Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide.^[1] It has a higher mortality rate among cancers. Hepatectomy, liver transplantation, and local ablative therapies^[2] are the treatment modalities which may provide a chance of cure for HCC. The common mode of treatment failure is tumor recurrence.^{[3, 4]} Tumor size and tumor number are associated with disease recurrence after hepatectomy^{[3, 5]} or liver transplantation.^[6] Venous invasion is another consistently reported risk factor for recurrence after hepatectomy, as intrahepatic metastasis via the portal venous system is an important mechanism of cancer spread.^{[7, 8]} These factors have been included in the more recent HCC staging systems.^{[9, 10]} However, the prognostic value of the presence of pseudo-capsule and the location of HCC has not been fully examined. They could be important in the treatment planning for the disease. We studied the preoperative radiological features of HCC displayed by computed tomography or magnetic resonance imaging with the aim of identifying features which may be of prognostic significance in hepatectomy.


Methods
The study covered patients who underwent resection of HCC at our hospital from January 2005 to December 2008. Patient data including preoperative imaging details were collected prospectively and stored in a single database. Preoperative imaging details were reviewed blindly, and the data on tumor number and size, portal vein invasion, hepatic vein invasion and presence of pseudo-capsule were analyzed retrospectively. The radiological features are illustrated in Fig. 1. The lesions were categorized into three types: peripheral lesions that did not involve the middle one-third of the liver; middle lesions that did not involve the inner one-third of the liver; and central lesions that involved the inner one-third of the liver. Pseudo-capsules were hypoattenuating or hypointense rings on unenhanced computed tomography scans or magnetic resonance imaging scans and became hyperattenuating or hyperintense in the portal-dominant phase.^[11]

Values were expressed as median with range. Non-parametric tests were used for analysis. The primary end-point was overall survival and the second end-point was disease-free survival. Survival curves were computed with the Kaplan-Meier method and compared between groups by the log-rank test. Cox proportional hazard models were performed to define factors that determined the overall and disease-free survival rates. All statistical analyses were made using statistical software (SPSS 16.0 for Windows, SPSS Inc., Chicago, IL., USA). A P value <0.05 was considered to be statistically significant.


Results
Ninety-two patients were the subjects of the study. We had their full set of relevant data including radiological details. Table 1 lists the patient demographics and radiological and histopathological features of the HCCs. Radiological imaging showed that 53 patients had a median largest tumor size of >5 cm, 15 between 3 and 5 cm, and 24 with <3 cm. The majority of patients (75/92, 81.5%) had single nodular HCC. Forty-three (46.7%) had gross hepatic vein invasion and 40 (43.5%) of these had gross portal vein invasion. The feature of pseudo-capsule was present in 18 (19.6%) patients.

With a median follow-up period of 41.7 months, the 1-, 3-, and 5-year overall survival rates were 85%, 65%, and 58%, respectively (Fig. 2A). The median disease-free survival rate was 22.1 months (Fig. 3A). Patients who had HCC with pseudo-capsule had better overall survival (P=0.038) and disease-free survival (P=0.01) (Fig. 2E, 3E). Patients who had HCC with portal vein invasion had poorer overall survival (P=0.004) and disease-free survival (<0.001). Patients who had central lesions tended to have poorer overall survival (P=0.057). Patients who had solitary, small, or peripheral tumors had better disease-free survival (P<0.05) but not overall survival. Patients who had hepatic vein invasion had poorer disease-free survival (P=0.016) (Fig. 3G) but not overall survival (Fig. 2G).

Multivariate analysis found that no factor was significantly associated with overall survival, and that patients who had tumors with portal vein invasion had poorer disease-free survival with a hazard ratio of 2.26 (95% CI, 1.05-4.91; P=0.038) and patients who had single nodular HCC or pseudo-capsulated HCC had better disease-free survival with hazard ratios of 0.50 (95% CI, 0.27-0.94; P=0.032) and 0.38 (95% CI, 0.14-0.99; P=0.048), respectively (Table 2).


Discussion
The presence of pseudo-capsule was found to be a favorable prognostic factor in the study. Nevertheless, this feature is not included in existing HCC staging systems. In fact, more aggressive treatment can be considered for patients who have HCC with pseudo-capsule, particularly potential candidates for primary or salvage liver transplantation, despite a large HCC. In the study, pseudo-capsules were present in 19.6% of patients with HCCs between 1.8 and 9.8 cm. It has been reported that solitary large HCCs (>5 cm in diameter) growing expansively within an intact capsule or pseudo-capsule have a clinical outcome similar to that of small HCCs and significantly better than that of nodular HCCs,^[12] and that histologically confirmed encapsulated HCCs entail a better long-term outcome.^{[13, 14]} Pseudo-capsulated HCC with a peripheral enhancing rim can be detected by computed tomography or magnetic resonance imaging.^[15-17] Histopathologically, the pseudo-capsule is composed of an inner layer rich in collagen and an outer layer containing various amounts of the portal vein, bile duct, compressed artery and collagen fibers.^{[18, 19]} Encapsulation is associated with markedly lower tumor invasiveness represented by a lower incidence of venous permeation, liver invasion, and tumor microsatellite formation as well as a higher incidence of negative surgical margins.^[20]

HCC is characterized by its propensity for vascular invasion. Portal venous invasion is widely accepted as an important mechanism of intrahepatic recurrence.^[21] T3b (major vascular invasion of portal or hepatic veins) in the 7th AJCC staging system has been shown to have poorer prognosis than T3a (multiple tumors, any >5 cm).^[22] Microvascular invasion is also regarded as a histological prognostic factor, and irregular circumferential peritumoral enhancement on magnetic resonance imaging has been reported to be a surrogate marker.^[23] It was not surprising to find a poorer outcome in HCC patients with portal venous invasion in our study. HCC with pseudo-capsule shown in radiological imaging entailed a better outcome after hepatectomy. The findings are consistent with a previous pathological finding that encapsulated tumors show a lower incidence of direct liver invasion, tumor microsatellite formation, and venous permeation compared with non-encapsulated ones.^[16]

In the present study, disease recurrence increased with portal vein invasion and decreased with HCC which was solitary or with pseudo-capsule. In principle, anatomical resection should eradicate the spread of HCC via the portal vascular territory of the supplied segments. However, such a surgical plan may not be executed precisely in all cases in practice. On the other hand, HCC which is solitary or with pseudo-capsule is a feature of expanding instead of permeating growth of the tumor, albeit malignant. Achieving adequate and clear margins will be easier if reference is made to preoperative imaging or intraoperative ultrasonography. In the present study, patients with HCCs which were central in location had poorer disease-free survival (P=0.001) and tended to have poorer overall survival (P=0.057). The central location of the lesions increased the chance of involvement of more proximal branches of the portal vein and thus intrahepatic spread of the tumor.

The present study only included patients with full documentation of preoperative imaging in the hospital network system, so these were not consecutive cases, which could be a potential source of bias. Nonetheless, all the images were from one single institute using one single protocol, which lowered the chance of error caused by variation in image quality.

The presence of pseudo-capsule and portal vein invasion were associated with overall survival (P<0.05, univariate analysis) but they were not independent predictive factors (P>0.05, multivariate analysis). Actually, there was a negative correlation between portal vein invasion and the presence of pseudo-capsule; nearly all tumors with portal vein invasion (38 of 40 patients, 95%) were not encapsulated.
Prognostication is of value for patients to know their chance of cure. If disease-free survival is much worse than overall survival, a radical change of treatment modality should be considered. A staging system should also direct treatment strategy. Primary liver transplantation, which incorporates total native liver hepatectomy, is the most radical oncological resection of HCC and gives patients the lowest chance of local recurrence. Also a radical secondary prevention measure, it eliminates the development of new HCC.[^24]

In current patient selection systems for liver transplantation, for example the Milan,^[6] UCSF^[25] and Hangzhou criteria,^[26] tumor morphology is not included but only size and number. The presence of multiple tumors (n>3) is more likely to entail post-transplant recurrence and is related to poorer patient survival after transplantation.^[27] However, it has been shown that the correlation between imaging findings and explant histology in tumor size and number is not accurate enough, especially for small lesions.^[28] We have found in this study that demonstrable pseudo-capsule of HCC and solitary HCC on imaging and absence of portal vein invasion are features implying better disease-free survival after hepatectomy. Therefore, the inclusion of tumor morphology may improve the prognostic power of these selection systems.