- Email: [email protected]
Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis
Clinical Radiology xxx (2013) 1e10
Contents lists available at SciVerse ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Review
Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis K.S. Lim* Department of Diagnostic Radiology, Tan Tock Seng Hospital, Jalan Tan Tock Seng, Singapore 308433, Singapore
art icl e i nformat ion Article history: Received 13 April 2013 Received in revised form 16 July 2013 Accepted 18 July 2013
The internationally accepted diagnostic criteria for hepatocellular carcinoma (HCC) in cirrhosis are highly accurate for large tumours, but offer relatively low sensitivity for small (<2 cm) tumours. Diffusion-weighted imaging (DWI) is a functional magnetic resonance imaging (MRI) technique that has been studied extensively as an aid to visualize various abdominal malignancies, including HCC in cirrhosis. DWI maps water diffusivity, which in HCC may be restricted as a result of changes ensuing from hepatocarcinogenesis. The present review is based on up-to-date evidence and describes the strengths and weaknesses of DWI, both as a standalone technique and as an adjunct sequence to conventional protocols, in the diagnosis, staging, prognostication, and assessment of treatment response of HCC in cirrhosis. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Radiological diagnosis of hepatocellular carcinoma (HCC) in cirrhosis is now so well-established that it obviates routine histological confirmation. Arterial enhancement followed by washout is considered a diagnostic feature of HCC >1 cm by the American Association for the Study of Liver Diseases (AASLD) and European Association for Study of Liver Diseases (EASL).1 Amongst other techniques, magnetic resonance imaging (MRI) has the highest accuracy in diagnosing cirrhotic HCC.2 However, the published efficacy in detecting early HCC has been less consistent, and the reported sensitivity of the described criteria for HCC 2 cm is as low as 30%.3e5 This is due to several reasons: early HCC may retain significant portal blood supply and does not show the “diagnostic” delayed washout.4 Approximately 17% of small HCC appear hypovascular at imaging6 (Fig 1). With improved MRI technology and field strength, small (<2 cm) flash-enhancing foci are increasingly seen in the cirrhotic liver, and only a proportion * Guarantor and correspondent: K.S. Lim, Department of Diagnostic Radiology, Tan Tock Seng Hospital, Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel.: þ65 97363598; fax: þ65 63578112. E-mail address: [email protected]
of these lesions represent HCC.7 The distorted texture of the cirrhotic liver also causes poor conspicuity for small HCC. In short, any endeavour to improve HCC diagnosis needs to interrogate other biological changes subsequent to hepatocarcinogenesis besides neovascularity. Diffusion-weighted imaging (DWI) is a functional MRI technique that has increasingly been used a cancer-imaging tool in clinical practice. Advances in MRI technology, particularly in gradient strength and parallel imaging, have greatly expanded the use of DWI in extra-cranial oncological imaging.8e10 The utility of DWI in detecting, characterizing, histological grading, and assessing treatment response in various abdominal malignancies has been extensively studied,8,9 and HCC is no exception. The present review describes the strengths and weaknesses of the use of DWI in the diagnosis, grading, staging, and assessment of treatment response of HCC in cirrhosis, in light of the available evidence, complemented with illustrative cases.
DWI DWI measures the diffusivity, or freedom of movement of water molecules, in a tissue by applying a pair of equal
0009-9260/$ e see front matter Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2013.07.022
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
2
K.S. Lim / Clinical Radiology xxx (2013) 1e10
Figure 1 A 58-year-old man undergoing MRI surveillance for right lobe HCC treated with RFA. (a) Contrast-enhanced arterial-phase image shows a hypovascular nodule in the lateral segment (arrow). (b) DWI (b ¼ 1000) image shows the lesion to be hyperintense (arrow) in keeping with a malignant focus. Subsequent biopsy confirmed HCC.
and symmetrical gradients about the 180 refocusing pulse in a T2 echoplanar spin-echo sequence. Immobile water molecules in the tissue experience a phase drift from the first gradient (dephasing), which is cancelled out by the second gradient (rephasing). Conversely, mobile water molecules do not undergo significant rephasing by the second gradient due to location change between the gradients. The net dephasing causes a T2 signal loss, the magnitude of which is proportional to the diffusivity of the tissue.11 The sensitivity of DWI in differentiating tissues of different diffusivities, its diffusion weighting, depends on the magnitudes of the bipolar gradients, which can be increased by increasing the b-value (expressed in s/mm2) on the MRI machine. Tissue with relatively restricted diffusivity typically appears T2 hyperintense on high b-value DWI images, whereas that with relatively free diffusivity loses most of its signal on these images. The diffusivity of a tissue may be quantitatively expressed as an apparent diffusion coefficient (ADC) value, which equates to the gradient of the straight line superimposed on the graph of the logarithm of relative signal intensity (y-axis) against increasing b-values (x-axis). The more restricted the diffusivity of a tissue, the lower its ADC value.
HCC in cirrhosis and DWI Cirrhotic liver is composed of regenerative nodules supported by bridging fibrous septa. A tiny proportion of the nodules undergo dysplasiaeneoplasia transformation
to eventually become HCC.12,13 In this multistep pathway of hepatocarcinogenesis and the subsequent tumour dedifferentiation, there is increasing cellular and structural atypia, typified by increasing cellular density, nuclear-tocytoplasmic ratio, intracellular organelles, and thickening of cellular plates.12 These changes, together with the resultant shrinkage of the extracellular space, should progressively impede movement of water molecules, i.e., restrict diffusivity. Therefore, diffusivity of a cirrhotic nodule may be used as a surrogate marker for its malignant potential and degree of subsequent dedifferentiation. In contrast, benign nodules usually present a similar microstructure and hence water diffusivity to the surrounding cirrhotic parenchyma.12 Moreover, most anti-HCC therapies induce tumour necrosis, which is characterized by cell death and impaired membrane integrity, with the resultant increase in diffusivity. Therefore, DWI may be useful in detecting HCC amongst benign nodules, predicting the histological grade, and assessing its response to treatment.
Visibility of HCC in cirrhosis at DWI As a malignant lesion, HCC in cirrhosis typically appears hyperintense at DWI. In reality, the visibility and signal intensity of HCC at DWI is the product of complex interplay between various biological and technical factors. These are often compounded by overlaps in the biological properties of HCC and those of benign cirrhotic lesions and background cirrhotic parenchyma, which govern water diffusivity.
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
3
Figure 2 A 56-year-old man with hepatitis B was found to have a mass in the right lobe at ultrasound surveillance. (a) Left. Contrast-enhanced arterial-phase image shows a subcapsular mass with avid enhancement in the posterior segment (arrow). Right. Contrast-enhanced equilibriumphase image shows contrast medium washout from the lesion (arrow), in keeping with HCC. (b) Left. DWI (b ¼ 1000) image shows the lesion to be iso-intense (arrow). Right. The corresponding ADC map does not reveal significant restriction to diffusivity (arrow). Histology after surgical resection revealed well-differentiated HCC.
b-Value Low b-values of 50e100 are routinely employed in hepatic DWI to produce “dark-blood” images as fast-moving
water molecules in blood and duct vessels are dephased rapidly at these values, rendering these structures DWI invisible, and increasing the conspicuity of small T2 hyperintense lesions close to these structures. This is a
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
4
K.S. Lim / Clinical Radiology xxx (2013) 1e10
unique advantage of DWI, as these structures are usually visible on morphological images and may obscure nearby small tumours. Using a b-value of 50, Parikh et al.14 reported that approximately 80% of HCC appear hyperintense at DWI. Using a b-value of 100 with a 3 T MRI system, Kim et al.15 reported that 73% of HCC <1 cm were hyperintense at DWI. Despite using a higher b value of 500, Piana et al.4 reported that 72e82% of HCC remained hyperintense at DWI, including 64e74% of tumours that were <2 cm. Using the same b-value, Nasu et al.16 and Xu et al.17 reported much higher sensitivities of >90%, although this may be due to the generally larger lesions included in their studies. Using a bvalue of 1000, Muhi et al.18 reported that 72% HCC were hyperintense at DWI. The relatively low detection rate was compensated for by the extremely high specificity, as none of the included dysplastic nodules appeared hyperintense at DWI.18 Similarly, Motosugi et al.,19 using the same b-value, reported that although only 67% of HCC were hyperintense at DWI, no arterially enhancing pseudolesions were visible at DWI. Hence, high b-values offer excellent specificity in distinguishing HCC amongst benign cirrhotic lesions and arterially enhancing pseudolesions, at the expense of slightly lower sensitivity. The relatively low HCC detection rate with higher b-values is, in part, due to the poor signal-to-noise ratio of these images, caused by the resultant long TE (time to echo) on echoplanar sequences. As yet, there is no consensus on the optimal b-value for diagnosing HCC in cirrhosis. Vandecaveye et al.20 reported that a b-value of 600 offered the best performance (sensitivity: 91.2%, specificity: 81.8%) amongst b-values of 300, 600, and 1000, in differentiating well-differentiated HCC from benign cirrhotic nodules. However, the relatively high performance of DWI reported in this study may be attributable, in part, to the inclusion of a small number of highgrade dysplastic nodules in the HCC group.
Histological grade As hepatocarcinogenesis and subsequent tumour dedifferentiation are different parts of a continuous process, HCC in cirrhosis is best considered as a heterogeneous group of lesions in terms of diffusivity; therefore, the visibility of lesions at DWI depends on their position along this pathway. Nasu et al.16 (b ¼ 500) reported a general trend of increasing DWI hyperintensity, albeit with large overlaps, with increasing tumour dedifferentiation. Muhi et al.18 (b ¼ 500, 1000) noted >90% of moderately and poorly differentiated HCCs, including all iso-hypovascular lesions, were visible at DWI, whereas 51% of well-differentiated HCCs and all dysplastic nodules were DWI invisible (Fig 3).
Background liver The micro-architecture of the background cirrhotic liver may also influence DWI visibility of HCC lesions. The increased conspicuity of HCC on DWI echo-planar images may be associated with iron deposition, causing resultant T2* shortening and subsequent darkening of the background liver.14 This was postulated to be the reason for the
superiority of low b-value DWI compared to conventional T2-weighted sequences for HCC detection.14 However, cirrhotic parenchyma itself also shows restricted diffusivity, presumably owing to the abundance of fibrotic tissue,21 which results in reduced HCC conspicuity at DWI. This may explain why the efficacy of DWI in diagnosing HCC decreases with increasing severity of background cirrhosis.22
DWI and morphological sequences The efficacy of DWI for detecting HCC in cirrhosis has been studied in conjunction with conventional morphological techniques. The internationally accepted morphological criteria, i.e., arterial enhancement and delayed washout, in differentiating HCC from benign cirrhotic nodules, are biomarkers of tumour neovascularization. Conversely, DWI demonstrates tumour cellularity. On comparing the two techniques to diagnose HCC 2 cm, Vandecaveye et al.20 reported sensitivity and specificity values of 91.2% and 82.9% for DWI (b ¼ 600), and 67.6% and 61% for morphological imaging. However, the diagnostic performances of these techniques were not significantly different for HCC >2 cm. These results suggest that DWI can potentially be used as an alternative in those cases where gadolinium contrast medium is contraindicated. As most patients tolerate gadolinium contrast medium, the two techniques are used in combination in clinical practice. Piana et al.4 (b ¼ 500) reported that the addition of hyperintensity at DWI as a diagnostic criterion for HCC improved the sensitivity of conventional MRI from 59.6% (30% for HCC <2 cm) to approximately 85%. Using the same b-value, Xu et al.23 reported improved sensitivity of 98% when using combined DWI and morphological imaging to detect HCC <2 cm from approximately 83e85% when using morphological imaging alone. The results suggest that DWI may potentially improve the detection rate of morphological sequences for HCC in cirrhosis. Gadoxetic acid is a hepatocyte-specific gadoliniumbased contrast agent that is used to detect and characterize liver lesions at both dynamic and hepatobiliary imaging. Hypointensity on the gadoxetic acid-enhanced hepatobiliary (GA-HP) phase indicates the absence of hepatocytes and has been reported to be accurate in distinguishing HCC from the normally hepatocyte-containing benign cirrhotic lesions.24 In two reports, hyperintensity at DWI was shown to be more specific than hypointensity on GAHP images in diagnosing small HCC,15,25 with comparable sensitivity. Motosugi et al.19 (b ¼ 500, 100) reported that 15% (16 out of 104) of arterially enhancing pseudolesions were hypointense on GA-HP images, but none were visible at DWI (Fig 2). Based on the evidence presented so far, the ideal MRI protocol for diagnosing HCC in cirrhosis should include gadoxetic acid enhanced dynamic and hepatobiliary phases, and DWI. Dynamic images detect neovascularity, GA-HP images confirm the absence of hepatocytes, and DWI depicts hypercellularity; the three biological hallmarks of HCC over benign cirrhotic nodules. This protocol has been reported to improve the diagnostic accuracy of either gadoxetic acid-enhanced or DWI sequences alone, as DWI
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
5
Figure 3 A 62-year-old woman with cirrhosis was found to have a new hypoechoic nodule in the lateral segment at routine sonographic surveillance. (a) T2-weighted fat-saturated image shows the same nodule to be hyperintense (arrow). (b) DWI (b ¼ 1000) image shows the lesion to be hyperintense (arrow), suspicious for a malignant focus. Contrast-enhanced images (not shown) did not reveal any hypervascularity. The patient opted for close surveillance, and the lesion appeared stable for the ensuing 2 years, presumably a benign cirrhotic nodule.
hyperintensity has been shown to increase the probability of HCC in cirrhotic nodules that have isolated findings of either arterial enhancement or hypointensity on GA-HP images.26 DWI hyperintensity has also been reported to reliably predict the progression of hypovascular cirrhotic nodules, which are hypointense on GA-HP images.27 A tiny proportion of benign cirrhotic nodules may also appear DWI hyperintense15,20 (Fig 4). The precise reason for this is not known, but cell swelling (from cytotoxic oedema) and increased T2 relaxation times due to infarction are possible explanations. Distinguishing this group of benign lesions from hypovascular HCC is difficult. Therefore, all DWI hyperintense cirrhotic lesions with benign morphological findings should be closely monitored.
Quantitative analysis Quantification of diffusivity in terms of ADC value may potentially offer a more accurate and objective way of differentiating HCC from benign cirrhotic nodules. In practice, ADC measurement suffers from poor inter- and intraoperator consistency in drawing the region of interest (ROI) on the ADC map. Accurate and reproducible ADC requires the use of multiple (to produce the best-fit line on the ADC graph) consistent b-values and identical imaging parameters, all of which currently lack international standardization. Perhaps most importantly, accurate and reproducible ADC requires a more complex analytical method. The overall diffusivity within a DWI image voxel, according to the theory
of intravoxel incoherent motion (IVIM), is the sum total of water motion in extravascular (intra- and extracellular) and intravascular spaces.28,29 The intravascular water molecules, due to fast flowing blood, dephase rapidly even at low bvalues compared with those in extravascular spaces. Hence, the signal of a lesion decreases rapidly in the initial increase in b-values, dependent on lesion vascularity, and then gradually as the b-value increases further, dependent on lesion cellularity. In other words, the signal loss with increasing b-values is a bi-exponential process, with a fast perfusion (Dfast) followed by a slow diffusion (Dslow) component. This is potentially relevant in imaging cirrhotic nodules as some studies have reported that the ADCslow of HCC was not significantly different from the background liver, whereas its perfusion fraction (f) was significantly lower than the background liver.30,31 This may be explained by “faulty” angiogenesis, which produces microvessels with leaky basement membranes and poor pericyst coverage, leading to a reduction of the “pool” of intravascular water molecules.31 Moreover, antiHCC therapies, such as chemoembolization and antiangiogenic drugs, which act by altering tumour vascularity, may affect Dfast more than Dslow,31 and measuring their effectiveness may necessitate bi-exponential analysis of diffusivity.
Staging and prognostication The management and prognosis of HCC in terms of survival and recurrence rate depend on the size of the lesion and the presence of vascular invasion, intrahepatic metastases, and degree of dedifferentiation.32 Accurate assessment of
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
6
K.S. Lim / Clinical Radiology xxx (2013) 1e10
with well and moderately differentiated HCC after curative treatment.33 Poorly differentiated HCC necessitates wider surgical clearance margins and closer post-treatment surveillance. Preoperative prediction of tumour grade is hence pivotal to treatment planning and prognostication. The histopathological grade of a malignant tumour usually depends on its cellular and structural atypia.12 The increasing cellular density, nuclear-to-cytoplasmic ratio, and architectural complexity accompanying dedifferentiation may cause progressively restricted diffusivity. An et al.34 reported that the combined absence of DWI hyperintensity and arterial enhancement carried a 100% positive predictive value in distinguishing welldifferentiated HCC from those of higher grades. However, the graded nature of dedifferentiation necessitates a more quantitative approach to diffusivity measurement, and therefore, most studies used ADC measurement rather than visual analysis. At least two studies did not report any correlation between tumour grade and ADC.4,16 Both of these two groups used a single b-value of 500 and measured the ADC by drawing a ROI over the entire lesion irrespective of lesion heterogeneity. Using b-values of 500 and 1000, Muhi et al.18 reported that mean ADC values of moderately or poorly differentiated HCCs were significantly lower than well-differentiated HCCs or dysplastic nodules. Using different methods of avoiding necrotic areas in the tumours when drawing the ROI, at least three studies have reported significant correlation between ADC values and histological grade of HCC.35e37 This is presumably because as a malignant tumour dedifferentiates to a higher grade, the increasing oxygen tension leads to progressive intratumoural necrosis, producing foci of reduced cell density and increased membrane permeability. The resultant increased water diffusivity in the necrotic areas may hence, paradoxically, increase the mean ADC of the entire lesion.
Vascular invasion
Figure 4 A 72-year-old woman with cirrhosis and raised alphafetoprotein (AFP) level. (a) Contrast-enhanced arterial-phase image shows a heterogeneous mass in the right lobe (arrow) extending into the expanded right portal vein (star). Enlarged nodes are also noted in the liver hilum (bullet). (b) DWI (b ¼ 1000) image shows the mass (arrow) and the involved right portal vein (star) to be hyperintense and of identical intensity at DWI. The portal vein nodes (bullet) also appear similarly DWI hyperintense. Findings are suggestive of infiltrative HCC invading the portal vein with, most probably, regional adenopathy. The primary tumour was histologically confirmed.
these factors is a fundamental role of imaging after HCC has been detected. The potential value of DWI in these functions has also been studied.
Histological grading The survival of patients with poorly differentiated HCC was reported to be significantly worse than that of patients
Tumour involvement of the portal vein effectively precludes most treatment options for HCC except systemic therapy and possibly radioembolization.38 Its diagnosis is hampered by the presence of frequent bland thrombus in the cirrhotic liver. Catalano et al.39 reported that 15 out of 18 malignant thrombi in their study were isointense with the primary tumours at DWI, whereas all bland thrombi were DWI hypointense (Fig 5). However, as blood products can show variable T2 prolongation and water diffusivity, falsepositive cases are not infrequently encountered.40 DWI is likely to play only a limited role in distinguishing malignant from bland thrombi.
Intrahepatic metastases The presence of small satellite HCC, i.e., intrahepatic metastases, is an important determinant of a patient’s prognosis and therapeutic approach, and these lesions require immediate and accurate diagnosis. Without immediate curative or palliative therapy, intrahepatic metastases show aggressive behaviour, unlike single or multicentric primary tumours of
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
small size.41 The high diagnostic accuracy of DWI over conventional MRI sequences in detecting small HCC discussed earlier may be assumed to be applicable to small intrahepatic metastases (Fig 6). Yu et al. reported that DWI detected significantly more HCC metastases of 1 cm than contrastenhanced images, although not for those >1 cm.42
7
Prediction of treatment response The advent of locoregional therapies, such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and radioembolization, have contributed significantly to the control of some unresectable but localized tumours.43 As
Figure 5 A 64-year-old man with cirrhosis and HCC nodules in the posterior sector treated with RFA. (a) Top. DWI (b ¼ 1000) image revealed one of the ablated nodules (bullet). There is also a tiny hyperintense nodule adjacent to the ablated nodule (arrow). Bottom. A slightly more inferior DWI (b ¼ 1000) image reveals another tiny hyperintense nodule in posterior sector (arrows).The ablated nodule is again seen (bullet). (b) Corresponding contrast-enhanced arterial phase images through the same region do not reveal the DWI visible nodules. (c) Contrastenhanced arterial phase subtraction images 3 months later reveal two rim-enhancing nodules (arrows) corresponding to the DWI hyperintense nodules seen at the previous MRI examination, with interval enlargement, in keeping with metastases. Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
8
K.S. Lim / Clinical Radiology xxx (2013) 1e10
these therapies may be repeated and interchangeably applied in cases of residual or recurrent disease, accurate early assessment of treatment response is vital to direct management. Response Evaluation Criteria In Solid Tumors (RECIST) criteria have conventionally been used to measure therapeutic response in solid malignancies, but these criteria rely on changes in lesion size. They are not applicable to HCC as locoregional therapies aim to achieve tumour necrosis, rather than tumour shrinkage or disappearance. In 2000, the EASL proposed to evaluate response to locoregional treatment by assessing the decrease in viable tumour volume, seen as a decrease in contrast-enhancing areas.1 However, differentiation of viable tumour tissue from other treatment-induced changes, such as inflammation, granulation tissue,44 and vascular injuries,45 is not always easy, as these non-tumoural changes can show contrast enhancement. DWI may have a potential role in the differentiation of viable tumour from treatment-induced necrosis and other misleading changes, and has been used to assess treatment response in other malignancies.46 In theory, viable tumours are highly cellular with intact cell membranes, causing diffusivity restriction. Conversely, treatment-induced necrotic and inflammatory tissues cause reduced cellular density and increased membrane permeability, enabling relatively free diffusion of water molecules.
TACE A significant increase in the mean ADC with corresponding reduction in tumour enhancement has been
reported in post-TACE HCC.47,48 An increase in ADC values with increasing tumour necrosis has also been demonstrated in a small group of post-TACE HCC, with pathological correlation.49 Mannelli et al.50 reported that although a decrease in the contrast-enhanced area on subtraction images had more significant correlation with the histopathological findings than an increase in ADC in the evaluation of HCC necrosis after TACE, there was no difference between the two methods in diagnosis of complete tumour necrosis. Although the above reports generally based their results on ADC values at 4e6 weeks after TACE, ADC increase has been reported as early as 3 days after TACE.51 Kamel et al.52 (b ¼ 500) reported that the increase in tumour ADC value was most significant at 1e2 weeks after TACE, and insignificant at 24 h and at 4 weeks after therapy.52 These two studies, however, did not attempt to uncover a relationship between these ADC changes and treatment response. Although quantitative analysis of diffusivity appears potentially to be of value in assessing response to TACE, visual analysis appears less promising for this function. Goshima et al.53 reported that DWI was significantly less sensitive than contrast-enhanced images in detecting local residual/recurrent tumour post-TACE, whereas Yu et al.54 reported that the addition of DWI to contrastenhanced images reduced specificity and diagnostic accuracy of the latter, in detecting perilesional recurrence. They postulated that false positives at DWI may be attributable to hypercellular granulation tissue and fibrotic tissue.
Figure 6 A 46-year-old woman with cirrhosis and right lobe HCC treated with TACE. (a) Contrast-enhanced arterial-phase image shows a hypointense focus in keeping with the chemoembolized tumour. There is a semi-circumferential iso-vascular soft-tissue rim (arrow) noted. (b) DWI (b ¼ 1000) image shows the rim of the soft tissue to be strongly hyperintense (arrow), suggestive of recurrent tumour. Subsequent biopsy confirmed perilesional recurrence. Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
9
RFA
References
As yet, no study specifically studying the efficacy of DWI in detecting post-RFA residual/recurrent disease has been published in the English literature.
1. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421e30. 2. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 2006;101:513e23. 3. Kelekis NL, Semelka RC, Worawattanakul S, et al. Hepatocellular carcinoma in North America: a multiinstitutional study of appearance on T1weighted, T2-weighted, and serial gadolinium-enhanced gradient-echo images. AJR Am J Roentgenol 1998;170:1005e13. 4. Piana G, Trinquart L, Meskine N, et al. New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases. J Hepatol 2011;55:126e32. 5. Forner A, Vilana R, Ayuso C, 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. 6. Bolondi L, Gaiani S, Celli N, et al. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology 2005;42:27e34. 7. Holland AE, Hecht EM, Hahn WY, et al. Importance of small (< or ¼ 20mm) enhancing lesions seen only during the hepatic arterial phase at MR imaging of the cirrhotic liver: evaluation and comparison with whole explanted liver. Radiology 2005;237:938e44. 8. Lim KS, Tan CH. Diffusion-weighted MRI of adult male pelvic cancers. Clin Radiol 2012;67:899e908. 9. Koh DM, Collins DJ. Diffusion-weighted MRI in the body: applications and challenges in oncology. AJR Am J Roentgenol 2007;188:1622e35. 10. Taouli B, Koh DM. Diffusion-weighted MR imaging of the liver. Radiology 2010;254:47e66. 11. Koh DM, Takahara T, Imai Y, Collins DJ. Practical aspects of assessing tumors using clinical diffusion-weighted imaging in the body. Magn Reson Med Sci 2007;6:211e24. 12. Coleman WB. Mechanisms of human hepatocarcinogenesis. Curr Mol Med 2003;3:573e88. 13. Efremidis SC, Hytiroglou P. The multistep process of hepatocarcinogenesis in cirrhosis with imaging correlation. Eur Radiol 2002;12:753e64. 14. Parikh T, Drew SJ, Lee VS, et al. Focal liver lesion detection and characterization with diffusion-weighted MR imaging: comparison with standard breath-hold T2-weighted imaging. Radiology 2008;246:812e22. 15. Kim JE, Kim SH, Lee SJ, et al. Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver disease: characterization with gadoxetic acid-enhanced MRI that includes diffusion-weighted imaging. AJR Am J Roentgenol 2011;196:W758e65. 16. Nasu K, Kuroki Y, Tsukamoto T, et al. Diffusion-weighted imaging of surgically resected hepatocellular carcinoma: imaging characteristics and relationship among signal intensity, apparent diffusion coefficient, and histopathologic grade. AJR Am J Roentgenol 2009;193:438e44. 17. Xu PJ, Yan FH, Wang JH, et al. Contribution of diffusion-weighted magnetic resonance imaging in the characterization of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver. J Comput Assist Tomogr 2010;34:506e12. 18. Muhi A, Ichikawa T, Motosugi U, et al. High-b-value diffusion-weighted MR imaging of hepatocellular lesions: estimation of grade of malignancy of hepatocellular carcinoma. J Magn Reson Imaging 2009;30:1005e11. 19. Motosugi U, Ichikawa T, Sou H, et al. Distinguishing hypervascular pseudolesions of the liver from hypervascular hepatocellular carcinomas with gadoxetic acid-enhanced MR imaging. Radiology 2010;256:151e8. 20. Vandecaveye V, De Keyzer F, Verslype C, et al. Diffusion-weighted MRI provides additional value to conventional dynamic contrast-enhanced MRI for detection of hepatocellular carcinoma. Eur Radiol 2009;19: 2456e66. 21. Taouli B, Tolia AJ, Losada M, et al. Diffusion-weighted MRI for quantification of liver fibrosis: preliminary experience. AJR Am J Roentgenol 2007;189:799e806. 22. Kim AY, Kim YK, Lee MW, et al. Detection of hepatocellular carcinoma in gadoxetic acid-enhanced MRI and diffusion-weighted MRI with respect to the severity of liver cirrhosis. Acta Radiol 2012;53:830e8. 23. Xu PJ, Yan FH, Wang JH, et al. Added value of breathhold diffusionweighted MRI in detection of small hepatocellular carcinoma lesions
Radioembolization Catheter-directed intra-arterial administration of yttrium-90 aims to deliver a high radiation dose to targeted HCC, sparing the uninvolved liver parenchyma. This form of targeted beta radiation therapy for HCC has been shown to be relatively safe in patients with cirrhosis.38,55,56 Although a small study reported a 60% increase in the mean ADC after radioembolization,57 two other studies reported more modest ADC increases of approximately 10e20% posttreatment,58,59 with a corresponding decrease in the contrast enhancement59 or subsequent lesion shrinkage.58 These studies show the potential value of DWI in predicting response to radioembolization.
Systematic systemic therapy The anti-angiogenic drug, sorafenib, a multikinase inhibitor, is so far the only drug that has shown overall survival benefit in patients with advanced HCC.60 However, its cytostatic action does not result in size shrinkage in responding HCC, and its therapeutic effect is hence difficult to monitor by conventional anatomical imaging. Sorafenib acts by destroying tumour vascularity and inhibiting neovascularization. The end results may be reflected in changes in the perfusion fraction (f) of the ADC. A pilot study by Llovet et al.60 reported that although Dslow and overall ADC did not significant change between responders and nonresponders, a significant increase in f was noted in responders at 2 weeks and at 2 months, whereas a decrease in f was noted in non-responders at the same intervals.31 These results may be explained by the anti-angiogenic actions of sorafenib, which not only destroy tumoural vessels, but improve the basement membrane integrity of the remaining microvessels, leading to less “water leakage” from the perfusion pool.31 Bi-exponential analysis of ADC may be a potential method to assess sorafenib-induced responses.
Conclusions The high efficacy of DWI in diagnosing HCC in cirrhosis justifies its inclusion in routine MRI protocols for cirrhotic nodules. It has been shown to be a useful adjunct to contrast-enhanced sequences for this purpose. Restricted diffusivity at DWI should be advocated as a diagnostic criterion for HCC. However, the role of DWI in histological grading, staging, and prediction of treatment response, needs further evaluation. This should involve international standardization of b-values and imaging parameters. The potential values of bi-exponential analysis of ADC, which enables the study of both tumour perfusion and its cellular microenvironment, should also be explored in future works.
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
10
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
K.S. Lim / Clinical Radiology xxx (2013) 1e10 compared with dynamic contrast-enhanced MRI alone using receiver operating characteristic curve analysis. J Magn Reson Imaging 2009;29: 341e9. Sano K, Ichikawa T, Motosugi U, et al. Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 2011;261:834e44. Lee MH, Kim SH, Park MJ, et al. Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease. AJR Am J Roentgenol 2011;197: W868e75. Park MJ, Kim YK, Lee MW, et al. Small hepatocellular carcinomas: improved sensitivity by combining gadoxetic acid-enhanced and diffusion-weighted MR imaging patterns. Radiology 2012;264:761e70. Kim YK, Lee WJ, Park MJ, et al. Hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis: potential of DW imaging in predicting progression to hypervascular HCC. Radiology 2012;265:104e14. Le Bihan D, Breton E, Lallemand D, et al. MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. Radiology 1986;161:401e7. Le Bihan D, Breton E, Lallemand D, et al. Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology 1988;168:497e505. Yamada I, Aung W, Himeno Y, et al. Diffusion coefficients in abdominal organs and hepatic lesions: evaluation with intravoxel incoherent motion echo-planar MR imaging. Radiology 1999;210:617e23. Lewin M, Fartoux L, Vignaud A, et al. The diffusion-weighted imaging perfusion fraction f is a potential marker of sorafenib treatment in advanced hepatocellular carcinoma: a pilot study. Eur Radiol 2011;21: 281e90. Haratake J, Takeda S, Kasai T, et al. Predictable factors for estimating prognosis of patients after resection of hepatocellular carcinoma. Cancer 1993;72:1178e83. Lauwers GY, Terris B, Balis UJ, et al. Prognostic histologic indicators of curatively resected hepatocellular carcinomas: a multi-institutional analysis of 425 patients with definition of a histologic prognostic index. Am J Surg Pathol 2002;26:25e34. An C, Park MS, Jeon HM, et al. Prediction of the histopathological grade of hepatocellular carcinoma using qualitative diffusion-weighted, dynamic, and hepatobiliary phase MRI. Eur Radiol 2012;22:1701e8. Nishie A, Tajima T, Asayama Y, et al. Diagnostic performance of apparent diffusion coefficient for predicting histological grade of hepatocellular carcinoma. Eur J Radiol 2011;80:e29e33. Heo SH, Jeong YY, Shin SS, et al. Apparent diffusion coefficient value of diffusion-weighted imaging for hepatocellular carcinoma: correlation with the histologic differentiation and the expression of vascular endothelial growth factor. Korean J Radiol 2010;11:295e303. Nakanishi M, Chuma M, Hige S, et al. Relationship between diffusionweighted magnetic resonance imaging and histological tumor grading of hepatocellular carcinoma. Ann Surg Oncol 2012;19:1302e9. Salem R, Lewandowski R, Roberts C, et al. Use of yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis. J Vasc Interv Radiol 2004;15:335e45. Catalano OA, Choy G, Zhu A, et al. Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging. Radiology 2010;254:154e62. Yu JS, Chung JJ, Kim JH, et al. Limited value of diffusion-weighted MR imaging for differentiating bland from malignant portal venous thrombi. Radiology 2010;256:673e4 author reply 4.41.
41. Poon RT, Fan ST, Ng IO, et al. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer 2000;89:500e7. 42. Yu JS, Chung JJ, Kim JH, et al. Detection of small intrahepatic metastases of hepatocellular carcinomas using diffusion-weighted imaging: comparison with conventional dynamic MRI. Magn Reson Imaging 2011;7:985e92. 43. Ramsey DE, Kernagis LY, Soulen MC, et al. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 2002;13:S211e21. 44. Vossen JA, Buijs M, Kamel IR. Assessment of tumor response on MR imaging after locoregional therapy. Tech Vasc Interv Radiol 2006;9:125e32. 45. Hwang SH, Yu JS, Chung J, et al. Transient hepatic attenuation difference (THAD) following transcatheter arterial chemoembolization for hepatic malignancy: changes on serial CT examinations. Eur Radiol 2008;18: 1596e603. 46. Afaq A, Andreou A, Koh DM. Diffusion-weighted magnetic resonance imaging for tumour response assessment: why, when and how? Cancer Imaging 2010;10(Spec no A):S179e88. 47. Kamel IR, Bluemke DA, Eng J, et al. The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma. J Vasc Interv Radiol 2006;17:505e12. 48. Sahin H, Harman M, Cinar C, et al. Evaluation of treatment response of chemoembolization in hepatocellular carcinoma with diffusion-weighted imaging on 3.0-T MR imaging. J Vasc Interv Radiol 2012;23:241e7. 49. Kamel IR, Bluemke DA, Ramsey D, et al. Role of diffusion-weighted imaging in estimating tumor necrosis after chemoembolization of hepatocellular carcinoma. AJR Am J Roentgenol 2003;181:708e10. 50. Mannelli L, Kim S, Hajdu CH, et al. Assessment of tumor necrosis of hepatocellular carcinoma after chemoembolization: diffusion-weighted and contrast-enhanced MRI with histopathologic correlation of the explanted liver. AJR Am J Roentgenol 2009;193:1044e52. 51. Chen CY, Li CW, Kuo YT, et al. Early response of hepatocellular carcinoma to transcatheter arterial chemoembolization: choline levels and MR diffusion constantsdinitial experience. Radiology 2006;239:448e56. 52. Kamel IR, Liapi E, Reyes DK, et al. Unresectable hepatocellular carcinoma: serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging. Radiology 2009;250:466e73. 53. Goshima S, Kanematsu M, Kondo H, et al. Evaluating local hepatocellular carcinoma recurrence post-transcatheter arterial chemoembolization: is diffusion-weighted MRI reliable as an indicator? J Magn Reson Imaging 2008;27:834e9. 54. Yu JS, Kim JH, Chung JJ, et al. Added value of diffusion-weighted imaging in the MRI assessment of perilesional tumor recurrence after chemoembolization of hepatocellular carcinomas. J Magn Reson Imaging 2009;30:153e60. 55. Goin JE, Salem R, Carr BI, et al. Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a riskstratification analysis. J Vasc Interv Radiol 2005;16:195e203. 56. Al-Kalbani A, Kamel Y. Y-90 microshperes in the treatment of unresectable hepatocellular 1carcinoma. Saudi J Gastroenterol 2008;14:90e2. 57. Deng J, Miller FH, Rhee TK, et al. Diffusion-weighted MR imaging for determination of hepatocellular carcinoma response to yttrium-90 radioembolization. J Vasc Interv Radiol 2006;17:1195e200. 58. Rhee TK, Naik NK, Deng J, et al. Tumor response after yttrium-90 radioembolization for hepatocellular carcinoma: comparison of diffusionweighted functional MR imaging with anatomic MR imaging. J Vasc Interv Radiol 2008;19:1180e6. 59. Kamel IR, Reyes DK, Liapi E, et al. Functional MR imaging assessment of tumor response after 90Y microsphere treatment in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2007;18:49e56. 60. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378e90.
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
Contents lists available at SciVerse ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Review
Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis K.S. Lim* Department of Diagnostic Radiology, Tan Tock Seng Hospital, Jalan Tan Tock Seng, Singapore 308433, Singapore
art icl e i nformat ion Article history: Received 13 April 2013 Received in revised form 16 July 2013 Accepted 18 July 2013
The internationally accepted diagnostic criteria for hepatocellular carcinoma (HCC) in cirrhosis are highly accurate for large tumours, but offer relatively low sensitivity for small (<2 cm) tumours. Diffusion-weighted imaging (DWI) is a functional magnetic resonance imaging (MRI) technique that has been studied extensively as an aid to visualize various abdominal malignancies, including HCC in cirrhosis. DWI maps water diffusivity, which in HCC may be restricted as a result of changes ensuing from hepatocarcinogenesis. The present review is based on up-to-date evidence and describes the strengths and weaknesses of DWI, both as a standalone technique and as an adjunct sequence to conventional protocols, in the diagnosis, staging, prognostication, and assessment of treatment response of HCC in cirrhosis. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Radiological diagnosis of hepatocellular carcinoma (HCC) in cirrhosis is now so well-established that it obviates routine histological confirmation. Arterial enhancement followed by washout is considered a diagnostic feature of HCC >1 cm by the American Association for the Study of Liver Diseases (AASLD) and European Association for Study of Liver Diseases (EASL).1 Amongst other techniques, magnetic resonance imaging (MRI) has the highest accuracy in diagnosing cirrhotic HCC.2 However, the published efficacy in detecting early HCC has been less consistent, and the reported sensitivity of the described criteria for HCC 2 cm is as low as 30%.3e5 This is due to several reasons: early HCC may retain significant portal blood supply and does not show the “diagnostic” delayed washout.4 Approximately 17% of small HCC appear hypovascular at imaging6 (Fig 1). With improved MRI technology and field strength, small (<2 cm) flash-enhancing foci are increasingly seen in the cirrhotic liver, and only a proportion * Guarantor and correspondent: K.S. Lim, Department of Diagnostic Radiology, Tan Tock Seng Hospital, Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel.: þ65 97363598; fax: þ65 63578112. E-mail address: [email protected]
of these lesions represent HCC.7 The distorted texture of the cirrhotic liver also causes poor conspicuity for small HCC. In short, any endeavour to improve HCC diagnosis needs to interrogate other biological changes subsequent to hepatocarcinogenesis besides neovascularity. Diffusion-weighted imaging (DWI) is a functional MRI technique that has increasingly been used a cancer-imaging tool in clinical practice. Advances in MRI technology, particularly in gradient strength and parallel imaging, have greatly expanded the use of DWI in extra-cranial oncological imaging.8e10 The utility of DWI in detecting, characterizing, histological grading, and assessing treatment response in various abdominal malignancies has been extensively studied,8,9 and HCC is no exception. The present review describes the strengths and weaknesses of the use of DWI in the diagnosis, grading, staging, and assessment of treatment response of HCC in cirrhosis, in light of the available evidence, complemented with illustrative cases.
DWI DWI measures the diffusivity, or freedom of movement of water molecules, in a tissue by applying a pair of equal
0009-9260/$ e see front matter Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2013.07.022
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
2
K.S. Lim / Clinical Radiology xxx (2013) 1e10
Figure 1 A 58-year-old man undergoing MRI surveillance for right lobe HCC treated with RFA. (a) Contrast-enhanced arterial-phase image shows a hypovascular nodule in the lateral segment (arrow). (b) DWI (b ¼ 1000) image shows the lesion to be hyperintense (arrow) in keeping with a malignant focus. Subsequent biopsy confirmed HCC.
and symmetrical gradients about the 180 refocusing pulse in a T2 echoplanar spin-echo sequence. Immobile water molecules in the tissue experience a phase drift from the first gradient (dephasing), which is cancelled out by the second gradient (rephasing). Conversely, mobile water molecules do not undergo significant rephasing by the second gradient due to location change between the gradients. The net dephasing causes a T2 signal loss, the magnitude of which is proportional to the diffusivity of the tissue.11 The sensitivity of DWI in differentiating tissues of different diffusivities, its diffusion weighting, depends on the magnitudes of the bipolar gradients, which can be increased by increasing the b-value (expressed in s/mm2) on the MRI machine. Tissue with relatively restricted diffusivity typically appears T2 hyperintense on high b-value DWI images, whereas that with relatively free diffusivity loses most of its signal on these images. The diffusivity of a tissue may be quantitatively expressed as an apparent diffusion coefficient (ADC) value, which equates to the gradient of the straight line superimposed on the graph of the logarithm of relative signal intensity (y-axis) against increasing b-values (x-axis). The more restricted the diffusivity of a tissue, the lower its ADC value.
HCC in cirrhosis and DWI Cirrhotic liver is composed of regenerative nodules supported by bridging fibrous septa. A tiny proportion of the nodules undergo dysplasiaeneoplasia transformation
to eventually become HCC.12,13 In this multistep pathway of hepatocarcinogenesis and the subsequent tumour dedifferentiation, there is increasing cellular and structural atypia, typified by increasing cellular density, nuclear-tocytoplasmic ratio, intracellular organelles, and thickening of cellular plates.12 These changes, together with the resultant shrinkage of the extracellular space, should progressively impede movement of water molecules, i.e., restrict diffusivity. Therefore, diffusivity of a cirrhotic nodule may be used as a surrogate marker for its malignant potential and degree of subsequent dedifferentiation. In contrast, benign nodules usually present a similar microstructure and hence water diffusivity to the surrounding cirrhotic parenchyma.12 Moreover, most anti-HCC therapies induce tumour necrosis, which is characterized by cell death and impaired membrane integrity, with the resultant increase in diffusivity. Therefore, DWI may be useful in detecting HCC amongst benign nodules, predicting the histological grade, and assessing its response to treatment.
Visibility of HCC in cirrhosis at DWI As a malignant lesion, HCC in cirrhosis typically appears hyperintense at DWI. In reality, the visibility and signal intensity of HCC at DWI is the product of complex interplay between various biological and technical factors. These are often compounded by overlaps in the biological properties of HCC and those of benign cirrhotic lesions and background cirrhotic parenchyma, which govern water diffusivity.
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
3
Figure 2 A 56-year-old man with hepatitis B was found to have a mass in the right lobe at ultrasound surveillance. (a) Left. Contrast-enhanced arterial-phase image shows a subcapsular mass with avid enhancement in the posterior segment (arrow). Right. Contrast-enhanced equilibriumphase image shows contrast medium washout from the lesion (arrow), in keeping with HCC. (b) Left. DWI (b ¼ 1000) image shows the lesion to be iso-intense (arrow). Right. The corresponding ADC map does not reveal significant restriction to diffusivity (arrow). Histology after surgical resection revealed well-differentiated HCC.
b-Value Low b-values of 50e100 are routinely employed in hepatic DWI to produce “dark-blood” images as fast-moving
water molecules in blood and duct vessels are dephased rapidly at these values, rendering these structures DWI invisible, and increasing the conspicuity of small T2 hyperintense lesions close to these structures. This is a
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
4
K.S. Lim / Clinical Radiology xxx (2013) 1e10
unique advantage of DWI, as these structures are usually visible on morphological images and may obscure nearby small tumours. Using a b-value of 50, Parikh et al.14 reported that approximately 80% of HCC appear hyperintense at DWI. Using a b-value of 100 with a 3 T MRI system, Kim et al.15 reported that 73% of HCC <1 cm were hyperintense at DWI. Despite using a higher b value of 500, Piana et al.4 reported that 72e82% of HCC remained hyperintense at DWI, including 64e74% of tumours that were <2 cm. Using the same b-value, Nasu et al.16 and Xu et al.17 reported much higher sensitivities of >90%, although this may be due to the generally larger lesions included in their studies. Using a bvalue of 1000, Muhi et al.18 reported that 72% HCC were hyperintense at DWI. The relatively low detection rate was compensated for by the extremely high specificity, as none of the included dysplastic nodules appeared hyperintense at DWI.18 Similarly, Motosugi et al.,19 using the same b-value, reported that although only 67% of HCC were hyperintense at DWI, no arterially enhancing pseudolesions were visible at DWI. Hence, high b-values offer excellent specificity in distinguishing HCC amongst benign cirrhotic lesions and arterially enhancing pseudolesions, at the expense of slightly lower sensitivity. The relatively low HCC detection rate with higher b-values is, in part, due to the poor signal-to-noise ratio of these images, caused by the resultant long TE (time to echo) on echoplanar sequences. As yet, there is no consensus on the optimal b-value for diagnosing HCC in cirrhosis. Vandecaveye et al.20 reported that a b-value of 600 offered the best performance (sensitivity: 91.2%, specificity: 81.8%) amongst b-values of 300, 600, and 1000, in differentiating well-differentiated HCC from benign cirrhotic nodules. However, the relatively high performance of DWI reported in this study may be attributable, in part, to the inclusion of a small number of highgrade dysplastic nodules in the HCC group.
Histological grade As hepatocarcinogenesis and subsequent tumour dedifferentiation are different parts of a continuous process, HCC in cirrhosis is best considered as a heterogeneous group of lesions in terms of diffusivity; therefore, the visibility of lesions at DWI depends on their position along this pathway. Nasu et al.16 (b ¼ 500) reported a general trend of increasing DWI hyperintensity, albeit with large overlaps, with increasing tumour dedifferentiation. Muhi et al.18 (b ¼ 500, 1000) noted >90% of moderately and poorly differentiated HCCs, including all iso-hypovascular lesions, were visible at DWI, whereas 51% of well-differentiated HCCs and all dysplastic nodules were DWI invisible (Fig 3).
Background liver The micro-architecture of the background cirrhotic liver may also influence DWI visibility of HCC lesions. The increased conspicuity of HCC on DWI echo-planar images may be associated with iron deposition, causing resultant T2* shortening and subsequent darkening of the background liver.14 This was postulated to be the reason for the
superiority of low b-value DWI compared to conventional T2-weighted sequences for HCC detection.14 However, cirrhotic parenchyma itself also shows restricted diffusivity, presumably owing to the abundance of fibrotic tissue,21 which results in reduced HCC conspicuity at DWI. This may explain why the efficacy of DWI in diagnosing HCC decreases with increasing severity of background cirrhosis.22
DWI and morphological sequences The efficacy of DWI for detecting HCC in cirrhosis has been studied in conjunction with conventional morphological techniques. The internationally accepted morphological criteria, i.e., arterial enhancement and delayed washout, in differentiating HCC from benign cirrhotic nodules, are biomarkers of tumour neovascularization. Conversely, DWI demonstrates tumour cellularity. On comparing the two techniques to diagnose HCC 2 cm, Vandecaveye et al.20 reported sensitivity and specificity values of 91.2% and 82.9% for DWI (b ¼ 600), and 67.6% and 61% for morphological imaging. However, the diagnostic performances of these techniques were not significantly different for HCC >2 cm. These results suggest that DWI can potentially be used as an alternative in those cases where gadolinium contrast medium is contraindicated. As most patients tolerate gadolinium contrast medium, the two techniques are used in combination in clinical practice. Piana et al.4 (b ¼ 500) reported that the addition of hyperintensity at DWI as a diagnostic criterion for HCC improved the sensitivity of conventional MRI from 59.6% (30% for HCC <2 cm) to approximately 85%. Using the same b-value, Xu et al.23 reported improved sensitivity of 98% when using combined DWI and morphological imaging to detect HCC <2 cm from approximately 83e85% when using morphological imaging alone. The results suggest that DWI may potentially improve the detection rate of morphological sequences for HCC in cirrhosis. Gadoxetic acid is a hepatocyte-specific gadoliniumbased contrast agent that is used to detect and characterize liver lesions at both dynamic and hepatobiliary imaging. Hypointensity on the gadoxetic acid-enhanced hepatobiliary (GA-HP) phase indicates the absence of hepatocytes and has been reported to be accurate in distinguishing HCC from the normally hepatocyte-containing benign cirrhotic lesions.24 In two reports, hyperintensity at DWI was shown to be more specific than hypointensity on GAHP images in diagnosing small HCC,15,25 with comparable sensitivity. Motosugi et al.19 (b ¼ 500, 100) reported that 15% (16 out of 104) of arterially enhancing pseudolesions were hypointense on GA-HP images, but none were visible at DWI (Fig 2). Based on the evidence presented so far, the ideal MRI protocol for diagnosing HCC in cirrhosis should include gadoxetic acid enhanced dynamic and hepatobiliary phases, and DWI. Dynamic images detect neovascularity, GA-HP images confirm the absence of hepatocytes, and DWI depicts hypercellularity; the three biological hallmarks of HCC over benign cirrhotic nodules. This protocol has been reported to improve the diagnostic accuracy of either gadoxetic acid-enhanced or DWI sequences alone, as DWI
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
5
Figure 3 A 62-year-old woman with cirrhosis was found to have a new hypoechoic nodule in the lateral segment at routine sonographic surveillance. (a) T2-weighted fat-saturated image shows the same nodule to be hyperintense (arrow). (b) DWI (b ¼ 1000) image shows the lesion to be hyperintense (arrow), suspicious for a malignant focus. Contrast-enhanced images (not shown) did not reveal any hypervascularity. The patient opted for close surveillance, and the lesion appeared stable for the ensuing 2 years, presumably a benign cirrhotic nodule.
hyperintensity has been shown to increase the probability of HCC in cirrhotic nodules that have isolated findings of either arterial enhancement or hypointensity on GA-HP images.26 DWI hyperintensity has also been reported to reliably predict the progression of hypovascular cirrhotic nodules, which are hypointense on GA-HP images.27 A tiny proportion of benign cirrhotic nodules may also appear DWI hyperintense15,20 (Fig 4). The precise reason for this is not known, but cell swelling (from cytotoxic oedema) and increased T2 relaxation times due to infarction are possible explanations. Distinguishing this group of benign lesions from hypovascular HCC is difficult. Therefore, all DWI hyperintense cirrhotic lesions with benign morphological findings should be closely monitored.
Quantitative analysis Quantification of diffusivity in terms of ADC value may potentially offer a more accurate and objective way of differentiating HCC from benign cirrhotic nodules. In practice, ADC measurement suffers from poor inter- and intraoperator consistency in drawing the region of interest (ROI) on the ADC map. Accurate and reproducible ADC requires the use of multiple (to produce the best-fit line on the ADC graph) consistent b-values and identical imaging parameters, all of which currently lack international standardization. Perhaps most importantly, accurate and reproducible ADC requires a more complex analytical method. The overall diffusivity within a DWI image voxel, according to the theory
of intravoxel incoherent motion (IVIM), is the sum total of water motion in extravascular (intra- and extracellular) and intravascular spaces.28,29 The intravascular water molecules, due to fast flowing blood, dephase rapidly even at low bvalues compared with those in extravascular spaces. Hence, the signal of a lesion decreases rapidly in the initial increase in b-values, dependent on lesion vascularity, and then gradually as the b-value increases further, dependent on lesion cellularity. In other words, the signal loss with increasing b-values is a bi-exponential process, with a fast perfusion (Dfast) followed by a slow diffusion (Dslow) component. This is potentially relevant in imaging cirrhotic nodules as some studies have reported that the ADCslow of HCC was not significantly different from the background liver, whereas its perfusion fraction (f) was significantly lower than the background liver.30,31 This may be explained by “faulty” angiogenesis, which produces microvessels with leaky basement membranes and poor pericyst coverage, leading to a reduction of the “pool” of intravascular water molecules.31 Moreover, antiHCC therapies, such as chemoembolization and antiangiogenic drugs, which act by altering tumour vascularity, may affect Dfast more than Dslow,31 and measuring their effectiveness may necessitate bi-exponential analysis of diffusivity.
Staging and prognostication The management and prognosis of HCC in terms of survival and recurrence rate depend on the size of the lesion and the presence of vascular invasion, intrahepatic metastases, and degree of dedifferentiation.32 Accurate assessment of
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
6
K.S. Lim / Clinical Radiology xxx (2013) 1e10
with well and moderately differentiated HCC after curative treatment.33 Poorly differentiated HCC necessitates wider surgical clearance margins and closer post-treatment surveillance. Preoperative prediction of tumour grade is hence pivotal to treatment planning and prognostication. The histopathological grade of a malignant tumour usually depends on its cellular and structural atypia.12 The increasing cellular density, nuclear-to-cytoplasmic ratio, and architectural complexity accompanying dedifferentiation may cause progressively restricted diffusivity. An et al.34 reported that the combined absence of DWI hyperintensity and arterial enhancement carried a 100% positive predictive value in distinguishing welldifferentiated HCC from those of higher grades. However, the graded nature of dedifferentiation necessitates a more quantitative approach to diffusivity measurement, and therefore, most studies used ADC measurement rather than visual analysis. At least two studies did not report any correlation between tumour grade and ADC.4,16 Both of these two groups used a single b-value of 500 and measured the ADC by drawing a ROI over the entire lesion irrespective of lesion heterogeneity. Using b-values of 500 and 1000, Muhi et al.18 reported that mean ADC values of moderately or poorly differentiated HCCs were significantly lower than well-differentiated HCCs or dysplastic nodules. Using different methods of avoiding necrotic areas in the tumours when drawing the ROI, at least three studies have reported significant correlation between ADC values and histological grade of HCC.35e37 This is presumably because as a malignant tumour dedifferentiates to a higher grade, the increasing oxygen tension leads to progressive intratumoural necrosis, producing foci of reduced cell density and increased membrane permeability. The resultant increased water diffusivity in the necrotic areas may hence, paradoxically, increase the mean ADC of the entire lesion.
Vascular invasion
Figure 4 A 72-year-old woman with cirrhosis and raised alphafetoprotein (AFP) level. (a) Contrast-enhanced arterial-phase image shows a heterogeneous mass in the right lobe (arrow) extending into the expanded right portal vein (star). Enlarged nodes are also noted in the liver hilum (bullet). (b) DWI (b ¼ 1000) image shows the mass (arrow) and the involved right portal vein (star) to be hyperintense and of identical intensity at DWI. The portal vein nodes (bullet) also appear similarly DWI hyperintense. Findings are suggestive of infiltrative HCC invading the portal vein with, most probably, regional adenopathy. The primary tumour was histologically confirmed.
these factors is a fundamental role of imaging after HCC has been detected. The potential value of DWI in these functions has also been studied.
Histological grading The survival of patients with poorly differentiated HCC was reported to be significantly worse than that of patients
Tumour involvement of the portal vein effectively precludes most treatment options for HCC except systemic therapy and possibly radioembolization.38 Its diagnosis is hampered by the presence of frequent bland thrombus in the cirrhotic liver. Catalano et al.39 reported that 15 out of 18 malignant thrombi in their study were isointense with the primary tumours at DWI, whereas all bland thrombi were DWI hypointense (Fig 5). However, as blood products can show variable T2 prolongation and water diffusivity, falsepositive cases are not infrequently encountered.40 DWI is likely to play only a limited role in distinguishing malignant from bland thrombi.
Intrahepatic metastases The presence of small satellite HCC, i.e., intrahepatic metastases, is an important determinant of a patient’s prognosis and therapeutic approach, and these lesions require immediate and accurate diagnosis. Without immediate curative or palliative therapy, intrahepatic metastases show aggressive behaviour, unlike single or multicentric primary tumours of
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
small size.41 The high diagnostic accuracy of DWI over conventional MRI sequences in detecting small HCC discussed earlier may be assumed to be applicable to small intrahepatic metastases (Fig 6). Yu et al. reported that DWI detected significantly more HCC metastases of 1 cm than contrastenhanced images, although not for those >1 cm.42
7
Prediction of treatment response The advent of locoregional therapies, such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and radioembolization, have contributed significantly to the control of some unresectable but localized tumours.43 As
Figure 5 A 64-year-old man with cirrhosis and HCC nodules in the posterior sector treated with RFA. (a) Top. DWI (b ¼ 1000) image revealed one of the ablated nodules (bullet). There is also a tiny hyperintense nodule adjacent to the ablated nodule (arrow). Bottom. A slightly more inferior DWI (b ¼ 1000) image reveals another tiny hyperintense nodule in posterior sector (arrows).The ablated nodule is again seen (bullet). (b) Corresponding contrast-enhanced arterial phase images through the same region do not reveal the DWI visible nodules. (c) Contrastenhanced arterial phase subtraction images 3 months later reveal two rim-enhancing nodules (arrows) corresponding to the DWI hyperintense nodules seen at the previous MRI examination, with interval enlargement, in keeping with metastases. Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
8
K.S. Lim / Clinical Radiology xxx (2013) 1e10
these therapies may be repeated and interchangeably applied in cases of residual or recurrent disease, accurate early assessment of treatment response is vital to direct management. Response Evaluation Criteria In Solid Tumors (RECIST) criteria have conventionally been used to measure therapeutic response in solid malignancies, but these criteria rely on changes in lesion size. They are not applicable to HCC as locoregional therapies aim to achieve tumour necrosis, rather than tumour shrinkage or disappearance. In 2000, the EASL proposed to evaluate response to locoregional treatment by assessing the decrease in viable tumour volume, seen as a decrease in contrast-enhancing areas.1 However, differentiation of viable tumour tissue from other treatment-induced changes, such as inflammation, granulation tissue,44 and vascular injuries,45 is not always easy, as these non-tumoural changes can show contrast enhancement. DWI may have a potential role in the differentiation of viable tumour from treatment-induced necrosis and other misleading changes, and has been used to assess treatment response in other malignancies.46 In theory, viable tumours are highly cellular with intact cell membranes, causing diffusivity restriction. Conversely, treatment-induced necrotic and inflammatory tissues cause reduced cellular density and increased membrane permeability, enabling relatively free diffusion of water molecules.
TACE A significant increase in the mean ADC with corresponding reduction in tumour enhancement has been
reported in post-TACE HCC.47,48 An increase in ADC values with increasing tumour necrosis has also been demonstrated in a small group of post-TACE HCC, with pathological correlation.49 Mannelli et al.50 reported that although a decrease in the contrast-enhanced area on subtraction images had more significant correlation with the histopathological findings than an increase in ADC in the evaluation of HCC necrosis after TACE, there was no difference between the two methods in diagnosis of complete tumour necrosis. Although the above reports generally based their results on ADC values at 4e6 weeks after TACE, ADC increase has been reported as early as 3 days after TACE.51 Kamel et al.52 (b ¼ 500) reported that the increase in tumour ADC value was most significant at 1e2 weeks after TACE, and insignificant at 24 h and at 4 weeks after therapy.52 These two studies, however, did not attempt to uncover a relationship between these ADC changes and treatment response. Although quantitative analysis of diffusivity appears potentially to be of value in assessing response to TACE, visual analysis appears less promising for this function. Goshima et al.53 reported that DWI was significantly less sensitive than contrast-enhanced images in detecting local residual/recurrent tumour post-TACE, whereas Yu et al.54 reported that the addition of DWI to contrastenhanced images reduced specificity and diagnostic accuracy of the latter, in detecting perilesional recurrence. They postulated that false positives at DWI may be attributable to hypercellular granulation tissue and fibrotic tissue.
Figure 6 A 46-year-old woman with cirrhosis and right lobe HCC treated with TACE. (a) Contrast-enhanced arterial-phase image shows a hypointense focus in keeping with the chemoembolized tumour. There is a semi-circumferential iso-vascular soft-tissue rim (arrow) noted. (b) DWI (b ¼ 1000) image shows the rim of the soft tissue to be strongly hyperintense (arrow), suggestive of recurrent tumour. Subsequent biopsy confirmed perilesional recurrence. Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
K.S. Lim / Clinical Radiology xxx (2013) 1e10
9
RFA
References
As yet, no study specifically studying the efficacy of DWI in detecting post-RFA residual/recurrent disease has been published in the English literature.
1. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421e30. 2. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 2006;101:513e23. 3. Kelekis NL, Semelka RC, Worawattanakul S, et al. Hepatocellular carcinoma in North America: a multiinstitutional study of appearance on T1weighted, T2-weighted, and serial gadolinium-enhanced gradient-echo images. AJR Am J Roentgenol 1998;170:1005e13. 4. Piana G, Trinquart L, Meskine N, et al. New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases. J Hepatol 2011;55:126e32. 5. Forner A, Vilana R, Ayuso C, 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. 6. Bolondi L, Gaiani S, Celli N, et al. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology 2005;42:27e34. 7. Holland AE, Hecht EM, Hahn WY, et al. Importance of small (< or ¼ 20mm) enhancing lesions seen only during the hepatic arterial phase at MR imaging of the cirrhotic liver: evaluation and comparison with whole explanted liver. Radiology 2005;237:938e44. 8. Lim KS, Tan CH. Diffusion-weighted MRI of adult male pelvic cancers. Clin Radiol 2012;67:899e908. 9. Koh DM, Collins DJ. Diffusion-weighted MRI in the body: applications and challenges in oncology. AJR Am J Roentgenol 2007;188:1622e35. 10. Taouli B, Koh DM. Diffusion-weighted MR imaging of the liver. Radiology 2010;254:47e66. 11. Koh DM, Takahara T, Imai Y, Collins DJ. Practical aspects of assessing tumors using clinical diffusion-weighted imaging in the body. Magn Reson Med Sci 2007;6:211e24. 12. Coleman WB. Mechanisms of human hepatocarcinogenesis. Curr Mol Med 2003;3:573e88. 13. Efremidis SC, Hytiroglou P. The multistep process of hepatocarcinogenesis in cirrhosis with imaging correlation. Eur Radiol 2002;12:753e64. 14. Parikh T, Drew SJ, Lee VS, et al. Focal liver lesion detection and characterization with diffusion-weighted MR imaging: comparison with standard breath-hold T2-weighted imaging. Radiology 2008;246:812e22. 15. Kim JE, Kim SH, Lee SJ, et al. Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver disease: characterization with gadoxetic acid-enhanced MRI that includes diffusion-weighted imaging. AJR Am J Roentgenol 2011;196:W758e65. 16. Nasu K, Kuroki Y, Tsukamoto T, et al. Diffusion-weighted imaging of surgically resected hepatocellular carcinoma: imaging characteristics and relationship among signal intensity, apparent diffusion coefficient, and histopathologic grade. AJR Am J Roentgenol 2009;193:438e44. 17. Xu PJ, Yan FH, Wang JH, et al. Contribution of diffusion-weighted magnetic resonance imaging in the characterization of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver. J Comput Assist Tomogr 2010;34:506e12. 18. Muhi A, Ichikawa T, Motosugi U, et al. High-b-value diffusion-weighted MR imaging of hepatocellular lesions: estimation of grade of malignancy of hepatocellular carcinoma. J Magn Reson Imaging 2009;30:1005e11. 19. Motosugi U, Ichikawa T, Sou H, et al. Distinguishing hypervascular pseudolesions of the liver from hypervascular hepatocellular carcinomas with gadoxetic acid-enhanced MR imaging. Radiology 2010;256:151e8. 20. Vandecaveye V, De Keyzer F, Verslype C, et al. Diffusion-weighted MRI provides additional value to conventional dynamic contrast-enhanced MRI for detection of hepatocellular carcinoma. Eur Radiol 2009;19: 2456e66. 21. Taouli B, Tolia AJ, Losada M, et al. Diffusion-weighted MRI for quantification of liver fibrosis: preliminary experience. AJR Am J Roentgenol 2007;189:799e806. 22. Kim AY, Kim YK, Lee MW, et al. Detection of hepatocellular carcinoma in gadoxetic acid-enhanced MRI and diffusion-weighted MRI with respect to the severity of liver cirrhosis. Acta Radiol 2012;53:830e8. 23. Xu PJ, Yan FH, Wang JH, et al. Added value of breathhold diffusionweighted MRI in detection of small hepatocellular carcinoma lesions
Radioembolization Catheter-directed intra-arterial administration of yttrium-90 aims to deliver a high radiation dose to targeted HCC, sparing the uninvolved liver parenchyma. This form of targeted beta radiation therapy for HCC has been shown to be relatively safe in patients with cirrhosis.38,55,56 Although a small study reported a 60% increase in the mean ADC after radioembolization,57 two other studies reported more modest ADC increases of approximately 10e20% posttreatment,58,59 with a corresponding decrease in the contrast enhancement59 or subsequent lesion shrinkage.58 These studies show the potential value of DWI in predicting response to radioembolization.
Systematic systemic therapy The anti-angiogenic drug, sorafenib, a multikinase inhibitor, is so far the only drug that has shown overall survival benefit in patients with advanced HCC.60 However, its cytostatic action does not result in size shrinkage in responding HCC, and its therapeutic effect is hence difficult to monitor by conventional anatomical imaging. Sorafenib acts by destroying tumour vascularity and inhibiting neovascularization. The end results may be reflected in changes in the perfusion fraction (f) of the ADC. A pilot study by Llovet et al.60 reported that although Dslow and overall ADC did not significant change between responders and nonresponders, a significant increase in f was noted in responders at 2 weeks and at 2 months, whereas a decrease in f was noted in non-responders at the same intervals.31 These results may be explained by the anti-angiogenic actions of sorafenib, which not only destroy tumoural vessels, but improve the basement membrane integrity of the remaining microvessels, leading to less “water leakage” from the perfusion pool.31 Bi-exponential analysis of ADC may be a potential method to assess sorafenib-induced responses.
Conclusions The high efficacy of DWI in diagnosing HCC in cirrhosis justifies its inclusion in routine MRI protocols for cirrhotic nodules. It has been shown to be a useful adjunct to contrast-enhanced sequences for this purpose. Restricted diffusivity at DWI should be advocated as a diagnostic criterion for HCC. However, the role of DWI in histological grading, staging, and prediction of treatment response, needs further evaluation. This should involve international standardization of b-values and imaging parameters. The potential values of bi-exponential analysis of ADC, which enables the study of both tumour perfusion and its cellular microenvironment, should also be explored in future works.
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022
10
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
K.S. Lim / Clinical Radiology xxx (2013) 1e10 compared with dynamic contrast-enhanced MRI alone using receiver operating characteristic curve analysis. J Magn Reson Imaging 2009;29: 341e9. Sano K, Ichikawa T, Motosugi U, et al. Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 2011;261:834e44. Lee MH, Kim SH, Park MJ, et al. Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease. AJR Am J Roentgenol 2011;197: W868e75. Park MJ, Kim YK, Lee MW, et al. Small hepatocellular carcinomas: improved sensitivity by combining gadoxetic acid-enhanced and diffusion-weighted MR imaging patterns. Radiology 2012;264:761e70. Kim YK, Lee WJ, Park MJ, et al. Hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis: potential of DW imaging in predicting progression to hypervascular HCC. Radiology 2012;265:104e14. Le Bihan D, Breton E, Lallemand D, et al. MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. Radiology 1986;161:401e7. Le Bihan D, Breton E, Lallemand D, et al. Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology 1988;168:497e505. Yamada I, Aung W, Himeno Y, et al. Diffusion coefficients in abdominal organs and hepatic lesions: evaluation with intravoxel incoherent motion echo-planar MR imaging. Radiology 1999;210:617e23. Lewin M, Fartoux L, Vignaud A, et al. The diffusion-weighted imaging perfusion fraction f is a potential marker of sorafenib treatment in advanced hepatocellular carcinoma: a pilot study. Eur Radiol 2011;21: 281e90. Haratake J, Takeda S, Kasai T, et al. Predictable factors for estimating prognosis of patients after resection of hepatocellular carcinoma. Cancer 1993;72:1178e83. Lauwers GY, Terris B, Balis UJ, et al. Prognostic histologic indicators of curatively resected hepatocellular carcinomas: a multi-institutional analysis of 425 patients with definition of a histologic prognostic index. Am J Surg Pathol 2002;26:25e34. An C, Park MS, Jeon HM, et al. Prediction of the histopathological grade of hepatocellular carcinoma using qualitative diffusion-weighted, dynamic, and hepatobiliary phase MRI. Eur Radiol 2012;22:1701e8. Nishie A, Tajima T, Asayama Y, et al. Diagnostic performance of apparent diffusion coefficient for predicting histological grade of hepatocellular carcinoma. Eur J Radiol 2011;80:e29e33. Heo SH, Jeong YY, Shin SS, et al. Apparent diffusion coefficient value of diffusion-weighted imaging for hepatocellular carcinoma: correlation with the histologic differentiation and the expression of vascular endothelial growth factor. Korean J Radiol 2010;11:295e303. Nakanishi M, Chuma M, Hige S, et al. Relationship between diffusionweighted magnetic resonance imaging and histological tumor grading of hepatocellular carcinoma. Ann Surg Oncol 2012;19:1302e9. Salem R, Lewandowski R, Roberts C, et al. Use of yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis. J Vasc Interv Radiol 2004;15:335e45. Catalano OA, Choy G, Zhu A, et al. Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging. Radiology 2010;254:154e62. Yu JS, Chung JJ, Kim JH, et al. Limited value of diffusion-weighted MR imaging for differentiating bland from malignant portal venous thrombi. Radiology 2010;256:673e4 author reply 4.41.
41. Poon RT, Fan ST, Ng IO, et al. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer 2000;89:500e7. 42. Yu JS, Chung JJ, Kim JH, et al. Detection of small intrahepatic metastases of hepatocellular carcinomas using diffusion-weighted imaging: comparison with conventional dynamic MRI. Magn Reson Imaging 2011;7:985e92. 43. Ramsey DE, Kernagis LY, Soulen MC, et al. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 2002;13:S211e21. 44. Vossen JA, Buijs M, Kamel IR. Assessment of tumor response on MR imaging after locoregional therapy. Tech Vasc Interv Radiol 2006;9:125e32. 45. Hwang SH, Yu JS, Chung J, et al. Transient hepatic attenuation difference (THAD) following transcatheter arterial chemoembolization for hepatic malignancy: changes on serial CT examinations. Eur Radiol 2008;18: 1596e603. 46. Afaq A, Andreou A, Koh DM. Diffusion-weighted magnetic resonance imaging for tumour response assessment: why, when and how? Cancer Imaging 2010;10(Spec no A):S179e88. 47. Kamel IR, Bluemke DA, Eng J, et al. The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma. J Vasc Interv Radiol 2006;17:505e12. 48. Sahin H, Harman M, Cinar C, et al. Evaluation of treatment response of chemoembolization in hepatocellular carcinoma with diffusion-weighted imaging on 3.0-T MR imaging. J Vasc Interv Radiol 2012;23:241e7. 49. Kamel IR, Bluemke DA, Ramsey D, et al. Role of diffusion-weighted imaging in estimating tumor necrosis after chemoembolization of hepatocellular carcinoma. AJR Am J Roentgenol 2003;181:708e10. 50. Mannelli L, Kim S, Hajdu CH, et al. Assessment of tumor necrosis of hepatocellular carcinoma after chemoembolization: diffusion-weighted and contrast-enhanced MRI with histopathologic correlation of the explanted liver. AJR Am J Roentgenol 2009;193:1044e52. 51. Chen CY, Li CW, Kuo YT, et al. Early response of hepatocellular carcinoma to transcatheter arterial chemoembolization: choline levels and MR diffusion constantsdinitial experience. Radiology 2006;239:448e56. 52. Kamel IR, Liapi E, Reyes DK, et al. Unresectable hepatocellular carcinoma: serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging. Radiology 2009;250:466e73. 53. Goshima S, Kanematsu M, Kondo H, et al. Evaluating local hepatocellular carcinoma recurrence post-transcatheter arterial chemoembolization: is diffusion-weighted MRI reliable as an indicator? J Magn Reson Imaging 2008;27:834e9. 54. Yu JS, Kim JH, Chung JJ, et al. Added value of diffusion-weighted imaging in the MRI assessment of perilesional tumor recurrence after chemoembolization of hepatocellular carcinomas. J Magn Reson Imaging 2009;30:153e60. 55. Goin JE, Salem R, Carr BI, et al. Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a riskstratification analysis. J Vasc Interv Radiol 2005;16:195e203. 56. Al-Kalbani A, Kamel Y. Y-90 microshperes in the treatment of unresectable hepatocellular 1carcinoma. Saudi J Gastroenterol 2008;14:90e2. 57. Deng J, Miller FH, Rhee TK, et al. Diffusion-weighted MR imaging for determination of hepatocellular carcinoma response to yttrium-90 radioembolization. J Vasc Interv Radiol 2006;17:1195e200. 58. Rhee TK, Naik NK, Deng J, et al. Tumor response after yttrium-90 radioembolization for hepatocellular carcinoma: comparison of diffusionweighted functional MR imaging with anatomic MR imaging. J Vasc Interv Radiol 2008;19:1180e6. 59. Kamel IR, Reyes DK, Liapi E, et al. Functional MR imaging assessment of tumor response after 90Y microsphere treatment in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2007;18:49e56. 60. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378e90.
Please cite this article in press as: Lim KS, Diffusion-weighted MRI of hepatocellular carcinoma in cirrhosis, Clinical Radiology (2013), http:// dx.doi.org/10.1016/j.crad.2013.07.022