Author Affiliations: Department of Radiology, Second Affiliated Hospital, Harbin Medical University, Harbin 150086, China (Jia GS, Feng GL, Li JP, Xu HL, Wang H, Cheng YP, Yan LL and Jiang HJ)

Corresponding Author: Hui-Jie Jiang, MD, PhD, Department of Radiology, Second Affiliated Hospital, Harbin Medical University, Harbin 150086, China (Tel: +86-451-86605576; Email: jhjemail@163.com)

 

© 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(17)60018-3

Published online May 18, 2017.

 

 

Contributors: JHJ proposed the study. JGS, FGL, LJP and XHL performed the research and wrote the first draft. WH, CYP and YLL collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. JHJ is the guarantor.

Funding: This study was supported by grants from the National Natural Science Foundation of China (81301275, 81471736 and 81671760), the National Science and Technology Pillar Program during the Twelfth Five-Year Plan Period (2015BAI01B09), and Heilongjiang Province Foundation for Returness (LC2013C38).

Ethical approval: This study was approved by the institutional review board of Harbin Medical University.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: The various combination of multiphase enhancement multislice spiral CT (MSCT) makes the diagnosis of a small hepatocellular carcinoma (sHCC) on the background of liver cirrhosis possible. This study was to explore whether the combination of MSCT enhancement scan and alpha-fetoprotein (AFP) level could increase the diagnostic efficiency for sHCC.

 

METHODS: This study included 35 sHCC patients and 52 cirrhotic patients without image evidence of HCC as a control group. The diagnoses were made by three radiologists employing a 5-point rating scale, with postoperative pathologic results as the gold standard. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of the three MSCT combination modes (arterial phase+portal-venous phase, arterial phase+delayed phase, arterial phase+portal-venous phase+delayed phase) and AFP levels for sHCC on the background of liver cirrhosis.

 

RESULTS: The area under ROC curve (AUC), sensitivity, and specificity of the combination of arterial phase+portal-venous phase+delayed phase were 0.93, 93%, and 82%, respectively. The average AUC of the arterial phase+portal-venous phase+delayed phase combination was significantly greater than that of the arterial phase+portal-venous phase (AUC=0.84, P=0.01) and arterial phase+delayed phase (AUC=0.85, P=0.03). Arterial phase+portal-venous phase had a smaller AUC (0.84) than arterial phase+delayed phase (0.85), but the difference was insignificant (P=0.15). After combining MSCT enhancement scan with AFP, the AUC, sensitivity, and specificity were 0.95, 94%, and 83%, respectively, indicating a greatly increased diagnostic efficiency for sHCC.

 

CONCLUSIONS: The combination of AFP and 3 phases MSCT enhancement scan could increase the diagnostic efficiency for sHCC on the background of liver cirrhosis. The application of ROC curve analysis has provided a new method and reference in HCC diagnosis.

 

(Hepatobiliary Pancreat Dis Int 2017;16:303-309)

 

KEY WORDS: hepatocellular carcinoma; receiver operating characteristic; multi-slice spiral CT; alpha-fetoprotein; delayed phase imaging

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has shown an increasing incidence in recent years.^[1] Liver cirrhotic patients have a far higher risk of HCC than other populations.^[2] Small hepatocellular carcinoma (sHCC) refers to HCC measuring less than 3 cm for 1 nodule or 2 nodules together.^[3] Early diagnosis of HCC is crucial to improving the prognostic effect of treatments. CT scanning is the primary method for HCC detection and diagnosis, in particular multislice spiral CT (MSCT), which plays an important role in sHCC diagnosis, differential diagnosis, and even HCC staging.^{[4, 5]} In recent years, some researchers^[6-9] have started to focus on the diagnostic value of delayed phase imaging for sHCC. Takayasu et al^[8] found that delayed phase imaging could improve diagnostic sensitivity for HCC (especially sHCC). Regarding HCC detection, CT enhancement imaging in the portal-venous phase is usually less sensitive than that in the arterial phase, because the majority of the blood supply of the hepatic parenchyma is through the portal vein. There is also hepatic parenchymal enhancement in the portal-venous phase; because hepatic parenchymal enhancement and tumor enhancement usually present similar densities, tumor detection rate is significantly reduced in the portal-venous phase. However, CT enhancement imaging in the portal-venous phase helps detect hypovascular liver tumors, such as liver metastasis from colorectal cancer, since hepatic parenchyma obtains the maximal level of enhancement in the portal-venous phase, resulting in a clear difference in the CT enhancement level from non-enhancement liver metastasis. In addition, portal-venous enhancement imaging helps identify some portal-venous complications, such as tumor thrombus. sHCCs are usually highly differentiated hypovascular tumors. Compared with large HCC or late-stage HCC, sHCC has less arterial blood supply and no enhancement; thus, it does not have obvious enhancement in arterial phase imaging, resulting in a lower detection rate of sHCC in arterial phase than that in late-stage HCC.

 

HCC patients usually have relatively elevated alpha-fetoprotein (AFP) levels, while cirrhotic patients have lower AFP levels.^[10] Although AFP level is commonly utilized as a biomarker for sHCC screening, its validity for sHCC diagnosis is still controversial. For instance, the study conducted by Sangiovanni et al found that only 38% of sHCC patients had elevated AFP levels.^[2] AFP levels depend on tumor size; late-stage HCC patients have relatively high AFP levels.^{[11, 12]} In order to further determine the diagnostic value of AFP levels for sHCC, the receiver operating characteristic (ROC) curve^[13] analysis method has been adopted by many researchers. There are currently two types of studies; the first type independently evaluates the diagnostic value for sHCC by calculating sensitivity, specificity, diagnostic accuracy, the area under ROC curve (AUC). In order to determine the value of AFP levels for diagnosis of sHCC on the background of liver cirrhosis, Sarwar et al^[14] plotted the ROC curve and found that the AUC was 0.85 and the best diagnostic threshold of AFP was 20.85 ng/mL. They suggested that although the AFP method has a low sensitivity in sHCC diagnosis, it is still an effective tumor marker for sHCC screening. The second approach determines AFP’s contribution to sHCC diagnosis by comparing sHCC diagnosis indexes between AFP and other tumor markers. Jiang et al^[15] performed ROC curve analysis to compare the HCC diagnosis contributions of AFP and AFP-IgM immunocomplex, and the best diagnostic thresholds were determined to be 10 µg/L and 300 AU/mL, respectively. They suggested that AFP has a certain value in sHCC diagnosis, and measuring it in combination with other tumor markers or imaging diagnostic methods would greatly improve the ability of sHCC diagnosis.

 

There are so far no studies that have utilized the ROC curve approach to evaluate sHCC diagnosis efficiency by the combination of different MSCT enhancement phases and AFP levels. In this study, ROC curve analysis was used to evaluate three combinations of MSCT enhancement phases (arterial phase+portal-venous phase, arterial phase+delayed phase, arterial phase+portal-venous phase+delayed phase) through a 5-point rating scale, in combination with AFP levels, in order to evaluate the diagnostic value for sHCC in cirrhotic patients. This study aimed to provide new methods and references for evaluating the clinical value of different combinations of CT enhancement phases in HCC diagnosis.

 

 

The study group consisted of pathologically proved 47 sHCC in 35 patients in the Second Affiliated Hospital of Harbin Medical University between January 2013 and December 2014. The study group consisted of 21 men and 14 women, aged 45-80 years old with an average age of 62 years. The control group consisted of 52 cirrhotic patients (patients received an ultrasound examination once every 3 months; each examination was conducted by three experienced radiologists using a double blind method for comprehensive diagnosis, and cancer nodule was never observed), including 30 men and 22 women, aged 34-85 years old with an average age of 61 years. The AFP values of all patients were recorded.

 

Lightspeed 64 Slice spiral CT (GE, USA) was used to scan all patients. The scanning range was from the diaphragmatic dome to the lower edge of the liver; the patients were in a supine position for the upper abdomen scan; the tube voltage was 120 kV; effective tube current was 200-300 mA; thread pitch was 1.375:1; and the rotate speed was 0.6-0.8 s/r. As a contrast agent, 80-100 mL of iopromide (Bayer Schering Pharma AG, Germany) was injected through the cubital vein at a flow rate of 3-3.5 mL/s. Enhancement scans of the three phases were performed at 20-30 seconds, 50-60 seconds, and 2-3 minutes after contrast agent injection.

 

All CT images were uploaded to a workstation with all identification information removed, including patient’s name, age, gender, and hospital record number. These images were evaluated blindly and independently by three experienced radiologists. In order to more accurately evaluate the diagnostic values of the arterial phase, portal-venous phase, and delayed phase for sHCC, the radiologists applied combinations of arterial phase+portal-venous phase, arterial phase+delayed phase, and arterial phase+portal-venous phase+delayed phase for separate diagnoses, and the interval between any two diagnoses was set at 2 weeks. In other words, each radiologist needed to wait for 2 weeks after each diagnosis to make a 2nd diagnosis using another combination of CT images in the same patient. In order to ensure the objectivity and repeatability of the analyses in this study, distinguishing criteria for HCC, dysplastic nodules, arterioportal shunt and focal nodular hyperplasia (FNH) were developed. The criterion for HCC is nodules showing obvious homogeneous or heterogeneous enhancement and appearing hyper-dense compared to surrounding tissue in the arterial phase, iso- or hypo-dense in the portal-venous phase, and hypo-dense in the delayed phase.^[16] Many well differentiated sHCCs share the similar enhancement pattern with dysplastic nodules, which is iso- or hypo-dense in the arterial and delayed phases and hypo-dense in the delayed phase.^[17] These two types of nodules are generally distinguished by size: the diameter of dysplastic nodules is usually smaller than that of well differentiated sHCC, and 10 mm is the cut-off value; nodules larger than 10 mm are considered HCC, while smaller than 10 mm are considered dysplastic nodules.^[18] Meanwhile, differential diagnosis needs to be performed for HCC nodules and arterioportal shunt, because these two usually present similar enhancement patterns: hyper-dense in the arterial phase, hyper- or iso-dense in the portal-venous phase, and iso-dense in the delayed phase. If a focus lesion manifests as a typical wedge shape with or without an internal linear branching structure, it is seen as an arterioportal shunt. If a lesion presents a round shape, it is presumed to be HCC;^[19] however, the confidence level was set at 3 (might happen). Since FNH is a benign tumor that is usually confused with HCC, it is necessary to differentiate it from HCC. On contrast-enhanced CT, FNH usually presents homogenous hyper-enhancement in the arterial and portal-venous phases and iso-enhancement in the delayed phase. A common feature of FNH is its central scar which is visible on contrast-enhanced CT. Therefore, if it manifests the typical stellate scars at the central of the nodule and iso-dense in the delayed phase, the nodule is seen as an FNH. The radiologists used a 5-point rating scale for their diagnosis: “1” corresponds to a definite negative, “2” to a possible negative, “3” to a possible positive, “4” to a highly possible positive, and “5” to a definite positive diagnosis.^[20] In order to calculate diagnostic accuracy, sensitivity, and specificity, results equal to or greater than 3 were considered sHCC, otherwise, the diagnosis was liver cirrhosis only. In order to confirm whether measuring AFP levels helps increase the diagnostic value of MSCT enhancement scan for sHCC, the radiologists were asked to re-assess with the 5-point rating scale based on a combination of AFP levels (a study^[14] showed that the best diagnostic threshold of AFP for HCC on the background of liver cirrhosis was 20.85 ng/mL; the corresponding sensitivity and specificity were 72.2% and 86.2%, respectively) and images of arterial phase+portal-venous phase+delayed phase. The 2nd review has to wait for at least 2 weeks after the 1st review. The same 5-point rating scale was used, and follow-up statistical analyses were also performed.

 

The detection rate is defined as the ratio of the total number of hyper-dense to hypo-dense foci found in a given MSCT phase. Data analysis was performed with SPSS 18.0 software. Pathological examination of the tumor tissue was employed as the gold standard. Based on the radiologists’ diagnoses and the patients’ pathological results, ROC curves were plotted for the diagnostic results (rescored based on AFP and 3-phase combination images) of MSCT images of arterial phase+portal-venous phase, arterial phase+delayed phase, and arterial phase+portal-venous phase+delayed phase, as well as 3-phase combination MSCT+AFP level. AUCs were obtained to evaluate the diagnostic value of different enhancement phase combinations for sHCC on the background of liver cirrhosis. Measurement data were analyzed through Wilcoxon signed-rank test; enumeration data were analyzed by Fisher’s exact test; and P<0.05 was considered statistically significant. The kappa statistic was utilized to assess the consistency of diagnostic results in a pair-wise manner; a kappa value <0.4 suggests poor consistency, a kappa value between 0.41 and 0.75 suggests good consistency, and a kappa value >0.75 suggests high consistency.^[21]

 

 

The diameter of sHCC ranged between 7 and 20 mm, with an average of 14 mm. The enhancement patterns of sHCC are shown in Table 1. Through statistical analysis of enhancement patterns, it was found that sHCC usually appeared hyper-dense compared to surrounding tissue in the arterial phase (Fig. 1A), iso- or hypo-dense in the portal-venous phase (Fig. 1B), and hypo-dense in the delayed phase (Fig. 1C). Fisher’s exact test showed significant differences between the enhancement pattern of the arterial phase and that of the portal-venous phase and the delayed phase (both P<0.01), as well as a significant difference between the enhancement patterns of the portal-venous phase and the delayed phase (P<0.01). The detection rates of the arterial, portal-venous and delayed phases were 83.0%, 61.7%, and 87.2%, respectively, with a significant difference in the detection rates of the three phases (P<0.01). Moreover, the detection rates of the arterial and delayed phases were significantly higher than that of the portal-venous phase (P<0.05; P<0.01), and there was no significant difference between the detection rates of the arterial phase and the delayed phase (P=0.77).

 

In this study, three radiologists participated in the sHCC diagnosis employing 3 phase combination modes of MSCT enhancement scan, while the kappa statistic was adopted to evaluate the diagnostic consistency between pairs of radiologists. The sHCC diagnostic results using any phase combination of MSCT enhancement scan were all highly consistent (kappa: 0.68-0.82). Arterial phase+portal-venous phase+delayed phase had the highest kappa value, and arterial phase+delayed phase had a slightly higher consistency than the combination of arterial phase+portal-venous phase (Table 2).

 

In Table 3, the arterial phase+portal-venous phase+ delayed phase combination had the highest accuracy (87%), sensitivity (93%), and specificity (82%), and the average AUC was 0.93, significantly greater than that of the arterial phase+portal-venous phase (AUC=0.84, P=0.01) and arterial phase+delayed phase (AUC=0.85, P=0.03). Arterial phase+portal-venous phase had a smaller AUC (0.84) than arterial phase+delayed phase (0.85), but the difference was insignificant (P=0.15).

 

In order to evaluate the overall diagnostic value of the 3 MSCT phase combinations (arterial phase+portal-venous phase, arterial phase+delayed phase, arterial phase+portal-venous phase+delayed phase) for sHCC on the background of liver cirrhosis, the three radiologists’ scores for each image set were averaged to plot ROC curves (Fig. 2), and the AUC values of arterial phase+portal-venous phase, arterial phase+delayed phase, and arterial phase+portal-venous phase+delayed phase were 0.88, 0.89, and 0.97, respectively, indicating that the 3-phase combination had the highest diagnostic accuracy, while the diagnostic accuracy of arterial phase+delayed phase was higher than that of arterial phase+portal-venous phase.

 

The average AFP level of patients in the sHCC group was 165.30 ng/mL, significantly higher than that of the control group (15.40 ng/mL, P<0.01). The radiologists re-scored based on AFP values and MSCT enhancement scan 3-phase combination images. After ROC curve analysis; the obtained AUC values were 0.94, 0.95, and 0.97 (Fig. 3), all greater than the AUC values obtained using only MSCT enhancement scan 3-phase combination. The sHCC diagnostic sensitivity, specificity and diagnostic accuracy based on both MSCT enhancement scan and AFP are shown in Table 3.

 

 

Most sHCC cases have a “fast-in, fast-out” feature: in the arterial phase, tumors appear hyper-dense compared with surrounding hepatic parenchyma, which is the diagnostic basis of sHCC.^[22] In the portal-venous phase, the degree of enhancement rapidly drops and the tumor appears iso- or hypo-dense. In the delayed phase, the enhancement degree keeps dropping and the tumor appears hypo-dense.^{[23, 24]} This is because most sHCC cases are hypervascular tumors; a great amount of portal-venous blood is supplied to the liver, resulting in peak values of the enhancement degree of hepatic parenchyma in the portal-venous phase. Because the hypervascular sHCC also presents a high enhancement state, the hepatic parenchyma and sHCC have similar densities, and thus some sHCC cases appear iso-dense in the portal-venous phase.^[25]

 

Comprehensive ROC curve analysis showed the AUC of arterial phase+portal-venous phase+delayed phase was greater than that of arterial phase+portal-venous phase, or arterial phase+delayed phase. These data indicated that the 3-phase combination for sHCC on the background of liver cirrhosis had the highest diagnostic accuracy. It was pointed out by Choi et al^[26] that the diagnostic accuracy of arterial phase+portal-venous phase was not significantly different from that of the 3-phase combination, and the delayed phase had no diagnostic significance for sHCC. However, sHCC cases in Choi’s study were all hypervascular nodules, whereas many sHCC cases in clinical practice are hypovascular. Arterial phase and portal-venous phase have poor diagnostic value for hypovascular sHCC cases, while the delayed phase plays an important role. MSCT 3-phase enhancement scan can detect the features of sHCC cases with different vascular types, and is favorable for early HCC diagnosis.^[27] Combining images of arterial phase, portal-venous phase, and delayed phase not only increase diagnostic accuracy of sHCC, but also improve focal lesion detection rate.

 

As a common HCC diagnostic method, MSCT multiphase enhancement scan has been frequently investigated by researchers, and selection of the best phase combination has become a research focus. Kim et al^[28] compared the diagnostic values of dynamic enhancement CT 3-phase scan (arterial phase, portal-venous phase and delayed phase) and 4-phase scan (early arterial phase, arterial phase, portal-venous phase and delayed phase) for HCC, and found no significant differences in sensitivity, specificity, AUC between 3-phase scan and 4-phase scan. They concluded that 4-phase enhancement scan does not improve diagnostic accuracy for HCC. Denecke et al^[23] performed MSCT plain scans and 3-phase scans (arterial phase, portal-venous phase and venous phase), calculated and compared the detection rates of plain scan and different phases of enhancement scan, and found all nodules were visible in the arterial or portal-venous phases, and that the detections rates of the arterial phase and the portal-venous phase were both significantly higher than that of the plain scan and the venous phase.

 

Table 1 showed that the detection rate of the delayed phase (87.2%) was higher than that of the portal-venous phase (61.7%), indicating that the delayed phase played an important role in improving diagnostic accuracy for sHCC. This is consistent with the research finding of Iannaccone et al,^[6] who compared the sensitivities and positive predictive values of MSCT enhancement images of different phase combinations in diagnosing sHCC on the background of liver cirrhosis, they found that the delayed phase could significantly increase diagnostic sensitivity, presenting a supporting effect on CT dual-phase scan for HCC diagnosis. Lim et al^[29] compared AUCs of the 3-phase combination and the arterial phase+portal-venous phase combination, and reached a similar conclusion: adding delayed phase imaging into dual-phase CT scan helps describe HCC features and improves diagnostic accuracy. Although adding delayed phase imaging will increase the patient’s exposure to radiation and add extra scanning time, it can improve detection rate and diagnostic accuracy for HCC, thus offsetting the cost of radiation exposure to some extent.

 

While imaging examination has many advantages, AFP is a specific tumor marker for HCC and has an important value in early sHCC diagnosis.^{[10, 30]} In this study, the combination of AFP and MSCT enhancement scan for sHCC diagnosis had an AUC of 0.95, higher than that of the AUC of the MSCT 3-phase combination (0.93). Through ROC curve analysis, this study further confirmed the important role of the combination of MSCT enhancement scan and AFP in improving the diagnostic accuracy for sHCC.

 

Although certain significant results have been obtained, there are still some shortcomings in this study. First, although all patients in this study underwent the same 64-slice spiral CT scan, there have been some changes to the technology over time; since the examinations were performed at different times, there might have been an influence on sHCC detection. Second, parameters such as the dose and injection rate of contrast agent, and the scanning time of each phase were not customized, but were rather set as fixed values due to the limitations of clinical practice, which could also affect the results.

 

In conclusion, the combination of arterial phase+ portal-venous phase+delayed phase and AFP is the most accurate approach for the diagnosis of sHCC on the background of liver cirrhosis, with the highest AUC, sensitivity, and specificity. Compared with the combination of arterial phase+portal-venous phase, the combination of arterial phase+delayed phase had greater AUC in sHCC diagnosis, indicating that the delayed phase has an important role in sHCC diagnosis that should not be overlooked.

 

 

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