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Ultraschall in Med 2013; 34(6): 529-540

DOI: 10.1055/s-0033-1355785

Original Article

© Georg Thieme Verlag KG Stuttgart · New York

Contrast Enhanced Ultrasound (CEUS) Characterization of Grey-scaleSonographic Indeterminate Focal Liver Lesions in Pediatric PracticeKontrastmittelultraschall (CEUS) in der Pädiatrie zur Charakterisierung von sonografisch nicht-differenzierbarenfokalen Leberläsionen

J. Jacob , A. Deganello , M. E. Sellars , N. Hadzic , P. S. Sidhu

Radiology, King’s College Hospital, London

Pediatric Liver Unit, King’s College Hospital, London

Zusammenfassung

Introduction

Materials and Methods

Patients

Contrast-Enhanced Ultrasound Examinations

Reference Standard

Retrospective Image Analysis

ResultsDiscussion

References

Abstract

Purpose: To determine the usefulness of contrast-enhanced ultrasound (CEUS) in characterizing grey-scale sonographic

indeterminate focal liver lesions (FLL) in pediatric practice.

Materials and Methods: Local Ethics Board approval waiver was attained. Consent for CEUS examinations was acquired

from parents. Forty-four children referred for CEUS assessment of grey-scale sonographic indeterminate FLL over a 5-year

period underwent standard multiphase CEUS performed by experienced operators. A phospholipid microbubble agent was

used and low mechanical index ultrasound imaging techniques employed. Interpretation by consensus of the CEUS

examination was compared to consensus interpretation of other imaging and to histology. Follow-up imaging was used to

confirm stability of benign abnormalities. Any contrast reactions were recorded.

Results: The CEUS examination interpretation agreed with reference imaging in 29/34 (85.3 %) of cases. In discordant

cases, reference imaging showed no abnormality (n=5), with fatty change (n=4) and regenerating nodules (n=1) on

CEUS and follow-up sonography. Where reference imaging was not performed (n =10), histology (n=7) or follow-up

sonography (n=3) confirmed the diagnosis. In one discordant case, all imaging modalities showed concordance identifying

a malignant lesion; however histology demonstrated a benign hepatocellular adenoma. The specificity was 98.0 % (95%

CI; 86–100 %) and the negative predictive value was 100 %. No adverse effects to the contrast material were noted.

Conclusion: These findings demonstrate the usefulness of CEUS in characterizing indeterminate grey-scale sonography FLL

in pediatric patients with the potential to reduce exposure to ionizing radiation.

Zusammenfassung

Ziel: Ermittlung des Nutzens des kontrastverstärkten Ultraschalls (CEUS) zur Charakterisierung von von im Graustufen-

Ultraschall nicht-bestimmbaren fokalen Leberläsionen in der pädiatrischen Praxis.

Methoden: Die Zustimmung der örtlichen Ethikkommission wurde erteilt und die Einverständniserklärung zur CEUS-

Untersuchung von den Eltern eingeholt. An der CEUS-Bewertung der sonografisch nicht-bestimmbaren FLLs nahmen 44

Kinder über einen Zeitraum von 5 Jahren teil, die sich einem standardisierten Multiphasen-CEUS unterzogen, der von

erfahrenen Untersuchern durchgeführt wurde. Hierfür wurde ein Phospholipid-Mikrobläschen Kontrastmittel verabreicht und

eine sonografische Technik mit niedrigem mechanischem Index verwendet. Die Auswertung des Konsensus der CEUS-

Untersuchung wurde mit der Konsensusauswertung anderer darstellender Verfahren und der histologischen Untersuchung

verglichen. Eine Kontrolluntersuchung wurde veranlasst, um die Konstanz der Befunde gutartiger Läsionen von gutartigen

Veränderungen zu bestätigen. Alle Kontrastmittelreaktionen wurden erfasst.

Ergebnisse: Die Auswertung der CEUS-Untersuchungen stimmte in 29/34 (85,3 %) der Fälle mit den Referenzmethodenüberein. In widersprüchlichen Fällen zeigte die Referenzmethode keine Anomalien (n=5), die CEUS und die

Kontrolluntersuchung jedoch 4 Fettverteilungsstörungen und einen Regenerationsknoten. In Fällen, in denen kein

Referenzverfahren gemacht wurde (n=10) bestätigten Histologie (n=7) oder Verlaufssonografie (n=3) die Diagnose. In 2

Fällen zeigten die bildgebenden Verfahren übereinstimmend eine maligne Läsion; die Histologie ergab ein hepatozelluläres

Adenom. Die Spezifität betrug 98% (95% CI; 86–100 %) und der negative Vorhersagewert 100 %. Kontrastmittel-

Nebenwirkungen wurden nicht beobachtet.

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Further Information

Abstract (/ejournals/abstract/10.1055/s-0033-1355785) Full Text (/ejournals/html/10.1055/s-0033-1355785) References

Figures

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Schlussfolgerung: Diese Befunde zeigen den Nutzen von CEUS hinsichtlich der Charakterisierung von ungeklärten B-Bild

Befunden bei pädiatrischen Patienten mit FLL mit der Möglichkeit, die Strahlenexposition zu verringern.

Key words

ultrasonography - contrast media - liver - neoplasms - paediatrics

Introduction

Primary liver lesions are uncommon in the general pediatric population comprising 1–2% of all pediatric tumors [1] and

encompass a spectrum of pathology that ranges from predominantly benign (about 2/3 of lesions), to malignant which

account for the remainder [2]. A subcategory of children with chronic liver disease distorts this distribution of benign andmalignant focal liver lesions (FLL); the pathways that result in liver cirrhosis increase the propensity to develop

hepatocellular carcinoma which accounts for 39 % of all pediatric hepatic malignancies, commonly occurring between the

ages of 12 and 14 years [3]. However, with the rise in the prevalence of childhood obesity, a myriad of indeterminate FLL,

often benign, may be encountered in the child as in the adult, raising clinical concern [4].

Grey-scale sonography is usually the first-line imaging modality employed to evaluate FLL both in the adult and pediatric

patient. Grey-scale sonography is particularly valuable when evaluating a solitary lesion in an otherwise healthy liver [5].

However the delineation and characterization of complex liver lesions as well as focal lesions on a background of significant

cirrhotic disease, localized areas of fatty sparing or infiltration or nodular regeneration can be a challenge. Whether on a

background of a normal or abnormal liver, further imaging investigations are nearly always required. Most often these

investigations will encompass contrast enhanced Computed Tomography (CT) and Magnetic Resonance (MR) imaging. The

significant ionizing radiation dose associated with CT in children is a concern [6], particularly when considering the

cumulative dose already received by many children with chronic liver disease who may have undergone previous CT

examinations. Current practice is to strive to reduce the population radiation dose from imaging procedures, particular inthe pediatric group, where dose reduction is achieved by various approaches [7]. MR imaging presents a different problem

in the pediatric patient; the sedation required can often limit the practicality of this modality.

Contrast-enhanced ultrasound (CEUS) is an imaging modality with a well-recognized accurate role in FLL characterization

[8] [9] [10]. The contrast material used remains within the vascular compartment and the enhancement pattern of a FLL

over time allows characterization in much the same way as occurs with a multiphase CT examination. However unlike CT

contrast media, the use of microbubble contrast has an excellent safety record in adults, being well tolerated with minimal

side effects. It is not associated with the potentially harmful renal effects of iodinated or gadolinium based contrast media

as used in CT and MR imaging [11]. While the additional benefits consequent to the obviation of ionizing radiation and

sedation when using this method are clear, a comparative study to assess the accuracy of this modality in the work up of

children with grey-scale sonographic indeterminate FLL has not been performed.

The aim of our study is to correlate the findings of CEUS in children with indeterminate FLL grey-scale sonographic findings

against the findings on CT, MR imaging or histology as the reference standard. A secondary assessment of the safety of the

CEUS procedure has also been performed.

Materials and Methods

Local Ethics Board approval for reporting this retrospective review was sought and waived. In all patients, fully informed

verbal consent for a CEUS examination was obtained from the parents; the contrast material is not licensed for use in

patients under the age of 18 years. Physician responsibility for using the agent off-label was in keeping with accepted

national regulatory board practice, literature review, and in keeping with established local pediatric clinical practice [12] [13]

[14] [15] [16].

Patients

Over a 5-year period (September 2007 to August 2012), all children referred for a CEUS assessment following anindeterminate FLL evaluation on grey-scale sonography were included in this study. An indeterminate FLL was defined as a

lesion not characterized (as benign or malignant) on grey scale sonography, precluding appropriate clinical management

and requiring further imaging or histology. Indeterminate FLL evaluation included those children with established background

chronic liver disease as well as incidental lesions on a background normal liver. Forty-four children (female=21, male=23,

median age 11.5yrs, range 4 –18yrs) were assessed. The predominant reason for referral was the presence of a FLL in a

child with known chronic liver disease (n=30) encountered on surveillance ultrasonography, a new FLL (n =3) following

treatment for a non-hepatic malignancy, and FLL in children with no underlying chronic liver disorder or known primary

malignancy, an incidental lesion (n=11). Any underlying liver disease was established in patients by conventional non-focal

liver biopsy and histology, clinical features, biochemical blood tests or imaging findings. The grey-scale lesion appearances

(either iso-, low- or high-echogenicity in comparison to adjacent liver), location (within a specific liver segment) and size (in

two dimensions, with the largest measurement representing the maximum lesion size) were documented. Once designated

as an indeterminate FLL on grey-scale sonography, by any of three experienced observers (AD, MES or PSS), a CEUS

examination was performed.

Contrast-Enhanced Ultrasound Examinations

The CEUS examination was performed by three observers experienced in CEUS techniques (AD, MES and PSS for 8, 13 and

16 years respectively), singly or in combination (MES and PSS n=20, ADand PSS n=8, MES n=6, PSS n=6, ADn=4). All

sonographic examinations were performed using either a Siemens S2000 (n =37, Siemens Acuson, Mountain View, CA,

USA) and a 4MHz curvilinear broadband transducer or with a Sequoia (n =7, Siemens Acuson, Mountain View, CA) and a 4

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MHz curvilinear broadband transducer. A CEUS examination was performed employing a low mechanical index (MI)

technique (Cadence Contrast Pulse Sequencing, CPS™, Siemens, Mountain View, CA) and SonoVue™ (Bracco SpA, Milan,

Italy) as microbubble contrast material following the normal departmental protocol for a CEUS examination of the liver

(bolus of 1.2–2.4mL of SonoVue™, followed by 10mL of normal saline via an arm vein cannula previously sited by an

experienced pediatrician, MI set at or below 0.10, split screen technology if needed, imaging recorded on cine loop, and

transferred to a Picture Archiving System (Centricity, GE Medical Systems, Barrington, IL)). A standard three-phase

examination of the FLL was performed with imaging for at least 3 minutes following administration of contrast material

according to accepted guidelines [9]. A report was issued by consensus by the observers’ involved following analysis of the

cine loop of the examination prior to any other imaging or histology, with interpretation of the CEUS findings according to

established guidelines [9]. Briefly, the pattern of enhancement throughout the three phases was observed, with attention

paid to presence or absence of early increased enhancement, and to the detection of any late phase washout of contrast

material. No sedation was required for the sonographic examinations.

Any reactions (minor; nausea, vomiting or local pain, major; hypotension, breathlessness or features of an anaphylactoid

reaction [17]) to the microbubble contrast material were recorded for the subsequent 30 minutes in the Ultrasound

Department, and from the clinical notes for the subsequent 24 hour period.

Reference Standard

All patients also underwent the normal pathway of investigation of an indeterminate FLL on grey-scale sonographic

evaluation as practiced in our institution. Patients underwent either a CT or a MR examination according to clinical dictation

and with established protocols, using standard contrast materials where indicated and sedation as necessary. If there was

clinical concern, following multidisciplinary medical consensus, patients underwent image guided-biopsy of the FLL or the

background liver in the standard manner. Histology from any FLL biopsy was considered as the final diagnosis. In patients

with background chronic liver disease, who underwent non-lesion biopsy, any evidence of hepato-steatosis was used to

indicate focal fatty change and evidence of cirrhosis (with regenerating nodules (RGN)) to suggest a RGN as a cause for the

FLL appearance. This was confirmed on subsequent follow-up sonography demonstrating no change. Follow up sonography

was usually performed using grey scale imaging alone with the decision to use CEUS determined on a case by case basis (n

=5). The duration of follow up took the form of an initial 6 month examination followed by annual grey scale sonography

over a number of years, as detailed in [Table 1]. Information from any form of follow-up imaging and clinical progress of the

patient were noted.

Table1

Details of the 44 patients with a contrast-enhanced ultrasound (CEUS) following the finding of an indeterminate focal liver lesion.

case sex underlying liver

disease

age

(years)

liver

segment

B mode US

finding

maximum

size(mm)

CEUS CT MR histology follow up

1 F autoimmune

hepatitis

17 V low

echogenicity

35 ×24 mm

35 RGN no lesion.

Portal

hypertension

no lesion NA US 5

years.

Lesion

unchanged

2 F NASH Wilson's

disease

8 V high

echogenicity

31 ×20 mm

31 FFI no lesion NA non-cirrhotic

liver with mild

portal fibrosis

(NL)

US 5

years.

Lesion less

obvious

3 F Cirrhosis Biliary

atresia

15 III low

echogenicity

52 ×28 mm

52 RGN RGN RGN. Cirrhosis regenerative

nodule

transplant

at 4 years.

4 F NASH

Allagilles syndrome

13 IVB low

echogenicity

69 ×40 mm

69 RGN RGN. Portal

hypertension

RGN NA US 4

years.

Increased

size

5 F autoimmune

sclerosing

cholangitis

15 IVB iso-echoic

52 ×24 mm

52 RGN RGN.

Cirrhosis

RGN NA US 4

years.

Lesion

unchanged

6 F NASH Caroli's

syndrome

16 VI low

echogenicity

13 ×10 mm

13 FFS NA NA congenital

hepatic fibrosis

and RGN

transplant

7 M neuroectodermal

spinal tumour

17 IV iso-echoic

34 ×32 mm

34 FNH/adenoma NA FNH/adenoma NA MR 3

years.

Lesion

unchanged

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8 M autoimmune

hepatitis

10 VI low

echogenicity

16 ×7mm

16 RGN RGN RGN. Cirrhosis chronic

hepatitis,

bridging

fibrosis,

parenchymal

nodules (NL)

US 3

years.

Lesion

unchanged

9 M Normal 12 IVB low

echogenicity

16 ×14 mm

16 FFI NA FFI minimal portal

inflammation

(NL)

US 3

years.

Lesion no

longer

visible

10 M autoimmune

hepatitis

16 IVB iso-

echogenicity

24 ×11 mm

24 RGN NA RGN. Cirrhosis post-hepatitic

scarring (NL)

US 3

years.

Lesion

unchanged

11 F autoimmune

hepatitis

15 VII low

echogenicity

20 ×10 mm

20 RGN RGN RGN. Cirrhosis NA US 3

months

(deceased)

12 F normal 15 IVB iso-echoic

23 ×21 mm

23 adenoma adenoma adenoma NA US 1 year.

Lesion

unchanged

13 M autoimmune

hepatitis

17 V iso-echoic

29 ×25 mm

29 RGN RGN no lesion.

Cirrhosis

NA US 2

years.

Lesion

unchanged

14 M normal 11 VI high

echogenicity

24 ×18 mm

24 FFI no lesion no lesion minimal non-

specific

changes (NL)

US 3

years.

Lesion no

longer

visible

15 F NASH 14 VI low

echogenicity

33 ×11 mm

33 FFS NA NA NA US 3

years.

Lesion

unchanged

16 M NASH 16 VI low

echogenicity

36 ×15 mm

36 FFS NA NA mild portal

fibrosis and

moderate

steatosis (NL)

US 3

months.

Lesion

unchanged

17 M Wilms Tumour and

Chronic Hepatic

Vein Thrombosis

12 VI iso-echoic

43 ×37 mm

43 FNH FNH NA FNH biopsy. US

3 years.

Lesion

unchanged

18 F autoimmune

hepatitis

10 IVB low

echogenicity

34 ×32 mm

34 RGN NA RGN, portal

hypertension

bridging

fibrosis and

parenchymal

nodular

transformation

(NL)

US 2

years.

Lesion

unchanged

19 F normal 10 VI high

echogenicity

12 ×10 mm

12 FFI NA NA NA US 2

years.

Lesion nolonger

visible

20 F Leydig cell ovarian

tumour

15 VIII high

echogenicity

19 ×12 mm

19 Metastasis Metastasis Metastasis adenoma Resection


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21 M NASH 14 IVB low

echogenicity

17 ×14 mm

17 FFS NA NA steato-

hepatitis (NL)

US 2

years.

Lesion

unchanged

22 M autoimmune

hepatitis

11 IVB low

echogenicity

23 ×21 mm

23 RGN NA RGN. Cirrhosis moderate

fibrosis (NL)

US 2

years.

Lesion

unchanged

23 M NASH 10 V low

echogenicity

24 ×15 mm


hepatitis with

moderatefibrosis (NL)

No follow

up

24 M APCKD Congenital

Hepatic Fibrosis

8 IVA low

echogenicity

21 ×19 mm

21 RGN NA NA NA US 2

years.

Lesion

unchanged.

Liver

cirrhotic

25 M autoimmune

hepatitis

13 VI high

echogenicity

15 ×12 mm

15 RGN NA RGN. Cirrhosis scarring,

bridging

fibrosis,

parenchymal

hyperplasia,

macronodular

cirrhosis (NL)

MR 1 year,

US 2

years.

Lesion

unchanged

26 M NASH 10 III low

echogenicity

45 ×28 mm

45 FFS NA FFS mild fibrosis,

marked

steatosis (NL)

US 18

months.

Lesion

decreased

in size

27 M NASH 11 V low

echogenicity

19 ×12 mm


hepatitis (NL)

US 1 year.

Lesion

unchanged

28 F NASH 11 IVB low

echogenicity

27 ×18 mm


hepatitis (NL)

US 1 year.

Lesion

unchanged

29 F Allagilies syndrome 18 IV iso-echoic

69 ×60 mm

69 FNH NA FNH NA US 2 year.

Lesion

unchanged

30 M NASH 11 V low

echogenicity

27 ×12 mm

27 FFS NA NA NA US 3

months.

Lesion

unchanged

31 M resected

hepatoblastoma

4 IVA iso-echoic

18 ×14 mm

18 RGN NA RGN NA No FU

32 M cirrhosis 6 II low

echogenicity

34 ×22 mm


Lesion

unchanged

33 M biliary atresia 8 VII iso-echoic

37 ×35 mm

37 RGN NA RGN FNH Biopsy. US

3 years.

Lesion

unchanged

34 F normal 12 III iso-echoic

40 ×36 mm

40 FFS NA no lesion NA US 6

months.

Lesion

reduced in

size

35 M α-1 Antitrypsin

Deficiency

10 II 22 FFI no lesion NA no lesion Transplant


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high

echogenicity

22 ×16 mm

36 M Normal 5 VI iso-echoic

79 ×66 mm

79 FNH NA FNH FNH Resection

37 M ARKPD Congenital

Hepatic Fibrosis

15 VIII low

echogenicity

27 ×14 mm

27 FFS NA FFS NA US 8

months.

Lesion

unchanged

38 F biliary atresia 11 VI iso-echoic48 ×41 mm

48 RGN NA RGN. Cirrhosis NA US 1 year.Lesion

unchanged

39 F NASH 11 VI high

echogenicity

53 ×32 mm

53 FFI NA FFI NA No follow

up

40 F normal 11 V iso-echoic

51 ×49 mm

51 FNH NA FNH FNH Resection

41 F normal 14 VIII iso-echoic

29 ×24 mm

29 adenoma NA adenoma NA US 1 year.

Lesionunchanged

42 F normal 15 V iso-echoic

35 ×30 mm


Lesion

unchanged

43 M normal 9 VII low

echogenicity

56 ×27 mm

56 abscess abscess NA NA US 6

months

44 F normal 9 VI high

echogenicity

61 ×41 mm


Lesion

unchanged

M: male, F: female, R: right, L: left, NA: not applicable, RGN: regenerating nodule, DN: dysplastic nodule, FFI: focal

fatty infiltration, FFS: focal fatty sparing, FNH: focal nodular hyperplasia, NASH: non-alcoholic steato-hepatitis,

ARKPD: autosomal recessive kidney polycystic disease, FU: follow-up, US: ultrasound, CT: computed tomography,

MR: magnetic resonance, NL: non-lesion. Cases highlighted (dark grey) showed discordance between CEUS and

reference imaging or were cases where the CEUS and the reference imaging were discordant with the final histology.

In 4/7 cases without lesion histology, follow-up with ultrasonographic imaging showed no progression.

Retrospective Image Analysis

All reference imaging available following the initial CEUS investigation was interrogated by the Radiologist, and a reportissued, and further reviewed in a multi-disciplinary clinical setting. For the purposes of this study, the reference imaging was

again retrospectively interrogated by two experienced pediatric liver radiologists (ADand MES, 8 and 13 years’ experience

respectively) in a random order and with the patient details obscured, and any discrepancies noted. The diagnosis of the

lesion in the retrospective review formed the consensus opinion for the reference imaging.

At a separate time from the retrospective reference imaging review, the cine loop recordings of all the CEUS procedures

were also retrospectively interrogated by all the observers (AD, MES and PSS), in a random order and with the patient

details obscured, and the interpretation recorded. The interpretation was matched with the clinical read at the time of the

examination and any differences in interpretation noted. The diagnosis of the lesion in the retrospective review formed the

consensus opinion for the reference imaging.

Results

All patients underwent a successful CEUS examination with no adverse reactions to the contrast material identified in the

first 30 minutes after the examination, and none recorded in the clinical notes attributed to the administration of contrast

material.


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The demographics, FLL characteristics, underlying liver abnormality, lesion size, reference imaging or histology and outcome

of the 44 patients undergoing a CEUS examination are detailed in [Table 1] and a flow diagram is detailed in [Fig.1].

The median size of the FLL was 30 mm (range 12–79 mm), which were low echogenicity (n =20), iso- echoic (n=15) and

high echogenicity (n =9). The FLL were identified when the underlying liver was normal (n=11), in Non-Alcoholic Steato-

Hepatitis (NASH) (n=9), in autoimmune hepatitis (n=7), in biliary atresia (n=3), with a previous tumor (n =4), in Alagille’ssyndrome (n=3), in Autosomal Recessive Polycystic Kidney Disease (ARKPD) with hepatic fibrosis (n =2) and others (n=5,

one each of Wilson’s disease, autoimmune sclerosing cholangitis, Caroli’s disease, α-1 antitrypsin deficiency, cryptogenic

cirrhosis).

The examiners identified and characterized the FLL on CEUS as follows; RGN (n =15), focal fatty sparing (FFS) (n=11)

([Fig.2]), focal nodular hyperplasia (FNH) (n=7) ([Fig.3]), focal fatty infiltration (FFI) (n=6), hepatocellular adenoma (HA)

(n=2) ([Fig.4]), malignant lesion (n=1) and abscess (n=1) ([F ig.5]). For a single lesion, there was uncertainty between a

FNH and a HA. The consensus review confirmed the CEUS interpretation in all cases.

Fig.1 A flow

diagram to

illustrate the

diagnostic accuracy

of contrast-

enhanced

ultrasound in 44

children with an

indeterminate focal

liver lesion. (RGN;

regenerative nodule: FLL: focal liver lesion; FFS: focal fatty sparing FFI: focal fatty infiltration; CEUS: contrast-

enhanced ultrasound; CT: computed tomography; MR: magnetic resonance; US: ultrasound).

Abb.1 Ein Flussdiagramm zur Darstellung der diagnostischen Genauigkeit des kontrastverstärkten Ultraschalls bei 44

Kindern mit fraglichen fokalen Leberläsion (RGN: Regenerativer Knoten; FLL: fokale Leberläsion; FFS: fokale

Minderverfettung; FFI: fokale fettige Infiltration; CEUS: kontrastverstärkter Ultraschall; CT: Computertomografie; MR:

Magnetresonanz; US: Ultraschall).

(/media/ultraschall/201306/uim-1244_10-1055-s-0033-1355785-i1.jpg)

Fig.2 Case

26 – Focal

Fatty Sparing.

A 10-year-old boy with a

focal liver

lesion found

incidentally on

liver sonography, and no known history of prior liver disease. Background liver histology confirmed hepato-steatosis

and there was no change in the appearances at 18 months sonographic follow-up. a Coronal right lateral view

demonstrates a low echogenicity lesion (long arrow) anterior to the portal vein (short arrow), against a background high

echogenicity liver. b Coronal dual screen right lateral view demonstrating the CEUS characteristics of the lesion (arrow)

which is identical to the rest of the liver parenchyma through the late portal venous phase (imaging 1min. 58sec.

shown). The CEUS examination indicates an area that behaves in an identical manner to the surrounding liver: focal

fatty sparing is likely. c Axial MR “in phase” image (TR 73 ms, TE 2.4ms and ST 5 mm) at the level of the abnormality

seen on the sonographic image demonstrates no abnormality at the site of interest (arrow). d Axial MR “out of phase”

image (TR 73ms, TE 4.8ms and ST 5 mm) at the level of the abnormality seen on the sonographic image

demonstrates absence of signal drop out in the region of the caudate lobe in keeping with a focus of focal fatty sparing

(arrow).

Abb.2 Fall 26 – Fokale Minderverfettung. 10-jähriger Junge mit Zufallsbefund einer fokalen Leberläsion in der

Lebersonografie und unbekannter Anamnese bezüglich früherer Lebererkrankungen. Eine zugrunde liegende

Leberhistologie bestätigte eine Steatosis hepatitis mit unverändertem Bild bei der Nachsorge im Alter von 18 Monaten.

a Die koronale rechtslaterale Ansicht zeigt eine schwach echogene Läsion (langer Pfeil) vor der Pfortader (kurzer Pfeil),

gegenüber einer stark echogenen Leber im Hintergrund. b Die koronale „dual-screen“ rechtslaterale Ansicht zeigt die

CEUS-Merkmale der Läsion (Pfeil), die dem Rest des Leberparenchyms während der späten portalen Phase gleicht (Bild

bei 1min, 58s gezeigt). Die CEUS-Untersuchung zeigt ein Gebiet, das sich ähnlich wie die umgebende Leber verhält:

Verdacht auf eine fokale Minderverfettung. c Die axiale MR „in phase“-Ansicht (TR 73 ms, TE 2,4ms und ST 5 mm) im

Bereich der Auffälligkeit, die im Ultraschallbild entdeckt wurde, weist keine Anomalie im Bereich des Interesses (Pfeil)

nach. d Die axiale MR„out of phase“-Ansicht (TR 73ms, TE 4,8ms und ST 5 mm) im Bereich der Auffälligkeit, die im

Ultraschallbild entdeckt wurde, zeigt einen fehlenden Signalabfall im Bereich des Kaudallappens entsprechend der Fokussierung auf eine fokale Minderverfettung (Pfeil).


Fig.3 Case 17 – Focal Nodular Hyperplasia. A 12-year-old boy with a focal lesion, with previously treated bilateral

Wilm’s tumors, hepatic vein thrombosis secondary to chemotherapy and consequent portal hypertension. a Coronal

right lateral view demonstrates a heterogeneous iso-reflective lesion (arrows) in the right lobe of the liver, at the level

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of the right

kidney (star).

b Coronal right

lateral view

with colour

Doppler flow which demonstrates a centripetal vessel within the iso-echoic lesion (arrows) in the right lobe of the liver

at the level of the right kidney (star). c Coronal dual screen right lateral view demonstrating the CEUS characteristics of

the lesion (short arrows) which is hyper-echoic relative to the rest of the liver parenchyma through the arterial phase

(imaging at 23sec. shown). There is also early enhancement of the caudate lobe (long arrows) relative to the

background liver as a consequence of the hepatic vein occlusion and direct venous drainage into the inferior vena cava.

d Coronal dual screen right lateral view demonstrating the CEUS characteristics of the lesion (short arrows) which

remains iso-echoic relative to the rest of the liver parenchyma through the late portal-venous phase (imaging at 1 min.

28

sec. shown). These appearances are in keeping with a benign lesion: focal nodular hyperplasia is the most likely

cause. e Axial pre-contrast MR imaging (TR 3.6ms, TE 1.6ms and ST 4mm) demonstrates a focal lesion (arrow), with

a central scar, adjacent to the right kidney.

Abb.3 Ein 12-jähriger Junge mit fokaler Läsion bei zuvor behandelten bilateralen Wilms Tumoren, sekundärer

hepatischer Venenthrombose aufgrund der Chemotherapie und in Folge Pfortaderhochdruck. a Die koronale

rechtslaterale Ansicht zeigt die heterogene isoreflektorische Läsion (Pfeile) im rechten Leberlappen auf Höhe der

rechten Niere (Stern). b Koronale rechtslaterale Ansicht mit Farbdopplerfluss, der ein zentripetales Gefäß innerhalb der

iso-echogenen Läsion (Pfeile) im rechten Leberlappen auf Höhe der rechten Niere (Stern) nachweist. c Die koronale

„dual-screen“ rechtslaterale Ansicht zeigt die CEUS-Merkmale der Läsion (kurze Pfeile), welche sich im Verhältnis zum

restlichen Leberparenchym in der arteriellen Phase schallverstärkt darstellt (Darstellung bei 23 sec gezeigt). Es gibt

auch eine frühe Kontrastverstärkung des Kaudallappens (lange Pfeile) in Relation zur Leber im Hintergrund – eine Folge

der Lebervenenverstopfung und der direkten venösen Drainage in die innere Hohlvene. d Die koronale „dual-screen“

rechtslaterale Ansicht zeigt die CEUS-Merkmale der Läsion (kurze Pfeile) welche isoechogen im Verhältnis zum

restlichen Leberparenchym während der späten portal-venösen Phase bleibt (Bild bei 1

min, 28

s gezeigt). DieseErscheinungen sprechen für eine gutartige Läsion: eine fokale noduläre Hyperplasie ist die wahrscheinlichste Ursache. e

Das axiale Vorkontrast-MR-Bild (TR 3,6ms, TE 1,6ms und ST 4mm) zeigt eine fokale Läsion (Pfeil) mit einer zentralen

Narbe neben der rechten Niere.


Fig.4 Case

12 – Hepatic

Adenoma. A

15-year-old

girl with an

incidental lesion seen on sonography performed for abdominal symptoms. a Coronal right lateral view demonstrates a

heterogeneous iso-echoic lesion (arrows) in the right lobe of the liver, close to the gallbladder. b Coronal dual screen

right lateral view demonstrating the CEUS characteristics of the lesion (arrows) which is of increased echogenicity relative to the rest of the liver parenchyma through the arterial phase (imaging at 17 sec. shown). c Coronal dual

screen right lateral view demonstrating the CEUS characteristics of the lesion (arrows) which is iso-echoic relative to

the rest of the liver parenchyma through the late portal venous phase (imaging at 2min. and 2 sec. shown). These

features are those of a benign lesion: hepatic adenoma is the most likely diagnosis. d Axial post-contrast MR imaging

(TR 4.1ms, TE 1.5 ms and ST 4mm) demonstrates an intensely enhancing lesion (arrow) on the arterial phase.

Abb.4 Fall 12 – Hepatisches Adenom. Ein 15-jähriges Mädchen mit einer zufällig entdeckten Läsion im Ultraschall,

der wegen abdominaler Symptome durchgeführt wurde. a Die koronale rechtlaterale Ansicht zeigt eine heterogene

isoechogene Läsion (Pfeile) im rechten Leberlappen nahe der Gallenblase. b Die koronale „dual-screen“ rechtslaterale

Ansicht zeigt die CEUS-Merkmale der Läsion (Pfeile), die eine ansteigende Echogenität in Verhältnis zum restlichen

Leberparenchym während der arteriellen Phase aufweist (Bild bei 17 s gezeigt). c Die koronale „dual-screen“

rechtslaterale Ansicht zeigt die CEUS-Merkmale der Läsion (Pfeile), die isoechogen im Verhältnis zum restliche

Leberparenchym während der späten portalen Phase ist (Bild bei 2 min und 2 sec. gezeigt). Diese Merkmale sprechen

für eine gutartige Läsion: Die wahrscheinlichste Diagnose ist ein hepatisches Adenom. d Das axiale post-kontrast MR-

Bild (TR 4,1

ms, TE 1,5

ms und ST 4

mm) zeigt eine intensiv verstärkte Läsion (Pfeil) in der arteriellen Phase.


Fig.5 Case

43 Liver

Abscess. A 9

year old with a

pyrexia of

unknown origin

found to have a lesion in the liver on sonographic examination. a A right axial sub-costal view of a heterogeneous low

echogenicity abnormality (arrows) in the posterior aspect of the right liver lobe. b Dual screen right subcostal axial view

demonstrating the CEUS characteristics of the lesion (arrows) which is hypo-echoic relative to the rest of the liver

parenchyma through the arterial phase (imaging at 26sec. shown). c Dual screen right subcostal axial view

demonstrating the CEUS characteristics of the lesion (arrows) which demonstrates uneven enhancement relative to the

rest of the liver parenchyma through the early portal venous (imaging at 46 sec. shown). The presence of intra-lesional

pockets of low reflectivity and septations indicate that this is benign and likely an abscess. d Axial CT image in the late

venous phase demonstrates an irregular margin to the lesion (arrows) with minimal central contrast enhancement.

Abb.5 Leberabszess. Bei einem 9-Jährigen mit einer Pyrexie unbekannten Ursprungs wurde sonografisch eine

Leberläsion entdeckt. a Rechte axiale subkostale Ansicht einer heterogenen niedrigechogenen Anomalie (Pfeile) im

hinteren Teil des rechten Leberlappens. b Die rechte „dual-screen“ axiale subkostale Ansicht zeigt die CEUS-Merkmale


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Thirty four patients underwent imaging; CT (n=14), or MR (n=30) imaging or both (n=10). Histology was available from

the FLL in 8 patients (FNH n=4, HA n=1, RGN n=2 and FFI n=1 following lesional/excisional biopsy or transplantation) and

the background liver was subject to biopsy in 14 patients confirming hepato-steatosis (n =9, patients with FFS n=7, FFI n=

2) and cirrhosis (n=5, RGN n=5). Reference imaging was not performed in 10/44 (22.7 %) of patients; FFS (n=8, six

patients had a biopsy of the background liver confirming NASH and sonographic follow-up, one had a liver transplant

demonstrating fibrosis and one had sonographic follow-up alone and no change), FFI (n =1, no histology and no change on

sonographic follow-up) and RGN (n =1, with no change on sonographic follow-up). In total there were 14 regenerating

nodules identified using CEUS, with concurrence with CT or MR imaging in 12/14 (85.7 %). Reference imaging

demonstrated cirrhosis (n=11) and portal hypertension (n=3).

The CEUS examination interpretation agreed with the reference imaging in 29/34 (85.3 %) of the cases. In the five cases

where there was disagreement, CEUS identified four focal lesions thought to be the effects of fatty change, not seen on

either CT or MR imaging that remained unchanged on follow-up sonography. One case was thought to be an RGN, not seen

on CT or MR imaging remaining unaltered on follow-up sonography. In two cases where all the imaging modalities

concurred, histology demonstrated a different lesion ([Fig.6]). While sensitivity and accuracy could not be calculated, the

specificity fo r identifying a benign lesion was 98% (95% CI; 86–100 %) and there was a negative predictive value of 100

%.

Discussion

Our study suggests that CEUS is useful in describing the benign nature of FLL that are indeterminate on grey-scale

sonography in children, potentially reducing the use of CT and MR imaging for their categorization and, in keeping with adult

studies, potentially reduce imaging costs [18] [19]. Furthermore, in the setting of a tertiary clinical practice, the ability to

confirm the benign nature of an abnormality at the outset should reduce patient and parent anxiety, an important

consideration [20]. While the use of CEUS in the pediatric population is not routine, the benefits have been recognized in

adult patients particularly with the more stable perfluoro-gas containing contrast material, and improvements in the

der Läsion (Pfeile), die sich schallarm im Verhältnis zum restlichen Leberparenchym während der arteriellen Phase

darstellt (Bild bei 26 s gezeigt). c Die rechte „dual-screen“ axiale subkostale Ansicht zeigt die CEUS-Merkmale der

Läsion (Pfeile), die eine ungleichmäßige Kontrastaufnahme in Relation zum restlichen Leberparenchym während der

frühen portal-venösen Phase zeigt (Bild bei 46s gezeigt). Das Vorhandensein von Taschen innerhalb der Läsion mit

niedrigem Reflexionsvermögen und Septierungen weist darauf hin, dass diese gutartig ist und möglicherweise einen

Abszess darstellt. d Das axiale CT-Bild in der späten venösen Phase zeigt einen irregulären Rand der Läsion (Pfeile)

sehr niedriger zentraler Kontrastaufnahme.

Fig.6 Case

20 –

Discrepancy

Lesion:

Metastasis on

imaging but Hepatic Adenoma on histology. A 15-year-old girl treated for a primary ovarian tumor, with an incidental

focal liver lesion on sonography for non-specific abdominal symptoms. a Coronal right lateral view demonstrates a

homogenous high echogenicity lesion (arrows) in the right lobe of the liver. b Coronal dual screen right lateral view

demonstrating the CEUS characteristics of the lesion (arrows) which is of high echogenicity relative to the rest of the

liver parenchyma through the arterial phase (imaging at 14 sec. shown). c Coronal dual screen right lateral view

demonstrating the CEUS characteristics of the lesion (arrows) which is continuing to “wash-out” relative to the rest of

the liver parenchyma through the late portal venous phase (imaging at 2

min. 13

sec. shown). The f inding of “wash-out” in the late phase suggests a malignant lesion. d Axial MR imaging, where the lesion shows signal suppression on an

“out of phase” MR image (TR 73ms, TE 4.8ms and ST 5 mm) indicating a fatty component (arrow). e Axial MR imaging

(TR 4.1ms, TE 1.5 ms and ST 4mm), where a low signal is seen on the post-contrast venous phase (arrow). The MR

features suggest a metastasis in this patient with a previous known malignancy. f The lesion on PET imaging

demonstrates increased uptake corresponding to the focal lesion (arrow) seen both on sonography and MR imaging.

Histological analysis demonstrated features consistent with a hepatic adenoma with no evidence of malignancy.

Abb.6 Fall 20 – Diskrepante Läsion: Metastasen in der Bildgebung aber hepatisches Adenom aufgrund der Histologie.

Ein 15-jähriges Mädchen unter Behandlung eines primären Eierstockkrebs mit Zufallsbefund einer fokalen Leberläsion in

der Sonografie, die wegen unspezifischer abdominaler Symptome durchgeführt wurde. a Die koronale rechtslaterale

Ansicht zeigt eine homogene hochechogene Läsion (Pfeile) im rechten Leberlappen. b Die koronale „dual-screen“

rechtslaterale Ansicht zeigt die CEUS-Merkmale der Läsion (Pfeile), die sich hochechogen im Verhältnis zum restlichen

Leberparenchyms während der arteriellen Phase darstellt (Bild bei 14s gezeigt). c Die koronale „dual-screen“

rechtslaterale Ansicht zeigt die CEUS-Merkmale der Läsion (Pfeile), die zu einem „wash-out“ im Verhältnis zum

restliche Leberparenchyms während der späten portal-venösen Phase führt (Bild bei 2 Min, 13s gezeigt). Der Befund

des „wash-out“ während der Spätphase spricht für eine maligne Läsion. d Axiales MR-Bild, bei dem die Läsion eine

Signalaufhebung im „out of phase“ MR-Bild zeigt (TR 73 ms, TE 4,8 ms und ST 5 mm) und auf eine fettige Komponente

hinweist (Pfeil). e Axiales MR-Bild (TR 4,1 ms, TE 1,5 ms und ST 4mm), bei dem ein schwaches Signal in der post-

kontrast venösen Phase (Pfeil) zu sehen ist. Die MR-Merkmale legen den Verdacht von Metastasen bei diesem

Patienten mit bekannter maligner Vorerkrankung nahe. f Die Läsion im PET-Bild zeigt eine erhöhte Aufnahme in

Zusammenhang mit der fokalen Läsion (Pfeil), die sowohl im Ultraschall als auch in der MR-Darstellung zu sehen ist.

Die histologische Untersuchung zeigte Kennzeichen, die für ein hepatisches Adenom sprechen und ergab keinen Hinweis

auf Malignität.


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technical capabilities of the ultrasound machines [9] [21]. In the current study we found that CEUS evaluation of

indeterminate FLL in pediatric patients delivers results in characterizing the nature of a FLL equal to those seen in adult

patients, and assumes a level of specificity acceptable in clinical practice.

In agreement with previously established adult data, we have found in our small series of benign lesions, that the continuing

iso- or hyper-echoic nature of the FLL in the late portal-venous phase imaging allowed confident interpretation indicating a

benign abnormality [9] [10]. More importantly on a number of occasions the grey-scale sonographic examination identified

a FLL, which was not identified on the reference imaging (n =5). These lesions were demonstrated to be “benign” on the

CEUS examination and subsequent follow-up sonography confirmed non-progression. These were all either areas of FFI,

FFS or RGN, where CEUS has been helpful to obviate the need to image further in adult patients with these and other

benign FLL [8] [22] [23].

Pediatric imaging with CEUS is particularly desirable for a number of reasons, the most important being the lack of ionizingradiation and the avoidance of iodinated contrast material in the most often “next-stage” imaging with CT, when grey-scale

sonography is inconclusive. The possibility of avoiding ionizing radiation in the pediatric population is paramount and is in the

forefront of campaigns to reduce the population radiation burden from medical imaging [7]. The real risk of the increased

life-time chance of developing cancer in children exposed to radiation has been established in a recent study; a CT

cumulative dose of about 50mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk

of brain cancer [24]. CEUS is most useful to confirm the benign nature of a FLL, to alleviate parental anxiety as to the need

for further imaging and exposure to ionizing radiation [20]. The complexity of sedation requirements with MR imaging in

young children makes CEUS an attractive alternate diagnostic modality. A CEUS examination in a child does have one

disadvantage in that a venous catheter needs placing, rendering ultrasonography an “invasive” procedure albeit to a minor

degree, but this mirrors the requirements for intravenous access in both CT and MR.

Ultrasonography has been devoid of any form of contrast material until recently, with a number now available

commercially, but at present only licensed in adult patients in some countries and for a small number of indications [10]

[25]. The contrast material used in this study has an excellent safety record in adult patients [17], with an incidence of

adverse reactions similar to that of conventional MR agents without the potential of nephrogenic systemic fibrosis [26].

Their use in pediatric patients is acceptable despite being “off-label” as supported by national physician regulatory bodies

[15]. Indeed, the use of unlicensed and off label drugs in the pediatric population is acknowledged to be common [27]. The

“off-label” implication in pediatric patients should not deter the physician from performing a CEUS examination in a child

particularly as we have demonstrated accuracy in a difficult group of FLL, without compromise to safety.

It is recognized in the adult population that a small proportion of FLL do not behave in a typical fashion on a CEUS

examination, and this may lead to false interpretation of the findings, and this might be expected in the child [9] [10]. The

paramount finding in differentiating a benign from a malignant lesion, the most useful aspect of the CEUS study, is the

‘washout’ that is nearly universal in all FLL that are malignant [28] [29] [30] [31]. There are some exceptions to this rule:

the well differentiated hepatocellular carcinoma (HCC) may show minimal washout in the late phase, with microbubble

destruction and enhancement loss preceding any washout [32]. Very occasionally a benign FLL may demonstrate some

washout; this is seen in some hepatocellular adenomas [23] [33] [34]. However, this phenomenon is not restricted toCEUS, but is also apparent on both CT and MR imaging where washout occurs in the delayed phase imaging necessitating

histology for confirmation [35].

In the single instance o f a false positive diagnosis in our study, all imaging modalities came to the same diagnostic

conclusion of a malignant FLL, demonstrated to be benign on histology. In a further case, all imaging concurred, with CEUS

and reference imaging diagnosing an RGN but this was found to be an FNH on histology. While the first discrepancy did

represent a false positive result, CEUS was nevertheless at least as accurate as the other imaging modalities in diagnosing a

lesion as benign. Hepatocellular adenoma behavior on CEUS highlights a difficulty that is increasingly recognized; atypical

imaging characteristics are related to the underlying genetic constitution [35].

The main limitation to our study is the small number of patients, and larger studies are needed to establish CEUS in the

pediatric patient group.The small numbers of patients recruited reflects the frequency in which a FLL that is indeterminate

on grey-scale sonography is encountered in clinical practice. Nevertheless, with the obesity epidemic apparent in the

pediatric population, focal fatty sparing may become a lesion that is encountered with increasing frequency; CEUS is well-placed to provide a rapid, safe and cost-effective method of accurate diagnosis [36]. The study contained no true

malignant FLL, which again relates to the low patient numbers, and often malignant FLL in pediatric patients are well

characterized at presentation to the management institution; we are a tertiary referral treatment center for pediatric liver

disease. CEUS is a newly developing area of ultrasonography, particularly in pediatric practice and there is virtually no

experience that combines pediatric liver disease and the use of CEUS; truly blinded independent readers with the necessary

skill are not available. Patients had a non-targeted liver biopsy to assess the general background cause for the chronic liver

parenchyma change; the actual focal lesion was not always subject to biopsy. For example, on occasion where the non-

lesion histological results indicated severe hepato-steatosis, a CEUS diagnosis of FFS was made, with meticulous

sonographic follow-up confirming non-progression of the lesion. Follow-up was not achieved in all patients to a satisfactory

level, but the nature of our clinical service with many international patients, coupled with the nature of this retrospective

clinical review makes this unavoidable. Nevertheless all efforts were made to have as comprehensive follow-up data as

possible.

CEUS imaging has anecdotally been used to assess focal liver lesions in children but no studies have been performed to

validate CEUS in this context. While its benefit is the lack of ionizing radiation or sedation required when assessing a

vulnerable subset of pediatric patients with chronic liver disease, who o ften need regular imaging surveillance, this would be

negated if the diagnostic yield were not comparable to these other imaging modalities. Our findings suggest that CEUS has

a favorable comparison against other imaging modalities; CEUS could become an important diagnostic tool in

characterizing focal liver lesions in children.

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Correspondence

Prof. Paul S Sidhu

King's College London Department of Radiology

King’s College Hospital

Denmark Hill

SE5 9RS LondonUnited Kingdom

Phone: ++44/203/299 41 64

Fax: ++44/203/299 31 57

Email: [email protected] (mailto:[email protected])

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