Contrast enhanced ultrasound for the evaluation of malignany focal liver lesions

1. WFUMB
Slide Series
World Federation for Ultrasound
in Medicine & Biology
Contrast enhanced ultrasound for the evaluation
of malignant focal liver lesions
November 2018
1
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date WFUMB does not guarantee the accuracy of the information contained in them
and the opinions expressed are those of the author and not of WFUMB.
The slides may be used for presentations in whole or in part but the author and
WFUMB shall be acknowledged and identified as the source of the material.

2. Contrast enhanced ultrasound for the
evaluation of malignant focal liver lesions
Prof. Ioan Sporea, MD, PhD
Department of Gastroenterology and Hepatology
University of Medicine and Pharmacy
WFUMB Center of Education
EFSUMB Ultrasound Learning Center
Timişoara, Romania

3. • Ultrasound is an excellent imaging modality for the detection of liver
tumors (focal lesions), but it lacks the necessary specificity.
• Other limitations: operator dependent method, acoustic window,
others
• Advantages: cheap method, no radiation, repeatable, accessible, real
time imaging modality
• The evaluation of focal liver lesions (FLL) can be very expensive (CT
scan, MRI and/or CEUS), need some waiting time (waiting list) and
usually is very stressful for the patients (during waiting time!).

4. When to perform a CEUS
examination of a FLL?
• First condition is usually to see the liver lesion in standard US! (1)
• In some conditions, when the liver structure is very heterogeneously, the
lesion can be missed in standard US (or not all the liver can be evaluated
by US).
• 1.Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2012 A WFUMB-EFSUMB Initiative in Cooperation
With Representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. M. Claudon, C. F. Dietrich, B. I. Choi, et al. Ultraschall in Med 2013; 34(1): 11-29 doi: 10.1055/s-0032-
1325499

5. Contrast Enhanced US (CEUS)
Phase Beginning End
ARTERIAL
PHASE
10-20 s 25-35 s
PORTAL PHASE 30-45 s 120 s
LATE PHASE 120 s Until the bubbles’
disapearance

6. Typical pattern for FLL

7. CEUS in malignant FLLs
• “Wash out” pattern in portal and late phase in malignancy is
very typical, a differentiation criteria from the benign FLLs
(who “keep” the contrast in the portal and late phases);
• Thus the vascular pattern during the portal and late phases
differentiate benign (“keep” contrast) from malignant
(“wash out” present) FLLs.

8. Hepatocellular carcinoma
• The most frequent primary malignant liver tumor. Represents 70-85%
of primary malignant liver tumors
• Usually apears on liver cirrhosis (than this patients are folowed by
hepatologist)!
• Early diagnosis – surveillance screening ultrasound of patients with
liver cirrhosis (sensitivity in meta-analysis aprox.70%).
• US Screening can (and must) be performed by hepatologists!

9. Hepatocellular carcinoma
• Typical pattern
• Arterial phase: hyper enhancement (90%), basket pattern
• Portal and late phase: wash out, often slow and weak
(sometimes very late)
• Variations (where CEUS is not able to establish a diagnosis)
• Arterial phase iso or hypo enhancement (aprox.10% of cases)
• Portal and late phases slow or no wash out.
• Always examine for 5-6 min for late “wash out”!
Jang HJ et al – Radiology 2007
Martie A et al: Med Ultrasound 2012

16. CEUS

17. How often hepatocellular carcinoma has a typical pattern in
contrast enhanced ultrasound? (1)
• 91 patients with chronic liver diseases, with a total of 114 liver nodules, which had
HCC as final diagnosis (using CEUS,CE-CT, CE MRI or biopsy).
• OUTCOMES: 90% of nodules had hyperenhancing arterial pattern and “wash out”
was observed 69.2%.
• In our study, CEUS established the diagnosis of hepatocellular carcinoma in 81.8%
nodules larger than 3 cm vs. 57.6% nodules smaller than 3 cm (p<0.001).
• CONCLUSIONS: Approx.. 70% of HCC had a typical enhancement pattern on CEUS,
performing better in nodules larger than 3 cm, than in smaller nodules (p<0.001).
• 1.Martie A, Sporea I, SIrli R et al: How often hepatocellular carcinoma has a typical pattern in contrast enhanced ultrasound? Maedica 2012
Sep;7(3):236-40

18. • CEUS for guidance of percutaneous treatment techniques of HCC and
metastases (when the lesions are not well seen) :
– radiofrequency ablation - RFA
– percutaneous ethanol injection – PEIT.
• Evaluation immediately or next day of local ablative techniques results:
– if the treatment is proved to be incomplete, it can be repeated
immediately.

19. Cholangiocarcinoma
• Usually on normal liver (no liver cirrhosis or not very often);
• Typical pattern
• Arterial phase – rapid enhancement;
• Quick wash out in the portal phase;
• Cholangiocarcinoma can be also iso or hypoenhanced in the arterial phase
(1).
• The accuracy of CEUS for the characterization of cholangiocarcinoma
was only 57% (2).
1.Fan ZH et al: AJR 2006; 186: 1512-1519
2.Qian CW et al:Hepatobiliary Pancr Dis Int 2009;4:370-376

21. Biliary cystadenocarcinoma
• Biliary cystadenocarcinoma is a very rare malignant cystic tumor of the
liver, which is often misdiagnosed due to poor recognition (1);
• CEUS: cystic wall enhancement, internal septa and intracystic solid areas
in the arterial phase; progressive wash out depicted as hypo-
enhancement in the portal and late phase.
• 1.Ren X-L et al: WJG 2010,7:131-135

23. Liver metastases
• Liver is a frequent location for the metastases in different malignancies;
• The presence of liver metastases influences the treatment strategy of the
primary tumor;
• CEUS is useful in the diagnosis of liver metastases for:
• Lesions’ characterization;
• Lesions’ detection (increased number of lesions).

24. Metastases
• Arterial phase – transient hypervascularity:
• Hypervascular liver metastases – complete enhancement;
• Hypovascular liver metastases – enhancement rim;
• Portal and late phase – rapid and complete wash out.

29. CEUS – “wash out” in portal phase

31. CEUS-wash out in portal phase

32. HYPERVASCULAR HYPOVASCULAR
Neuroendocrine tumors
(tumori carcinoide)
Adenocarcinoma – digestive tube
Ovarian cancer Lung cancer
Tyroid cancer Lymfoma
Renal CC
Breast cancer
Melanoma
Sarcoma
Lymfoma
Weskott HP: In: Advances in Diagnostic Imaging, Springer 2006 pag.17-45

33. CEUS – improves detection
• CEUS improves detection of liver metastases vs. standard ultrasound;
• Equivalent to CT scan and sometimes superior;
• The portal and late phase is used for detection;
• CEUS sensitivity as compared to US and CT scan – 95.4% vs. 76.9% and
90.8% respectively (109 lesions studied) (1)
1.Piscaglia F et al – BMC Cancer 2007;7:171

34. CEUS – metastases detection
• Konopke(1) reported an increase of the number of lesions detected
from 53% in standard ultrasound to 86% in CEUS (+33%).
• The study concluded that CEUS should be used as a routine
modality for the detection of liver metastases in the follow up of
patients with cancer.
1.Konopke R, Kersting S, Saeger HD et al. Ultraschall Med 2005; 26: 107-113

35. Other studies for the value of CEUS
• Wang WP et al (1) – CEUS vs. US (gold standard biopsy, MRI or medical
history):
•Indeterminate diagnosis rate decreased from
56.7% to 6.1%; CEUS accuracy 88%
1.Wang WP et al: Hepatobiliary Pancreat Dis 2009; 8(4): 370-376

36. DEGUM study
• The German study (1) was performed in 2004-2006 under the auspices
of the Germany Society of Ultrasound (DEGUM) in 14 hospitals, involving
physicians experienced in the use of CEUS.
• It included 1,349 patients with focal liver lesions discovered by
conventional ultrasound examination and for which standard ultrasound
was not able to clarify the diagnosis.
• 755 malignant FLL
• Reference standard: histology (1006), cytology (19), CT and/or MRI
1. Strobel D et al.: Contrast-enhanced Ultrasound for the Characterization of Focal Liver Lesions-Diagnostic
Accuracy in Clinical Practice (DEGUM multicenter trial). Klin Monatsbl Augenheilkd 2008;225:499-505.

37. CEUS
All lesions
Les>2 cm
Les<2cm
Se.
95.8%
96.5%
93.3%
Sp.
83.1%
86%
75.9%
PPV
95.4%
96.5%
91.5%
NPV
95.9%
96.4%
94.7%
Dg. Acc.
90.3%
92.2%
84.5%
Diagnostic value of CEUS for tumor
differentiation – DEGUM study

38. French study
• The multicenter French study (STIC study), published in 2008 (1), included 874 patients
and 1034 focal liver lesions. The gold-standard methods to which CEUS was compared
to were: spiral contrast CT, contrast MRI or biopsy.
• Differential diagnosis benign-malignant - CEUS sensitivity 79.4%, CEUS
specificity 88.1%
meta HCC
Se. 79.3% 69.8%
Sp. 92.5% 94.7%
1.Tranquart F et al.: Role of contrast-enhanced ultrasound in the blinded assessment of focal lesions in comparison with
MDCT and CEMRI: Results from a multicentre clinical trial. EJC 2008; suppl.6:9-15.

39. Romanian prospective multicenter study:
CEUS in FLL
• The prospective study (14 Romanian centers) was performed over a period
of 6 years (2011- 2017) and included 2062 FLLs assessed by CEUS.
• The lesions were evaluated by CEUS and that had a second imaging
technique (CT, MRI) or histology as reference.
• Results: From de 2062 FLL the CEUS performance for the malignant lesions
(1179 - 57.1%), was: 91.5% sensitivity, 97.5% specificity, 98.1% positive
predictive value (PPV), 89% negative predictive value (NPV) and a
diagnostic accuracy of 94.2%.
• Ioan Sporea, Daniela Larisa Săndulescu, Roxana Şirli, et al. SRUMB Study. Abstract Euroson 2017

40. Our experience (Dept. of Gastroenterology and
Hepatology Timisoara, RO)
Retrospective study performed in the Department of
Gastroenterology and Hepatology, Timisoara, including 1100 patients
with 1329 FLLs (evaluated between September 2009-January 2013).
A CEUS examination was considered conclusive if the FLL respected
the typical enhancement pattern as described in the EFSUMB
Guidelines (1).
1.Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2012 A WFUMB-EFSUMB Initiative in
Cooperation With Representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. M. Claudon, C. F. Dietrich, B. I. Choi, et al. Ultraschall in Med 2013; 34(1): 11-29

41. Our experience (Dept.of Gastroenterology and
Hepatology Timisoara, RO)(1)
From the 1329 FLL, CEUS was conclusive for a specific pathology in
1102 cases (82.9%).
For the differentiation of benign vs. malignant lesions, CEUS reached a
conclusive diagnosis in 1196 (90%) cases.
The percentage of conclusive CEUS examinations was significantly
higher in patients without chronic liver disease as compared with
those with chronic hepatopathies: 87.3% vs. 74.4%, p<0.0001.
 1. Sporea I, Martie A, Bota S et al. Characterization of focal liver lesions using contrast enhanced ultrasound as a first line method: a large monocentric experience
J Gastrointestin Liver Dis. 2014 Mar;23(1):57-63

42. Meta-analysis
Liver International 2013: 33: 739–755
 DOI:10.1111/liv.12115
Contrast-Enhanced Ultrasound for the
differentiation of benign and malignant focal
liver lesions: a meta-analysis
 Mireen Friedrich-Rust, Tom Klopffleisch, Julia Nierhoff, Eva Herrmann, Johannes Vermehren,
Maximilian D. Schneider, Stefan Zeuzem and Joerg Bojunga, J.W.Goethe-University, Frankfurt, Germany

43. Results
A total of 45 studies with 8147 focal liver lesions were
included in the analysis.
Overall sensitivity and specificity of CEUS for the
diagnosis of malignant liver lesions was 93% (95%-CI:
91–95%) and 90% (95%-CI: 88–92%) respectively.

44. CEUS vs. spiral enhanced-CT
• In a study [1] on a subgroup of patients from the DEGUM multicentre
study, CEUS was compared to spiral-CT .
• From the 267 patients, histological findings were available in 158 subjects.
• In this subgroup, CEUS/CT: accuracy 90.3% vs. 87.8%, sensitivity 94.0 vs.
90.7%, specificity 83.0 vs. 81.5%, PPV 91.6 vs. 91.5%, NPV 87.5 vs. 80.0%.
•No significant differences were found between
these two methods
• 1.Seitz K, Strobel D, Bernatik T, et al. Contrast-Enhanced Ultrasound (CEUS) for the characterization of focal liver lesions - prospective comparison in clinical practice: CEUS vs.
CT (DEGUM multicenter trial). Ultraschall Med. 2009;30(4), 383-389

45. CEUS vs. MRI
• CEUS was compared to contrast MRI in a study [1], on a subgroup of
patients from the DEGUM multicentre study.
• The definitive diagnosis of the 262 patients included was based on MRI as
the "diagnostic gold standard", on clinical evidence and additional follow-
up in 180 patients, or on histology in 82 patients.
•There were no statistically proven differences between
CEUS and MRI.
1.Seitz K, Bernatik T, Strobel D et al. Contrast-Enhanced Ultrasound (CEUS) for the Characterization of Focal Liver Lesions in Clinical Practice (DEGUM Multicenter Trial): CEUS vs. MRI -
a Prospective Comparison in 269 Patients. Ultraschall Med. 2010;31(5), 492-499

46. The diagnostic performances of CEUS, CE-CT and CE-MRI were
determined in a meta-analysis in patients with FLLs.
25 studies included:
• 1.The pooled estimate Sensitivity and Specificity for CEUS studies were 87% and 89%
respectively.
• 2.CE-CT studies: Sensitivity and specificity were 86% and 82% respectively,
• 3.CE-MRI studies: Sensitivity and specificity were 85% and 87% respectively.
• Conclusion: The diagnostic performance of CEUS for FLLs is not significantly different
than that of CE-CT and CE-MRI. CEUS is a highly specific and sensitive diagnostic
modality in detecting FLLs and should be considered as the first choice for patients with
limited financial support.
• Xie L et al: Diagnostic value of CEUS, CT and MRI for focal liver lesions: a meta-analysis. Ultrasound in Med. & Biol. 2011; 37 (6) : 854–861

47. New Meta-analysis (2018)
- This meta-analysis was performed to evaluate the accuracy of contrast-enhanced
ultrasound (CEUS) in differentiating malignant from benign focal liver lesions (FLLs).
- Fifty-seven studies were included in this meta-analysis and the overall CEUS diagnostic
accuracy in characterization of FLLs : sensitivity, 0.92 (95%CI: 0.91-0.93); specificity, 0.87
(95%CI: 0.86-0.88);
• Subgroup analysis indicated higher diagnostic accuracy of the second-generation contrast
agents (CAs) than the first-generation CA .
• Furthermore, Sonazoid demonstrated the highest diagnostic accuracy among three
major CAs (SonoVue, Levovist and Sonazoid).
1.Wu M et al. Contrast-enhanced US for characterization of focal liver lesions: a comprehensive meta-analysis. Eur Radiol 2018;28(5):2077-2088

48. Some comments
•Cholangiocarcinoma is a difficult diagnosis with CEUS;
•HCC had a very typical arterial enhancement, but “wash
out” is often very late or very poor!
•CEUS is a good method for evaluation of liver
metastasis!
•Experience can play a role for the improvement of the
accuracy of CEUS liver.

49. In conclusion
• CEUS is a very useful method for the characterization of the malignant
FLL, with sensitivity and specificity quite similar to CT or MRI (but with
a lower cost);
• CEUS should be the first imaging modality for the evaluation of a
“mass” discovered in an US examination, because in the vast majority
of cases, can give a final diagnosis.

50. Last Slide
50
WFUMB
Slide Series
Contrast enhanced ultrasound for the evaluation
of malignant focal liver lesions
Prepared by Prof. Ioan Sporea, MD, PhD