall Med 2008; 29: 28–44. 3. Wilson SR, Burns PN. An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography. Am J Roentgenol 2006; 186: 1401–12. 4. Wilson SR, Jang H-J, Kim TK, Burns PN. Diagnosis of focal iver masses on ultrasonography. J Ultrasound Med 2007; 26: 775–87. 5. Sporea I, Badea R, Martie A et al. Contrast enhanced ultrasound for the evaluation of focal liver lesions in daily practice. Med Ultrason 2012; 14: 95–100.
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