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Page 8 of 11 Garg et al. Hepatoma Res 2019;5:39 I http://dx.doi.org/10.20517/2394-5079.2019.009

HCC. The specificity can be increased by combined assessment of APHE & washout (PVWO or DPWO) [39,46] .
Sensitivity and specificity of combined APHE & washout for diagnosis of HCC ranges from 43% to 98%,
and 81% to 100%, respectively [43,46-48] .

For assessment of washout, either portal venous or delayed phase imaging can be used. In this study,
PVWO was absent in 17 (44.7%) of the HCCs. In contrast, DPWO was absent in only 7 (18.4%) HCCs. In
addition, the interobserver agreement was none to moderate for PVWO and weak to almost perfect for
DPWO. These results support the added value of delayed phase imaging in assessment of washout. Triple
phase CT is the standard protocol for HCC in chronic liver disease, however some centers may not include
[4]
the delayed phase to reduce the radiation dose . However, this may lead to loss of important diagnostic
information (washout characteristics). In a prior study with NAFLD associated HCC, PVWO was absent
[45]
in 30% cases but DPWO was not reported . Ehman et al. reported lack of washout (portal or delayed)
[49]
in only 18% (15% on CT and 21% on MRI) of the 184 pathologically proven HCCs with cirrhosis resulting
from several different etiologies . Washout in NAFLD associated HCC may not be demonstrated well
[45]
probably due to hepatic steatosis that can lead to liver hypo-attenuation on post-contrast enhanced
images, thereby resulting in the appearance of persistent HCC hyper-attenuation or iso-attenuation
during the portal venous and delayed phase imaging. Interestingly however in our study PVWO was
more commonly seen in subgroup with non-cirrhotic NAFLD, which had higher proportion of cases with
mild moderate steatosis in comparison to cirrhotic NAFLD subgroup. These findings suggest that degree
of hepatic steatosis may have more determining effect than presence of fibrosis for washout appearance.
Future studies with larger number of patients are required to confirm our findings. The findings should be
confirmed in studies with larger population of NAFLD associated HCCs.

Capsule appearance is a highly specific but not very sensitive feature of HCC [43,45,50] . Capsule is thought
to be caused by expansile growth of HCC causing perilesional compression of liver tissue, which appears
as enhancing rim around the HCC in portal venous or delayed phase. Capsule is supplied by the portal
[51]
venous system leading to this delayed enhancement . Interestingly, capsule is a recognized major feature
of HCC based on the LIRADS, OPTN guidelines but not on the AASLD and EASL guidelines . In our
[7,8]
study, capsule appearance was seen in only 17 (44.7%) of the NAFLD-associated-HCCs but still within the
reported range of 27 to 64% in studies including all chronic liver diseases [43,45] .

Inter-rater agreement was poor for PVWO, variable for DPWO and capsule suggesting the difficulty in
interpretation of washout and detection of capsule in NAFLD associated HCCs [Figure 4]. We had four
experienced abdominal radiologists working in tertiary level institute with large exposure to HCCs on
a daily basis. Even with this level of expertise, the interobserver agreement for PVWO was poor. We
think that this is due to the variable hepatic steatosis in background liver that affects interpretation of the
washout particularly PVWO.

The study has some limitations. Despite searching a large patient database containing around 2,500
patients (pathological data for HCC), our final study cohort was relatively small. Due to retrospective
nature of the study, the imaging (triphasic CT) technique including scanner, sequence protocol(s) and
contrast agent(s) was not uniform over the study period and this may have introduced variability in the
phase of image acquisition. Some cases of NAFLD associated HCCs may have been excluded that either
lacked pathological assessment or were interpreted as cryptogenic cirrhosis. The readers were aware of the
diagnosis of HCC in the lesions which may have introduced bias for imaging features. However this bias
of prior knowledge did not inflate interobserver agreement for the imaging features. Degree of hepatic
steatosis may have changed from time between histological analysis and radiological assessment, due to
systemic interventions or natural progression of NAFLD. This was unavoidable as several patients received
locoregional treatment before undergoing surgery or liver transplantation. These treatments may also have