Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
4
Hepatocellular carcinoma: Diagnostic criteria by imaging techniques Maxime Ronot, MD, PhD, Abdominal radiologists a, b, c, *, rie Vilgrain, MD, PhD, Abdominal radiologists a, b, c Vale a
Department of Radiology, APHP, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France University Paris Diderot, Sorbonne Paris Cit e, Paris, France c INSERM U1149, centre de recherche biom edicale Bichat-Beaujon, CRB3, Paris, France b
a b s t r a c t Keywords: Hepatocellular carcinoma Computed tomography Magnetic resonance imaging Contrast-enhanced ultrasound Hypervascularity Washout Hepatobiliary
Imaging plays a very important role in the diagnosis of HCC. Indeed, in high-risk patients a noninvasive diagnosis can only be obtained by imaging in presence of typical features. These features include arterial enhancement followed by washout during the portal venous and/or delayed phases on CT scan or MRI. This pattern is quite specific and has been endorsed by both Western and Asian diagnostic guidelines. However, its sensitivity is not very high, especially for small lesions. Therefore ancillary signs may be needed to increase the reliability of the diagnosis. Recent hepatobiliary MRI contrast agents seem to be interesting to improve characterization of small nodules in the cirrhotic liver. © 2014 Elsevier Ltd. All rights reserved.
Introduction Like any other tumour hepatocellular carcinoma (HCC), presents with numerous, variable imaging features depending on the extension and biological behaviour. None of these features are specific, and a diagnosis is based on their combination. The diagnosis of HCC is often faced with two different clinical situations. The first occurs in a patient without known chronic liver disease. In this setting, patients
ne ral Leclerc, 92118 Clichy, * Corresponding author. Department of Radiology, Beaujon Hospital, AP-HP, 100 Boulevard du Ge France. Tel.: þ33 1 40 87 55 66; fax: þ33 1 40 87 05 48. E-mail address: [email protected] (M. Ronot).
http://dx.doi.org/10.1016/j.bpg.2014.08.005 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
796
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
have not received regular monitoring and tumours are often large and may have vascular invasion. In these cases imaging features are usually typical enough to obtain a reliable diagnosis or to narrow it down to a limited group of differential diagnoses. Biopsy is usually performed to confirm the diagnosis. The second much more challenging situation occurs in patients with chronic liver disease (e.g. cirrhosis or advanced liver fibrosis) under regular monitoring, generally with ultrasound (US). In these cases small lesions are found and the role of imaging is to differentiate HCC from several non-malignant cirrhosis-associated nodules (e.g., regenerative, low and high grade dysplastic nodules), benign lesions or pseudolesions that may be encountered in the cirrhotic liver (e.g., haemangiomas, focal or confluent fibrosis, transient perfusion disorders), as well as other malignant lesions, intrahepatic cholangiocarcinoma (ICC), the most common being liver metastases. In oncology, the diagnosis of malignancy usually requires tissue sampling prior to determining the therapeutic strategy. However, HCC is an exception because a non-invasive diagnosis can be achieved with imaging in these high-risk populations, explaining its key role in patient management [1e4]. Nevertheless a necessary condition is that imaging criteria must be nearly 100% specific for HCC. Therefore, biopsy is mostly indicated in indeterminate nodules that do not satisfy radiological criteria for HCC [1e3,5]. It is also important to note that while tumours less than 2 cm in diameter represented 1 cm
Size 2 cm
Tumour enhancement in the arterial phase (hyper- or hypo)
Tumour enhancement in the arterial phase (hyper- or hypo)
None
None
Tumour enhancement in the arterial phase (hyper- or hypovascular) and Size ( 2 cm when hypo and 2 cm when hyper May increase of decrease the risk of HCC
None
None
Use of ancillary features
AASLD: American Association for the Study of the Liver Diseases; APASL: Asian Pacific Society for the Study of the Liver, CEUS: contrast-enhanced ultrasound, CT: computed tomography; EASL: European Association for the Study of the Liver; HCC: Hepatocellular Carcinoma; JSH: Japanese Society of Hepatology; LI-RADS: Liver Imaging Reporting and Data System; MRI: magnetic resonance imaging. a Unclear whether sufficient to establish HCC diagnosis in the absence of a typical imaging pattern. b Elevated levels suggest HCC, but insufficient to establish HCC diagnosis in the absence of a typical imaging pattern.
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
Table 1 Comparison of different guidelines for the non-invasive diagnosis of HCC.
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
809
Comparison of these different guidelines is difficult [78]. A recent publication comparing the repeatability of the diagnostic features and Western scoring systems for HCC showed that the interreader agreement of two of the three major features for HCC (washout appearance and pseudocapsule) was only moderate. The authors also showed that expert agreement was moderate for LI-RADS and AASLD while that of novices was less consistent and that the latter were less likely to diagnose HCC than experts [79]. Asian algorithms and guidelines Asian guidelines also use the typical hallmarks of HCC (i.e. hypervascularity and washout on portal venous phase images), on CT or MRI performed with an extracellular contrast agent as the backbone of the diagnosis of HCC [3,4]. However, they significantly differ from Western guidelines for several reasons [78]. First they do not include size criteria. Recommendations of the Asian Pacific Association for the Study of the Liver (APASL) state that Western non-invasive diagnostic criteria are only reliable in 61% of small nodules on cirrhosis [3]. Furthermore, the diagnosis of HCC in 1e2-cm sized lesions is missed in up to 38% of cases based on imaging criteria. Japanese guidelines state that although most smaller tumours present atypical features the typical enhancement pattern will be considered for the diagnosis of HCC [4], and, therefore a nodule as small as 1e2 cm, can be correctly diagnosed by typical imaging findings with one dynamic imaging study alone. This recommendation is similar to that of the AASLD, but differs from the EASL. Second, although the diagnostic algorithm is different for hypo- and hypervascular nodules, the guidelines acknowledge that CEUS is better to detect hypervascularity and recommend its use in case of hypovascular lesions on CT or MRI. A second-line imaging modality is indicated with atypical or hypovascular lesions or lesions without washout, gadoxetic acid enhanced MRI or Sonazoid-contrast enhanced US are recommended in Japanese guidelines [4] and superparamagnetic iron oxyde (SPIO) particle-enhanced MRI or Sonazoid-contrast enhanced US in AAPSL guidelines [3]. Because SPIO is no longer available on the market Sonazoid is currently used, and recommendations will probably change in the near future. When a defect in the Kupffer phase is observed on CEUS, or if the lesion is markedly hypointense during the hepatobiliary phase, the lesion is diagnosed as HCC. If not, close follow-up is indicated. Conclusion Imaging plays a very important role in the diagnosis of HCC. In high-risk patients a noninvasive diagnosis can be obtained with imaging alone, based on the presence of typical features. These features include arterial enhancement followed by washout on CT or MRI. This pattern is highly specific and has been endorsed by both Western and Asian diagnostic guidelines. Nevertheless the sensitivity of these hallmarks is low especially for small liver lesions. Different approaches have been suggested to move forward, i) first, the association of ancillary signs mainly on MRI, ii) second, technical improvements with CEUS and MRI using hepatobiliary contrast agents. There is still no worldwide consensus.
Practice points - Diagnosis of HCC is based on the association of hypervascularity and venous or delayed washout on CT or MRI. - Most HCCs are hypointense on hepatobiliary MR phase acquisitions using hepatobiliary contrast agents. - Hepatobiliary MR contrast agents help characterize liver nodules, especially if they are small. - CEUS is highly sensitive for visualizing hypervascularity - Diffusion-weighted MRI increases the rate of detection and characterization of liver nodules on cirrhosis. - Ancillary imaging findings such as a capsule, corona enhancement, fat content, iron sparing, and the mosaic pattern are useful for the diagnosis of HCC.
810
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
Research agenda - Whether or not hepatobiliary MR contrast agents should be used during first-line imaging must be investigated. - Prediction of tumoral differentiation based on imaging criteria requires further research. - The diagnostic accuracy of combined features from different imaging techniques (e.g. arterial enhancement on CEUS, and washout on CT or MRI) must be clarified. - Utility of elastography techniques must be confirmed.
References [1] EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908e43. [2] Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020e2. [3] Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439e74. [4] Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, et al. Management of hepatocellular carcinoma in Japan: consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis 2011;29:339e64. [5] Kudo M. Real practice of hepatocellular carcinoma in Japan: conclusions of the Japan Society of Hepatology 2009 Kobe Congress. Oncology 2010;78(Suppl. 1):180e8. [6] Carlos RC, Kim HM, Hussain HK, Francis IR, Nghiem HV, Fendrick AM. Developing a prediction rule to assess hepatic malignancy in patients with cirrhosis. AJR Am J Roentgenol 2003;180:893e900. [7] Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:97e104. [8] Luca A, Caruso S, Milazzo M, Mamone G, Marrone G, Miraglia R, et al. Multidetector-row computed tomography (MDCT) for the diagnosis of hepatocellular carcinoma in cirrhotic candidates for liver transplantation: prevalence of radiological vascular patterns and histological correlation with liver explants. Eur Radiol 2010;20:898e907. [9] Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, Lok AS. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 2005;11:281e9. [10] Rimola J, Forner A, Tremosini S, Reig M, Vilana R, Bianchi L, et al. Non-invasive diagnosis of hepatocellular carcinoma
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
4
Hepatocellular carcinoma: Diagnostic criteria by imaging techniques Maxime Ronot, MD, PhD, Abdominal radiologists a, b, c, *, rie Vilgrain, MD, PhD, Abdominal radiologists a, b, c Vale a
Department of Radiology, APHP, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France University Paris Diderot, Sorbonne Paris Cit e, Paris, France c INSERM U1149, centre de recherche biom edicale Bichat-Beaujon, CRB3, Paris, France b
a b s t r a c t Keywords: Hepatocellular carcinoma Computed tomography Magnetic resonance imaging Contrast-enhanced ultrasound Hypervascularity Washout Hepatobiliary
Imaging plays a very important role in the diagnosis of HCC. Indeed, in high-risk patients a noninvasive diagnosis can only be obtained by imaging in presence of typical features. These features include arterial enhancement followed by washout during the portal venous and/or delayed phases on CT scan or MRI. This pattern is quite specific and has been endorsed by both Western and Asian diagnostic guidelines. However, its sensitivity is not very high, especially for small lesions. Therefore ancillary signs may be needed to increase the reliability of the diagnosis. Recent hepatobiliary MRI contrast agents seem to be interesting to improve characterization of small nodules in the cirrhotic liver. © 2014 Elsevier Ltd. All rights reserved.
Introduction Like any other tumour hepatocellular carcinoma (HCC), presents with numerous, variable imaging features depending on the extension and biological behaviour. None of these features are specific, and a diagnosis is based on their combination. The diagnosis of HCC is often faced with two different clinical situations. The first occurs in a patient without known chronic liver disease. In this setting, patients
ne ral Leclerc, 92118 Clichy, * Corresponding author. Department of Radiology, Beaujon Hospital, AP-HP, 100 Boulevard du Ge France. Tel.: þ33 1 40 87 55 66; fax: þ33 1 40 87 05 48. E-mail address: [email protected] (M. Ronot).
http://dx.doi.org/10.1016/j.bpg.2014.08.005 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
796
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
have not received regular monitoring and tumours are often large and may have vascular invasion. In these cases imaging features are usually typical enough to obtain a reliable diagnosis or to narrow it down to a limited group of differential diagnoses. Biopsy is usually performed to confirm the diagnosis. The second much more challenging situation occurs in patients with chronic liver disease (e.g. cirrhosis or advanced liver fibrosis) under regular monitoring, generally with ultrasound (US). In these cases small lesions are found and the role of imaging is to differentiate HCC from several non-malignant cirrhosis-associated nodules (e.g., regenerative, low and high grade dysplastic nodules), benign lesions or pseudolesions that may be encountered in the cirrhotic liver (e.g., haemangiomas, focal or confluent fibrosis, transient perfusion disorders), as well as other malignant lesions, intrahepatic cholangiocarcinoma (ICC), the most common being liver metastases. In oncology, the diagnosis of malignancy usually requires tissue sampling prior to determining the therapeutic strategy. However, HCC is an exception because a non-invasive diagnosis can be achieved with imaging in these high-risk populations, explaining its key role in patient management [1e4]. Nevertheless a necessary condition is that imaging criteria must be nearly 100% specific for HCC. Therefore, biopsy is mostly indicated in indeterminate nodules that do not satisfy radiological criteria for HCC [1e3,5]. It is also important to note that while tumours less than 2 cm in diameter represented 1 cm
Size 2 cm
Tumour enhancement in the arterial phase (hyper- or hypo)
Tumour enhancement in the arterial phase (hyper- or hypo)
None
None
Tumour enhancement in the arterial phase (hyper- or hypovascular) and Size ( 2 cm when hypo and 2 cm when hyper May increase of decrease the risk of HCC
None
None
Use of ancillary features
AASLD: American Association for the Study of the Liver Diseases; APASL: Asian Pacific Society for the Study of the Liver, CEUS: contrast-enhanced ultrasound, CT: computed tomography; EASL: European Association for the Study of the Liver; HCC: Hepatocellular Carcinoma; JSH: Japanese Society of Hepatology; LI-RADS: Liver Imaging Reporting and Data System; MRI: magnetic resonance imaging. a Unclear whether sufficient to establish HCC diagnosis in the absence of a typical imaging pattern. b Elevated levels suggest HCC, but insufficient to establish HCC diagnosis in the absence of a typical imaging pattern.
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
Table 1 Comparison of different guidelines for the non-invasive diagnosis of HCC.
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
809
Comparison of these different guidelines is difficult [78]. A recent publication comparing the repeatability of the diagnostic features and Western scoring systems for HCC showed that the interreader agreement of two of the three major features for HCC (washout appearance and pseudocapsule) was only moderate. The authors also showed that expert agreement was moderate for LI-RADS and AASLD while that of novices was less consistent and that the latter were less likely to diagnose HCC than experts [79]. Asian algorithms and guidelines Asian guidelines also use the typical hallmarks of HCC (i.e. hypervascularity and washout on portal venous phase images), on CT or MRI performed with an extracellular contrast agent as the backbone of the diagnosis of HCC [3,4]. However, they significantly differ from Western guidelines for several reasons [78]. First they do not include size criteria. Recommendations of the Asian Pacific Association for the Study of the Liver (APASL) state that Western non-invasive diagnostic criteria are only reliable in 61% of small nodules on cirrhosis [3]. Furthermore, the diagnosis of HCC in 1e2-cm sized lesions is missed in up to 38% of cases based on imaging criteria. Japanese guidelines state that although most smaller tumours present atypical features the typical enhancement pattern will be considered for the diagnosis of HCC [4], and, therefore a nodule as small as 1e2 cm, can be correctly diagnosed by typical imaging findings with one dynamic imaging study alone. This recommendation is similar to that of the AASLD, but differs from the EASL. Second, although the diagnostic algorithm is different for hypo- and hypervascular nodules, the guidelines acknowledge that CEUS is better to detect hypervascularity and recommend its use in case of hypovascular lesions on CT or MRI. A second-line imaging modality is indicated with atypical or hypovascular lesions or lesions without washout, gadoxetic acid enhanced MRI or Sonazoid-contrast enhanced US are recommended in Japanese guidelines [4] and superparamagnetic iron oxyde (SPIO) particle-enhanced MRI or Sonazoid-contrast enhanced US in AAPSL guidelines [3]. Because SPIO is no longer available on the market Sonazoid is currently used, and recommendations will probably change in the near future. When a defect in the Kupffer phase is observed on CEUS, or if the lesion is markedly hypointense during the hepatobiliary phase, the lesion is diagnosed as HCC. If not, close follow-up is indicated. Conclusion Imaging plays a very important role in the diagnosis of HCC. In high-risk patients a noninvasive diagnosis can be obtained with imaging alone, based on the presence of typical features. These features include arterial enhancement followed by washout on CT or MRI. This pattern is highly specific and has been endorsed by both Western and Asian diagnostic guidelines. Nevertheless the sensitivity of these hallmarks is low especially for small liver lesions. Different approaches have been suggested to move forward, i) first, the association of ancillary signs mainly on MRI, ii) second, technical improvements with CEUS and MRI using hepatobiliary contrast agents. There is still no worldwide consensus.
Practice points - Diagnosis of HCC is based on the association of hypervascularity and venous or delayed washout on CT or MRI. - Most HCCs are hypointense on hepatobiliary MR phase acquisitions using hepatobiliary contrast agents. - Hepatobiliary MR contrast agents help characterize liver nodules, especially if they are small. - CEUS is highly sensitive for visualizing hypervascularity - Diffusion-weighted MRI increases the rate of detection and characterization of liver nodules on cirrhosis. - Ancillary imaging findings such as a capsule, corona enhancement, fat content, iron sparing, and the mosaic pattern are useful for the diagnosis of HCC.
810
M. Ronot, V. Vilgrain / Best Practice & Research Clinical Gastroenterology 28 (2014) 795e812
Research agenda - Whether or not hepatobiliary MR contrast agents should be used during first-line imaging must be investigated. - Prediction of tumoral differentiation based on imaging criteria requires further research. - The diagnostic accuracy of combined features from different imaging techniques (e.g. arterial enhancement on CEUS, and washout on CT or MRI) must be clarified. - Utility of elastography techniques must be confirmed.
References [1] EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908e43. [2] Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020e2. [3] Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439e74. [4] Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, et al. Management of hepatocellular carcinoma in Japan: consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis 2011;29:339e64. [5] Kudo M. Real practice of hepatocellular carcinoma in Japan: conclusions of the Japan Society of Hepatology 2009 Kobe Congress. Oncology 2010;78(Suppl. 1):180e8. [6] Carlos RC, Kim HM, Hussain HK, Francis IR, Nghiem HV, Fendrick AM. Developing a prediction rule to assess hepatic malignancy in patients with cirrhosis. AJR Am J Roentgenol 2003;180:893e900. [7] Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:97e104. [8] Luca A, Caruso S, Milazzo M, Mamone G, Marrone G, Miraglia R, et al. Multidetector-row computed tomography (MDCT) for the diagnosis of hepatocellular carcinoma in cirrhotic candidates for liver transplantation: prevalence of radiological vascular patterns and histological correlation with liver explants. Eur Radiol 2010;20:898e907. [9] Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, Lok AS. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 2005;11:281e9. [10] Rimola J, Forner A, Tremosini S, Reig M, Vilana R, Bianchi L, et al. Non-invasive diagnosis of hepatocellular carcinoma
