HCC screening: assessment of an abbreviated non-contrast MRI protocol

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Globally, it is the fifth most common cancer and the third most common cause of cancer-related mortality as determined by the World Health Organization [1]. Curative treatments are only available when detected at an early stage, where the 5-year survival is 50–70%. In contrast, patients presenting with advanced HCC are only eligible for palliative treatments and have a poor outcome with a median survival of less than 1 year [2, 3]. Therefore, early detection of HCC is crucial in increasing survival, but currently, only four in ten hepatocellular carcinomas are detected at an early stage [4].

Multiple international practice guidelines recommend screening for HCC [5‐13]. All recommend screening with ultrasound (generally 6 monthly) for high-risk groups, including all patients with cirrhosis and some non-cirrhotic patients positive for hepatitis B virus (HBV) infection (Table 1). Cirrhosis is the most significant risk factor for HCC, with 85–95% prevalence amongst HCC patients. As a consequence, in patients with cirrhosis, early detection by screening is crucial [8‐10]. Some guidelines suggest alpha-fetoprotein (AFP) or other additional biomarkers as an adjunct to imaging even though the evidence is not so strong for smaller HCC [8, 11, 13, 14] Three guidelines based in the Asia-Pacific region do suggest co-screening with AFP [8]. All guidelines recommend further evaluation with multiphase computed tomography (CT) or magnetic resonance imaging (MRI) for patients with a positive screening test [5, 6, 8‐13] (Table 1). The impact of ultrasound with AFP for HCC screening was demonstrated in 2004 by Zhang et al. [15] with a large randomised controlled trial that yielded a significant decrease in mortality in a Chinese population with a high prevalence of HBV.

Meta-analyses have demonstrated an overall wide pooled per-patient sensitivity of 61–94% for ultrasound only, improved to 69–97% for ultrasound with AFP [2, 4, 16, 17]. In the meta-analysis by Hanna et al. [17], the pooled per-lesion sensitivity of ultrasound only is 59.3% (CI 51.3–67.1%). Only two meta-analyses demonstrated a negative likelihood ratio of 0.50–0.51, suggesting a low diagnostic power to exclude HCC [4, 16].

Although ultrasound has improved in recent years, it has visualisation limitations in patients with obesity, steatosis and advanced fibrosis or cirrhosis [7, 9, 17]. Unfortunately, these factors have all been associated with an increased risk of HCC [18‐21]. Hence, HCC screening with ultrasound alone remains even more challenging in those with those risk factors [8, 19, 20]. The worldwide prevalence of non-alcoholic fatty liver disease is approximately 25% and is likely to continue to rise, supporting the need for an alternative screening option in this high-risk group [18, 21].

Limitations in ultrasound lesion visualisation, ranging from minimal (score A) to intermediate (score B) and to severe (score C), are currently addressed in the Liver Imaging Reporting and Data System (LI-RADS) [7] (Fig. 1). Data comparing visualisation score outcomes are lacking [7]. Lower sensitivity in ultrasound screening in patients with non-alcoholic steato-hepatitis when compared to other aetiologies and to cross-sectional imaging has been reported, for instance, by Samoylova et al. [22].

Although multiple meta-analyses demonstrate better sensitivity (per-patient/per-lesion) of contrast-enhanced CT (per-patient 68–70%, per lesion 72–74%) and MRI (81–83% and 79–86%, respectively) [4, 16, 17, 23], they are not cost-effective approaches for a population screening [5, 6, 8‐13].

Furthermore, the presence of multiple benign or indeterminate liver lesions such as haemangiomas, regenerative, and dysplastic nodules in cirrhotic patients can confound longitudinal comparison of lesions as well as the detection of new lesions (Figs. 2 and 3). The quality of screening ultrasound is highly operator-dependent, further limiting its use with confidence. Guidelines on how best to screen these high-risk patients who have a suboptimal ultrasound performance are not available [7]. In these patients, clinicians may resort to regular or alternate contrast-enhanced CT or MRI, at regular or increased screening interval or continue with 6 monthly screening with suboptimal ultrasound.

In addition, access to MRI is limited and expensive in many countries. A full contrast-enhanced MRI liver study usually takes 40 min to acquire. In some countries, hepatocyte-specific contrast agent such as gadoxetic acid (Primovist® or Eovist®, Bayer, Leverkusen, Germany) may be difficult to access [8]. Hence, an MRI screening protocol without contrast administration for high-risk patients would be a practical screening tool for those that have suboptimal or non-diagnostic ultrasound. Non-contrast MRI is more accessible, with faster scanning time and lower risk of complications due to cannulation, contrast reactions and gadolinium accumulation [24, 25].

Several abbreviated MRI HCC screening protocols have been developed. Besa et al. [26, 27] utilised an abbreviated methodology with contrast MRI. The former study showed a 80.6% sensitivity and a negative predictive value (NPV) of 90%. Non-contrast MRI sequences mainly based upon diffusion-weighted imaging (DWI) have demonstrated a 48–86% sensitivity and a 85–92% NPV [26, 28].

Our aim was to retrospectively estimate the diagnostic performance of an abbreviated non-contrast MRI (aNC-MRI) protocol to screen high-risk patients including axial T2-weighted, T1-weighted, and DWI sequences.

Of the 302 patients with contrast-enhanced liver MRI studies, 188 patients/studies were eligible to be included (Fig. 4), 95 females and 93 males. The patient age ranged from 22 to 89 years (mean 63 years, standard deviation ± 13, range 22–89 years). The clinical characteristics and aetiology of the liver disease of patients are summarised in Table 2. Hepatitis B was the most common cause of liver disease (28 patients, 14.9%). Cirrhosis was present in 44 patients (23.4%), steatosis in 36 (19.1%), and both cirrhosis and steatosis in 4 (2.1%). One hundred patients had no lesions, 60 patients had benign lesions and 28 patients had malignant lesions. In these 28 patients, there was a total of 42 discrete malignant lesions: 31 were LI-RADS 5, 10 LI-RADS 4 and 1 LI-RADS-M.

Biannual screening for HCC is critical for the early detection in high-risk patients. It is currently recommended by internationally recognised guidelines as a standard practice. The most recently updated guidelines demonstrate increasing convergence of accepted risk factors to be considered for screening [5, 6, 8‐13]. However, surveillance using ultrasound presents a number of limitations in high-risk patients with suboptimal or non-diagnostic scans. These include those with obesity, hepatic steatosis, cirrhosis and multiple benign liver lesions [22]. Currently, no guidelines address screening practices for these patients when ultrasound is inadequate.

In this retrospective study, we have demonstrated that an aNC-MRI protocol could be a potential alternative screening tool. It showed a pooled sensitivity of 84.5% and a NPV of 97.1%. These results are similar to those obtained by studies utilising DWI only [26, 28] and those with an abbreviated contrast-enhanced MRI protocol [26, 28, 35].

There was little difference in sensitivity and NPV between assessment with and without cirrhosis or hepatic steatosis. Our pooled per-patient sensitivities of 86.4% in cirrhotic patients and 88.9% in patients with hepatic steatosis were higher than per-lesion sensitivity of ultrasound as per the meta-analyses by Hanna et al. [17], which was 59.3%. Our NPV of 88.7% in cirrhotic patients and 98.9% in patients with hepatic steatosis could allow us to exclude malignancy, especially in patients with severe hepatic steatosis who otherwise would have a non-diagnostic ultrasound examination. Of the 42 LI-RADS 4, 5, and M lesions, only one was not detected by any of the three readers. The lesion was a 20-mm LI-RADS 4 lesion in segment 8 near the diaphragm. This region in the liver can be difficult to interpret on MRI due to the proximity to the diaphragm and patient respiratory motion. Coincidentally, this is also a region that is often difficult to visualise on ultrasound due to its high position and often can only be seen through intercostal scanning. Detailed assessment of negative likelihood ratios in future meta-analyses of different modalities would be useful in considering the role of combining modalities for future screening studies as shown by the meta-analysis by Colli et al. [16].

We observed a reduced sensitivity for lesions < 20 mm (64.7%) versus ≥ 20 mm (85.3%). This compares favourably with the pooled sensitivity of ultrasound (47%) for detecting early stage HCC according to the Milan criteria [4, 36]. Furthermore, blinding our readers from prior studies was not entirely representative of clinical practice and represents a worst-case scenario. When aNC-MRI screening is to be used in the clinical setting, we propose that the patient has an initial baseline contrast-enhanced liver MRI, followed by six monthly serial screening aNC-MRIs used for comparison. This should increase reader confidence, and we expect that it will result in improved sensitivity and specificity.

There is some variability in the appearance of HCC on DWI sequences, but, despite this, it remains a key sequence of unenhanced liver imaging [26, 28, 37]. Whilst DWI is neither extremely sensitive nor specific for HCC [38, 39], it is sensitive for malignancy and remains robust in the setting of hepatic steatosis. In our study, If restricted diffusion is present or suspected in the liver, the screening scan will be considered for further contrast-enhanced assessment, after evaluation in combination with the T1-weighted and T2-weighted sequences (to exclude definite benign lesions such as cyst and haemangioma). Future research on unenhanced liver MRI screening should include studies with larger cohorts, possibly in combination with AFP, and head-to-head analysis versus ultrasound such as the prospective randomised MIRACLE-HCC study proposed by An et al. [40].

The main issues with MRI are cost, time and accessibility. Although contrast-enhanced CT is more accessible than contrast-enhanced MRI and both have improved per-lesion sensitivity compared to ultrasound, it is not recommended by any of the screening guidelines [2, 4‐6, 8‐13, 16, 17]. The economic rationale for abbreviated protocols for screening has been raised by Besa et al. [26] for both unenhanced and contrast-enhanced abbreviated MRI protocols with acceptable sensitivity and NPV in populations with a 2% and 8% HCC prevalence. Of note, the scan time of our aNC-MRI is only one-third of that of our standard liver MRI protocol.

Economic analysis of those patients with LI-RADS US visualisation score C [7] and their outcomes with either ultrasound or MRI with economic analysis may also be useful. We note that a large tertiary or multi-centre institute may be required to generate statistically significant data as only a small proportion of patients screened at our institution fall into this category.

The results of this study must be considered within the context of its inherent limitations. There is potential for bias due to the retrospective study design, performed within a single centre and with a single 3-T MRI, which may not necessarily translate to scanners of different model or field strength. Although this study has a relatively small sample size, it is comparable in size to similar studies that utilised a non-contrast-enhanced series for evaluation [26, 28, 39]. The scans included in our aNC-MRI series were sourced from patients who have had contrast-enhanced MRI performed for any reason (with subsequent criteria for exclusion from the study). However, this still introduces an inherent bias, mainly as not all of the patients would fit the high-risk screening criteria. For clarification, all 28 patients who had a positive MRI screening study satisfied the high-risk criteria, while not all of the patients who had a normal/benign MRI screening study met the high-risk criteria. For the purpose of this study, we felt that the latter would have a minimal adverse effet on the reader's reading outcome. There was significant variability amongst readers, although there was moderate agreement between the readers in patients who required further contrast-enhanced assessment and those who did not. Ideally, more readers of an appropriate level could be utilised to compensate for a relatively small cohort. Finally, histopathological correlation and ultrasound correlation was not available for all MRI studies and missed HCCs on the routine contrast-enhanced assessment cannot be excluded.

In conclusion, this retrospective study of aNC-MRI HCC screening protocol demonstrated an acceptable sensitivity (84.5%) and a high NPV (97.1%), potentially offering an alternative screening tool for high-risk patients who otherwise have a suboptimal screening ultrasound.