Hepatocellular Carcinoma Is the Most Frequent Final Diagnosis of Focal Liver Lesions Identified in a Cross-Sectional Evaluation of Patients with Chronic Liver Disease in Saudi Arabia

1Department of Medicine, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia 2Department of Medicine, Jersey General Hospital, The Parade, St. Helier, Jersey, Channel Isles JE1 3QS, UK 3Gastroenterology Unit, Department of Internal Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, University of Genoa, 16132 Genoa, Italy 4Department of Radiology, King Fahad Hospital, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia


Introduction
Hepatocellular carcinoma (HCC) is responsible for approximately 6% of all human cancers [1,2].Typically, HCC develops in patients with chronic liver disease and cirrhosis in whom chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and alcohol consumption are the most common etiological factors for liver disease [3,4].Surveillance programs based on liver ultrasound are the cornerstone of early detection of HCC, and they are able to improve patients prognosis due to better staging at diagnosis and a greater likelihood of receiving curative treatments [5,6].Although the majority of focal liver lesions detected in a cirrhotic liver during cross-sectional imaging studies ultimately prove to be HCC, some other lesions-either benign or malignant-can be observed in these patients.Indeed, focal liver lesions may be heterogeneous andbesides HCC-dysplastic nodules, hemangioma, cysts, and lymphoma may be the final diagnosis, and the incidence of these various lesions may vary according to population and geographic area [7][8][9][10][11][12][13].
In this study, carried out in a population of patients residing in a Middle Eastern country, our aim was to conduct a cross-sectional evaluation analyzing the characteristics and final diagnosis of hepatic focal lesions identified in a series of unselected patients with chronic liver disease who underwent liver ultrasound evaluation.

Materials and Methods
We performed a cross-sectional study of patients with chronic liver disease undergoing liver ultrasound at the Department of Medicine, King Fahad Hospital, Armed Forces Hospital Southern Region, Khamis Mushait, Saudi Arabia, and where focal hepatic lesions were identified.Patients who were on regular surveillance for HCC were not included in this study.Recent (within 6 months of inclusion) radiological evaluation or hepatic/abdominal surgery, presence of known primary tumor elsewhere, and history of recent sepsis were considered exclusion criteria.
Focal hepatic lesions identified at ultrasonography were further evaluated by means of contrast-enhanced computed tomography, magnetic resonance imaging, or lesion biopsy until a final diagnosis was reached.Liver function tests, HBV and HCV serology, serum alpha-fetoprotein levels, and anti-Schistosoma antibodies titer were recorded in all patients.Diagnosis of cirrhosis was based on patients history, clinical and radiological evaluation, or histology.

Statistical Analysis.
Continuous variables are expressed as median and range and categorical variables as absolute number and proportion.One-way analysis of variance for nonparametric data was performed by post hoc analysis using Kruskal-Wallis  test, parametric variables were compared by post hoc analysis using Tukey test, and Fisher's exact test was used to compare categorical variables.Multivariate logistic regression analysis (forward method) was carried out on parameters significantly associated with HCC diagnosis in univariate analysis.Data analyses were performed on MedCalc software (MedCalc software, Acacialaan 22, 8400 Ostend, Belgium).

Results
Demographic and biochemical characteristics of the 77 patients who made up the study population are shown in Table 1.Etiology ofliver disease was infection with hepatitis viruses in 30 patients (39.0%):HBV in 22 (28.6%) and HCV in 8 (10.4%).Features consistent with a diagnosis of cirrhosis were observed in 54 patients (70.1%) and among them 24 (44.4%) had ascites, which was clinically evident in 2 patients (8.3%) and instrumentally detected alone in 22 patients (91.7%).
Forty patients (51.9%) had 1 nodule, 9 patients (11.7%) had 2-4 nodules, and 26 patients (33.8%) had ≥5 nodules, and 2 patients (2.6%) had infiltrative lesions (Figure 1).Diagnostic work-up led to the diagnosis of HCC in 50 patients (64.9%), hepatic hemangioma in 13 patients (16.9%), regenerative nodules in 8 patients (10.4%), complex hydatid cyst in 2 patients (2.6%), focal fat sparing in 2 patients (2.6%), and simple cyst in 2 patients 1 (2.6%).Presence of complete or partial portal vein thrombosis was found in 12 patients (15.6%): 5 affecting the main portal vein trunk, 5 affecting the right intrahepatic branch, 1 affecting the left intrahepatic branch, and 1 extending to the middle and right hepatic veins and the superior vena cava.According to the final diagnosis of the hepatic lesions (HCC versus benign lesions), we further subdivided our population into 2 groups and evaluated their main demographic and clinical characteristics (Table 2).Patients with HCC were older and presence of cirrhosis, ascites, and portal vein thrombosis was observed more frequently in these patients as compared to patients with benign lesions.Although serum alpha-fetoprotein levels were significantly higher in patients with HCC ( = 0.001), the proportion of patients with alpha-fetoprotein levels >10 ng/mL was not significantly different in the two groups ( = 0.525).Positivity for Schistosoma antibodies was numerically more frequent in patients with HCC (20% versus 7.4%,  = 0.198).Lastly, in multivariate logistic regression analysis, presence of cirrhosis (odds ratio: 3.283 (95% confidence interval, 1.141-9.450))and multinodularity (odds ratio 2.898 (95% confidence interval, 1.032-8.142))were the parameters independently associated with HCC diagnosis.

Discussion
Patients affected by chronic liver disease carry a higher risk of developing HCC as compared to the general population, and in patients with cirrhosis this risk is high enough to mandate screening and surveillance for the detection of early tumors [2,6].However, other malignant or benign diseases may be responsible for the presence of focal liver lesions in patients with chronic liver disease [7].In this crosssectional study, carried out in a population of patients with chronic liver disease residing in the Middle East, we found that approximately two-thirds of newly identified focal liver lesions were due to HCC and that the proportion of HCC was even higher (i.e., 80%) in patients with liver cirrhosis.As expected in our geographical area, the patients population was mainly made up of subjects with viral etiology of liver disease, and the majority of patients had advanced liver disease [14,15].We observed that patients with HCC were older and had more frequently liver cirrhosis and clinical features of portal hypertension thus confirming that HCC tends to develop in patients with more advanced liver disease.Patients with HCC also had more frequently a multinodular disease and portal vein thrombosis: although this study evaluated only patients who underwent a cross-sectional imaging study and did not include patients on regular follow-up, we feel that these advanced features may be attributable to the low uptake of HCC surveillance in our geographical area [16].Furthermore, although patients with HCC had significantly higher median alpha-fetoprotein levels, the proportion of patients with serum alpha-fetoprotein >10 ng/mL was not different as compared to patients with benign lesions.This finding underscores the poor performance of this marker also in Middle Eastern patients with prevalently chronic viral liver disease and further emphasizes the poor sensitivity of altered alpha-fetoprotein levels when its performance is assessed on the "background noise" of cirrhosis, advanced liver disease, and altered aminotransferases [17][18][19][20][21].In keeping with clinical and experimental studies suggesting that infection with Schistosoma may be a further risk factor for the presence of HCC, we observed a numerically greater prevalence of Schistosoma antibodies positivity in patients with HCC although the difference with patients harboring benign lesions was not statistically significant likely due to the relatively small cohort evaluated [22,23].Lastly, only presence of cirrhosis and multinodularity were the parameters that were independently associated with a final diagnosis of HCC.
Due to the current and estimated burden of chronic liver disease in the Middle East, the limited access to potential treatment, and the increasing epidemic of some diseases such as nonalcoholic fatty liver disease coupled with aging of the population, it is expected that in the future the proportion of patients with advanced liver disease diagnosed with HCC in our geographical area will likely increase [24,25].In this regard, it is interesting to note that, besides the presence of cirrhosis and multinodularity, there were no other features able to pinpoint patients with chronic liver disease and focal liver lesions who were more likely to have a malignant disease.On these bases, it is important that programs aimed at the early detection of HCC in cirrhotic patients be implemented in our region so as to detect lesions that can be effectively cured [2,6,26,27].
This study has some limitations such as the lack of information on the possible pretest suspicion of HCC in some patients (e.g., weight loss and worsening of ascites) and on the patients outcome as patients HCC management was carried out at a different facility.
In conclusion, in this cross-sectional study we observed that the majority of focal liver lesions identified in a population with prevalent liver cirrhosis in the Middle East can be attributable to HCC.This result calls for implementation of screening and surveillance programs for early HCC detection in our geographical area.

Figure 1 :
Figure 1: Proportion of patients with single, multinodular, or invasive focal liver lesions identified at imaging.

Table 1 :
Main demographic and biochemical characteristics of the 77 study patients.Data are shown as absolute value and percentage or median and range.

Table 2 :
Main demographic and characteristics of the study population subdivided according to the final diagnosis of the hepatic lesions.