Hepatocellular carcinoma (HCC) is the second most common cause of cancer related death worldwide, with increasing mortality rates in Europe, North America, South America and Africa[
Although most HCCs (75%-90%) develop in cirrhosis resulting from chronic hepatitis B or C infections and alcoholic injury[
NAFLD is a spectrum of disease ranging simple non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis[
The effect of hepatic steatosis in NAFLD on the imaging features of HCC has not yet been fully explored. For example, hepatic steatosis may decrease the liver attenuation on CT and as a result, washout observation may be absent or less conspicuous which could render the LIRADSv2017 imaging criteria not applicable[
In this institutional review board (IRB) approved (ID: 15-004925), HIPPA-compliant retrospective study. Written informed consent for retrospective review of data was waived.
We reviewed our institutional pathology and imaging database between January 2006 and December 2016 with key words NAFLD, hepatic steatosis or steatohepatitis and HCC or hepatocellular carcinoma. This yielded a cohort of 400 patients. Among these 400 patients, only 38 patients met the AASLD criteria for NAFLD[
Patient selection flow diagram. CT: computed tomography; HCC: hepatocellular carcinoma; NAFLD: non-alcoholic fatty liver disease; NAFL: non-alcoholic fatty liver; NASH: nonalcoholic steatohepatitis
Patient age, sex, height, weight, body mass index (BMI), serum cholesterol, serum triglycerides, presence or absence of obesity, tumor histopathological and clinical management information were obtained from electronic medical records.
Cytological and pathological TNM staging was evaluated according to criteria of the 7th American Joint Committee on Cancer[
All the CT images were independently reviewed on PACS Workstation (Centricity, GE Healthcare, Waukesha, WI) by four board-certified abdominal radiologists (SPS, ECE, AK, CAB) who were blinded to clinical and pathological findings other than the presence of HCC. Each reader recorded the imaging features of HCC, including size, location, APHE, PVWO, DPWO, and presence capsule. Readers also assessed for findings of cirrhosis-surface nodularity, caudate lobe hypertrophy, left lobe enlargement, widened fissures, widened gallbladder fossa, and portal hypertension (PH), splenomegaly, collaterals and gastroesophageal varices. In patients with multiple HCCs, only the largest HCC with histological confirmation was assessed. The final imaging features of HCCs were determined by majority. A fifth reader blinded to clinical and pathological findings reviewed cases lacking majority. LIRADs criteria is only applicable in patients with cirrhosis or chronic viral hepatitis and therefore would not be applicable for patients with NAFLD without cirrhosis.
Continuous variables were expressed as mean ± standard deviation and categorical data as percentage. Inter-rater agreement was determined by prevalence-adjusted bias-adjusted Cohen’s kappa[
Mean age of subjects was 63 years (range 45-79). Patients were predominantly male (
At pathology, HCCs were well differentiated in 14 patients (36.8%), well to moderately differentiated in 5 patients (13.2%), moderately differentiated in 16 patients (42.1%), moderate to poorly differentiated in 2 patients (5.3%) and poorly differentiated in 1 patient (2.6%). Hepatic steatosis was minimal (26.3%) in 10 patients (26.3%), mild in 26 patients (68.4%), and moderate in 2 patients (5.3%). Steatohepatitis was present in 25 patients (65.8%) and cirrhosis in 24 patients (63.2%). The clinical and pathological characteristics are summarized in
Clinical-pathological characteristics in patients with NAFLD-associated HCC (
Clinical and Pathological findings | Main Cohort ( |
Non-cirrhotic ( |
Cirrhotic ( |
|
---|---|---|---|---|
Age (years) (mean ± SD) | 63 ± 7.2 | 66.2 ± 6.3 | 60.9 ± 7.2 | 0.03 |
Gender | 0.47 | |||
Female | 12 (31.6) | 3 (21.4) | 9 (37.5) | |
Male | 26 (68.4) | 11 (78.6) | 15 (62.5) | |
BMI (kg/m2) (mean ± SD) | 32.2 ± 4.9 | 30.6 ± 4.6 | 33.1 ± 5.0 | 0.14 |
Diabetes (%) | 28 (73.7) | 9 (64.3) | 19 (79.2) | 0.45 |
Total Cholesterol (mean ± SD) | 151.9 ± 39.7 | 171 ± 36.4 | 147.4 ± 39.9 | 0.24 |
Triglycerides (mean ± SD) | 130.6 ± 53.5 | 129.2 ± 71.1 | 131 ± 50.7 | 0.95 |
HCC Pathology Source | ||||
Biopsy | 5 (13.2) | 3 (21.4) | 2 (8.3) | < 0.001 |
Surgical Resection | 12 (31.6) | 10 (71.4) | 2 (8.3) | |
Liver Explant at Transplant | 21 (55.3) | 1 (7.1) | 20 (83.3) | |
Pathologic Features | ||||
Tumor Grade | ||||
Well differentiated | 14 (36.8) | 4(29) | 10 (41.7) | 0.31 |
Well-Moderately differentiated | 5 (13.2) | 1 (7.1) | 4 (16.7) | |
Moderately differentiated | 16 (42.1) | 9 (64.3) | 7 (29.2) | |
Moderate-Poorly differentiated | 2 (5.3) | 2 (8.3) | ||
Poorly differentiated | 1 (2.6) | 1 (4.2) | ||
Hepatic Steatosis Grade | 0.003 | |||
Minimal | 10 (26.3) | 10 (41.7) | ||
Mild | 26 (68.4) | 12 (85.7) | 14 (58.3) | |
Moderate | 2 (5.3) | 2 (14.3) | ||
Hepatic Fibrosis Stage | ||||
0 | 9 (23.7) | 9 (64.3) | ||
1 | 3 (7.9) | 3 (21.4) | ||
2 | 2 (5.3)) | 2 (14.3) | ||
4 | 24 (63.2) | 24(100) |
Mean HCC size was 3.6 ± 2.8 cm (range: 1.1-16.0 cm). APHE was seen in 92.1%, PVWO in 55.3% DPWO in 81.6% and enhancing capsule in 44.7% [
A 70-year old male with histologically confirmed hepatocellular carcinoma in non-cirrhotic liver with mild steatosis and no steatohepatitis (non-alcoholic fatty liver). Patient was obese (BMI of 30.7), diabetic and dyslipidemic. On multiphase contrast enhanced CT (A-C), a heterogeneously enhancing mass (arrow) on arterial phase (A) with no washout on portal venous (B) and complete washout on delayed phase (C) images can be seen. In addition, a thin but incomplete capsule (arrowhead) can be seen on delayed phase image (C). No features of portal hypertension were seen on imaging
A 73-year old male with histologically confirmed hepatocellular carcinoma in non-cirrhotic liver with severe steatohepatitis (non-alcoholic steatohepatitis). Patient was obese (BMI of 31.1) and diabetic. On multiphase contrast enhanced CT (A-C), a heterogeneously enhancing mass (arrow) on arterial phase (A) showing no washout on portal venous (B) and delayed phase (C) images can be seen
Imaging features of HCC and liver parenchyma at CT by majority consensus in patients with NAFLD-associated HCC (
HCC imaging features | Main cohort ( |
Non-cirrhotic pathology ( |
Cirrhotic pathology ( |
|
---|---|---|---|---|
Tumor size (mean ± SD) | 3.6 ± 2.8 | 5.1 ± 3.9 | 2.7 ± 1.3 | 0.008 |
APHE | 35 (92.1) | 13 (92.8) | 22 (91.7) | 1.00 |
PVWO | 21 (55.3) | 11 (78.6) | 10 (41.7) | 0.04 |
DPWO | 31 (81.6) | 12 (85.7) | 19 (79.2) | 1.00 |
Enhancing “Capsule” | 17 (44.7) | 9 (64.3) | 8 (33.3) | 0.09 |
Cirrhotic Liver Morphology | 25 (65.8) | 2 (14.3) | 23 (95.8) | < 0.001 |
Portal hypertension | 24 (63.2) | 2 (14.3) | 22 (91.7) | < 0.001 |
LIRADS Score* | 0.29 | |||
2 | 3 (7.9) | 0 | 3 (12.5) | |
3 | 0 | 0 | 0 | |
4 | 11 (28.9) | 3 (21.4) | 8 (33.3) | |
5 | 24 (63.2) | 11 (78.6) | 13 (54.2) |
* LIRADS score applied to see if HCCs would meet the criteria, however if there is no cirrhosis, LIRADs criteria should not be applied as per guidelines. APHE: arterial phase hyperenhancement; PVWO: portal venous washout; DPWO: delayed phase washout
Non-Cirrhotic NAFLD (NAFL in 7 and NASH in 7) and cirrhotic NAFLD were present in 14 (36.8%) and 24 (63.2%) patients respectively. Patients with non-cirrhotic NAFLD were older (
Inter-rater agreement was moderate to almost perfect for HCC APHE (0.74-1.0), none to moderate for PVWO (0-0.42), weak to almost perfect for DPWO (0.47-0.95)
A 47-year old female with histologically confirmed hepatocellular carcinoma (HCC) in non-cirrhotic liver with minimal steatosis and moderate steatohepatitis (non-alcoholic steatohepatitis). Patient was obese (BMI of 30.5) and diabetic. On multiphase contrast enhanced CT (A-C), three of the four readers interpreted this as a heterogeneously enhancing mass (arrow) on arterial phase (A) with no washout on portal venous (B) and delayed phase (C) images. However 1of the four readers interpreted this as a heterogeneously enhancing mass (arrow) on arterial phase (A) with washout on portal venous (B) and delayed phase (C) images. A resected specimen (D) showing HCC (arrow) with background fatty liver can be seen
Inter-observer agreement for HCC features and liver parenchyma morphology at MRI in patients with NAFLD-associated HCC (
HCC imaging features | R1 |
R1 |
R1 |
R2 |
R2 |
R3 |
---|---|---|---|---|---|---|
APHE | 0.74 | 0.79 | 0.79 | 0.74 | 0.84 | 1.0 |
PVWO | 0.42 | 0.00 | 0.53 | 0.05 | 0.32 | 0.05 |
DPWO | 0.95 | 0.84 | 0.74 | 0.79 | 0.68 | 0.47 |
Enhancing “Capsule” | 0.47 | 0.05 | 0.42 | 0.37 | 0.79 | 0.37 |
Cirrhotic Liver Morphology | 0.79 | 0.89 | 0.89 | 0.79 | 0.79 | 0.89 |
Portal hypertension | 0.74 | 0.79 | 0.95 | 0.84 | 0.79 | 0.84 |
Data are presented as prevalence-adjusted bias-adjusted kappa. R1: reader 1; R2: reader 2; R3: reader 3; R4: reader 4; APHE: arterial phase hyperenhancement; PVWO: portal venous phase washout; DPWO: delayed phase washout
In our study of NAFLD associated HCC, many HCCs did not demonstrate major imaging features particularly PVWO and enhancing capsule were absent in nearly half and DPWO was absent in nearly 20% of the patients. Cirrhotic morphology was present in 25 (65.8%) patients. A third (36.8%) of HCC occurring in non-cirrhotic livers would not be eligible for LIRADs classification.
Our study results are in agreement with previous reports in literature that HCC can occur even in the absence of steatohepatitis or fibrosis/cirrhosis[
Imaging features of HCC on multiphase CT and MRI are based on sequential changes in the intra-lesional blood supply during hepatocarcinogenesis. Advanced HCCs receive their blood supply predominantly from the anomalous arteries (arterial blood supply)[
Effect of NAFLD on imaging features on HCC is currently being explored. In our study APHE was present in most (92.1%) of the cases. APHE is a major imaging criterion and has a good sensitivity for detection of HCC, ranging from 65%-96%[
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 the delayed phase to reduce the radiation dose[
Capsule appearance is a highly specific but not very sensitive feature of HCC[
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
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 contributed to the changes in the liver parenchyma. However we minimized this variation as most of the studies had histological evaluation within 6 months of CT study.
In conclusion, NAFLD associated HCC may not show portal venous phase washout on CT and may impact the imaging diagnosis of HCC. Our study should be confirmed in studies with larger population of NAFLD associated HCCs. There may be a need for modification of criteria for multiphase CT based diagnosis of NAFLD associated HCCs particularly in the non-cirrhotic patients.
Made substantial contributions to conception and design of the study and performed data analysis and interpretation: Garg I, Thompson SM, Mounajjed T, Ehman EC, Venkatesh SK
Performed data acquisition, as well as provided administrative, technical, and material support: Garg I, Thompson SM, Sheedy SP, Mounajjed T, Khandelwal A, Ehman EC, Bookwalter CA, Venkatesh SK
Not applicable.
None.
All authors declared that there are no conflicts of interest.
In this IRB approved (ID: 15-004925), HIPPA-compliant retrospective study. Written informed consent waived by the IRB.
Not applicable.
© The Author(s) 2019.