Multicentre study on dynamic contrast computed tomography findings of focal liver lesions with clinical and histological correlation

Background Current advancements in dynamic contrast imaging of the liver have enabled increased sensitivity in the diagnosis of liver lesions. Evaluation and characterisation of the enhancement pattern of liver lesions in respect to the liver parenchyma aids in making a specific diagnosis. Objectives The aim of this study was to determine the liver findings on dynamic contrast computed tomography (CT) scanning and correlate them with clinicopathologic findings. Methods This prospective cross-sectional study included 61 patients and took place between August 2017 and February 2018. Dynamic contrast CT was performed and the images were evaluated by two experienced radiologists. Correlation of the CT findings with histology results from an ultrasound-guided biopsy was done. Data analysis was performed using SPSS version 20.0. Results Hepatocellular carcinoma (HCC) was the most common malignant lesion seen and showed three patterns of enhancement: homogenous, abnormal internal vessels and heterogeneous enhancement. Abnormal internal vessel pattern was most specific (90.6%) and showed a high positive predictive value (PPV) of 78.6%. Rapid washout showed a specificity of 87.5% and a PPV of 72.2% in the diagnosis of HCC. Dynamic contrast CT scan had a sensitivity of 93%, specificity of 50%, PPV of 91% and diagnostic accuracy of 95.5% in differentiation of benign and malignant liver lesions. Considering only Liver Imaging Reporting and Data System (LI-RADS) category 5 as conclusive for HCC diagnosis, our study did not miss a significant number of HCCs. Liver Imaging Reporting and Data System category 5 showed specificity of 81.3% and PPV of 75%. Conclusion Enhancement patterns on a dynamic contrast CT scan of the liver are useful in the interpretation of CT images for specific diagnoses.

accuracy 95.5%. 5 A systematic review by Colli et al. in patients with chronic liver disease showed the sensitivity and specificity of helical CT in the diagnosis of hepatocellular carcinoma (HCC) to be 68% and 93%, respectively. 6 Another systematic review and meta-analysis showed 74.8% sensitivity and 95.6% specificity in the diagnosis of hepatic metastases. 7 Sensitivity estimates for helical CT in colorectal liver metastases in another meta-analysis was 64.7%. 8 The Liver Imaging Reporting and Data System (LI-RADS), launched in 2011, is used to standardise the reporting of dynamic imaging of the liver in patients at risk of HCC. Nodules are categorised as definitively benign (LI-RADS 1), probably benign (LI-RADS 2), indeterminate probability of being HCC (LI-RADS 3), probably HCC (LI-RADS 4) and definitively HCC (LI- RADS 5).
Liver imaging in various imaging centres in our country has no standard CT protocol. Most patients are scanned in the portovenous phase only, and this poses a challenge in the characterisation of lesions. The main reason for this is not documented; however, it is important to bring to the fore the diagnostic value of dynamic contrast CT and to avoid unnecessary extra radiation to patients who receive incomplete or inadequate studies.
Multiple studies have been conducted around the world on the role of dynamic contrast CT in characterising and distinguishing focal liver lesions. However, to the best of our knowledge, no data have been published locally, thus the purpose of this study was to compare local findings and diagnostic accuracy to studies in other parts of the world. This will help to evaluate our standard of diagnostic performance and hence initiate strategies for improvement where need be. This study aims at creating a local database on the spectrum of findings and the diagnostic performance of dynamic contrast CT imaging of the liver. The study findings will be useful to both radiologists and hepatobiliary surgeons.

Methods
This prospective, cross-sectional study was performed at the radiology departments of the Kenyatta National Hospital and Plaza Imaging Solutions. The aims of the study were firstly to determine the liver findings on dynamic contrast CT scanning and correlate these findings with clinicopathologic findings and secondly to evaluate the diagnostic performance of dynamic contrast CT of the liver.
The sample size was determined using Fisher's formula. Patient consent was obtained. The study included patients who were at least 18 years of age who presented to the radiology department for abdominal CT scan and who were suspected to have liver pathology (based on clinical examination and/or previous ultrasound findings) with no known primary malignancy. Patients who declined to give consent, had any contraindication to contrast media use, had a known extra-hepatic malignancy, had a known histologic diagnosis of the hepatic lesion or had inconclusive biopsy results were excluded. Sixty-one patients were recruited for the study.
A questionnaire was used to collect both qualitative and quantitative data. It recorded the patients' demographic information, clinical history, family history and socioeconomic history.
The CT scanner Somatom Definition AS 128 Slice by SIEMENS (2014) was used at Kentatta National Hospital (KNH) and the Aquilion One 640 slice by TOSHIBA (2013) was used at Plaza Imaging Solutions. Precontrast scans were done followed by contrast-enhanced triple-phase scans. Arterial phase scanning was acquired at 30-40 s following dynamic injection of the contrast agent, portovenous phase at 70 s and equilibrium/delayed phase at 180 s. Enhancement characteristics of each lesion in each phase were evaluated by two consultant radiologists and the principal investigator. The findings were then recorded in tabulated forms.
The patients had a follow-up ultrasound-guided liver biopsy. The histological specimens were sent to Pharmcet Healthcare Laboratory and analysed by an experienced consultant pathologist. Histology results were recorded alongside the radiological findings.
Data were analysed using the SPSS program (version 20.0). The quantitative data were analysed by using descriptive statistics and presented through percentages, means, standard deviations and frequencies. The information was displayed by the use of bar charts, pie charts, tables and in prose form.

Ethical consideration
Permission to conduct this research was obtained from Kenyatta National Hospital, University of Nairobi Ethics and Research Committee (reference number P931/12/2016).

Results
Sixty-one patients with focal liver lesions were analysed with dynamic contrast CT scanning. Ten presented with characteristically benign lesions and were thus not biopsied. These included eight simple hepatic cysts and two haemangiomas. Fifty-one patients with a total of 62 focal liver lesions underwent biopsy. Seven patients had more than one focal lesion; however, only the most suspicious lesion was biopsied. The assumption was that all lesions were part of the same disease process.
Out of the 51 focal liver lesions, seven ( Hepatocellular carcinoma lesions showed three patterns of enhancement: homogenous, abnormal internal vessels and heterogeneous enhancement. Abnormal internal vessel pattern ( Figure 1) was most sensitive (57.9%) and specific (90.6%) with a high PPV (78.6%).
Heterogeneous enhancement of FNH had 100% sensitivity and 95.9% specificity but had a low PPV (15.4%). The nonenhancing pattern of metastasis ( Figure 2) exhibited sensitivity of 50% and specificity of 89.2% with a PPV of 63.6%. An abscess showed incomplete ring enhancement as seen in Figure 3.
Delayed enhancement of cholangiocarcinoma ( Figure 4) showed 25% sensitivity and 95.3% specificity with a PPV of 50%.  The LI-RADS categories of the lesions are summarised in Table 2.
Lesions classified as LI-RADS 1 had characteristic benign findings, as either simple cysts or haemangiomas and were thus not biopsied. One (25%) of the LI-RADS 2 lesions was a metastatic lesion, while the remaining lesions (75%) were two adenomas and a haemorrhagic cyst. Three (75%) of the LI-RADS 3 lesions were metastases, and one (25%) was an abscess. Four (75%) of the lesions classified as accuracies for HCC diagnosis of the LI-RADS criteria are summarised in Table 3.

Discussion
Our study documented 84.3% malignant lesions, which is comparable to a retrospective study by Matilde et al. 9 that excluded simple cysts and showed 87% of the lesions to be malignant. Metastases were the most common malignant finding at 53%, followed by HCC at 31%. This was unlike our study, which showed HCC to be the most common malignant lesion at 44.2%.
The mean lesion size of 5.8 cm was higher than in the study by Matilde et al., 9  Studies by Ferdey et al. 12 and Lancomis et al. 13 showed 75% and 74%, respectively, of hyper attenuation of cholangiocarcinoma on delayed images. The hyperattenuating areas in cholangiocarcinoma on delayed phase images seem to be related to the large amount of interstitial space in the fibrous stroma of the tumour. 14 Delayed enhancement of cholangiocarcinoma showed a specificity of 95.3% and PPV of 50% in our study.
Various studies have shown most metastatic liver lesions to be hypovascular. The non-enhancing pattern of metastasis exhibited a specificity of 89.2% and PPV of 63.6% in this study. The non-enhancing pattern of metastasis demonstrated a specificity of 96% and a PPV of 75% in the study by Matilde et al. 9 In a retrospective study by Leslie and colleagues, 90% of metastases showed hypodense enhancement on arterial phase. 15 Precontrast imaging allowed depiction of all hepatic metastases (sensitivity, 100%), compared to 66% in the study by Soyer et al. 10   Malignant lesions were more frequent in men (65%), while benign lesions were mostly in women (75%). Kerlin et al. also demonstrated malignant lesions to be more common in males. 16 Hepatic adenomas and FNH were exclusively found in females. Baum et al. were the first to demonstrate the relationship of hepatic adenomas and oral contraceptive use. 17 In a study by Kerlin et al. it was observed that patients with hepatic adenoma were young and 91% were female. They observed that 89% of them had used oral contraceptives. 16 In this study both of the patients with adenoma reported oral contraceptive use. Hepatocellular carcinoma and cholangiocarcinoma occurred predominantly in males (M:F 16:3 and 3:1, respectively).
There was a significant correlation between the history of alcohol intake and HCC in this study (p = 0.046). Heavy alcohol consumption has been shown to increase the risk of HCC. 18 Globally, 78% of HCC is attributable to HBV (53%) or hepatitis C virus (HCV) (25%), according to a study by Perz et al. 19 Sampling errors resulting from liver biopsy technique were beyond the scope of this study. Only patients with conclusive histology findings were included. Although high diagnostic accuracy (86%) was noted in our results, we had four false positive results. Three of these lesions were labelled as malignant because of hypervascularity and proved to be FNH. One lesion was hypovascular and proved to be a tuberculous abscess. Higher diagnostic accuracy of 95% was recorded in a similar study by Hafeez et al. 5 This study demonstrated dynamic CT scan to have a sensitivity of 93%, specificity of 50% and PPV of 91% in differentiation of benign and malignant liver lesions. Possible causes of false negative cases could be inaccurate timing of the different phases of enhancement.
Considering only LI-RADS 5 as conclusive for HCC diagnosis, our study missed one out of the 19 HCC lesions (specificity = 81.3%). However, if both LI-RADS 4 and 5 are combined as definitely indicating the diagnosis of HCC, the specificity decreased to 62.5% but the sensitivity remained the same at 94.5%. A study by Trillaud et al. 20 on characterisation of liver nodules using MRI showed improved sensitivity and reduced specificity when combining LI-RADS 4 and 5. We confirmed that lesions classified as LI-RAD 5 that show arterial phase hyperenhancement and washout at CT should be considered as HCC, as documented in the latest LI-RADS version. 21 There is benefit in differentiating LI-RAD Category 4 and 5 lesions to improve diagnostic accuracy.

Conclusion
Dynamic contrast CT scan has high diagnostic accuracy in focal liver lesions. Various lesions show characteristic enhancement patterns that are useful in the interpretation of CT images for specific diagnoses, emphasising the need for national standardisation of protocols for liver evaluation.

Limitations of the study
Only one lesion per patient was biopsied, with the assumption that all lesions were the same disease process. A larger sample size and additional local studies are necessary to strengthen our findings. Some of the patients who were candidates for this study were lost to follow-up, either because of death or because of financial constraints. Sampling errors resulting from liver biopsy technique were beyond the scope of this study.