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Is the anatomical resection necessary for single hepatocellular carcinoma smaller than 3 cm?: single-center experience of liver resection for a small HCC.

Backgrounds/Aims
The superiority of anatomical resection (AR) for a small HCC remains controversial. In this study, we investigated the clinical outcomes after AR and non-anatomical liver resection (NAR) for single HCC smaller than 3 cm and the risk factors for HCC recurrence.


Methods
A total of 116 consecutive patients who underwent liver resection for single HCC (<3 cm) between Jan 2006 and Dec 2015 were included in this study. The medical records of these patients were reviewed and analyzed retrospectively.


Results
There was no significant difference in tumor recurrence and survival between AR and NAR group. Multivariate analysis showed that hepatitis B (p=0.035, HR=8.72), presence of satellite nodule (p=0.029, HR=3.97) and microvascular invasion (MVI) (p=0.039, HR=2.79) were independent risk factors for early recurrence within 1 year. The overall recurrence was independently related to the presence of satellite nodule (p=0.001, HR=4.98) and background liver cirrhosis (p=0.032, HR=1.96). In patients with MVI, HCC recurrence was significantly more frequent in width of safety margin <1 cm group than ≥1 cm group (p=0.049).


Conclusions
The outcomes of NAR are comparable with those of AR in single HCC smaller than 3 cm. The presence of satellite nodule, MVI and hepatitis B are the independent risk factors for early recurrence, however overall recurrence is correlated with background liver cirrhosis and the presence of satellite nodule rather than pathobiologic factors in single HCC smaller than 3 cm. Hepatic resection with sufficient margin (≥1 cm) is recommended for decreasing risk of recurrence in patients with suspected MVI.


INTRODUCTION
With the advance in imaging technologies and improved HCC surveillance, the incidence of early stage tumor has been improved gradually and effective treatment of early stage HCC has become increasingly important. 1 Although HCC surveillance and advance in treatment technologies have led to improved patient survival, the rate of recurrence is still high. Hepatic resection (HR) and radiofrequency ablation (RFA) are now widely used to treat patients with early stage HCC. Although it remains debatable which treatment has superiority over other, HR has been regarded as the first-line treatment for patients with early stage HCC and preserved hepatic function due to its acceptable mortality, morbidity and long-term outcomes. [2][3][4] Anatomical resection (AR) is defined as resection of the tumor including tumor-bearing portal vein territories. 5 Theoretically, HCC has a high propensity to invade the intrahepatic vascular structures and spreads mainly through the portal venous system rather than by adjacent diffusion; [6][7][8] thus, AR is regarded as effective treatment to avoid intrahepatic metastasis and recurrence. However, AR needs to sacrifice a large amount of liver parenchyma and is therefore significantly unfavorable for treating a liver that has an underlying disease. On the contrary, non-anatomical resection (NAR) is the conventional limited resection focused on achieving a non-tumoral liver parenchyma rim, without consideration of the Glisson's pedicles. 9,10 While some studies have reported the superi-ority of AR over NAR, [10][11][12][13] other studies have shown no prognostic difference between AR and NAR, 8,14,15 and some meta-analyses have also reported conflicting conclusions. [16][17][18] Therefore, the ideal treatment for HCC remains debatable.
A Japanese nationwide study demonstrated that AR is only beneficial for HCC of 2 to 5 cm, and not for very small HCC less than 2 cm. 19,20 Usually, HCC smaller than 2 cm is accepted as very early HCC and larger than 5 cm as large HCC. However, size range of 2 to 5 cm can be ambiguous and HCC of 2 to 3 cm is also accepted as early stage HCC in BCLC staging system. Therefore, we compared the outcomes following AR and NAR in patients with solitary HCC smaller than 3 cm and investigated the prognostic risk factors for HCC recurrence in these patients.

Comparison of demographics and clinicopathologic features between resection groups
The demographics and clinical features of the 116 patients are summarized in Table 1. Among these patients 92 patients were male (79.3%) and 24 patients were female (20.7%). The mean age of patients was 56.4 years.
All of these patients were classified as Child-Pugh A in  1A) and recurrence-free survival rates were 84, 63 and 47%, respectively (Fig. 1B).
In comparison of the clinicopathologic characteristics between AR and NAR group, there was no significant differences in demographics and pathologic findings except tumor location (Table 1 and 2). The 1-, 3-and 5-year  2A). There was no significant difference in overall survival between AR and NAR group (p=0.78). The 1-, 3-and 5-year recurrence-free survival rates were 75, 56 and 43% in AR group, and 90, 70 and 51% in NAR group, re-spectively (Fig. 2B). There was also no significant difference in recurrence-free survival between AR and NAR group (p=0.455).
Although there was no significant difference between groups in recurrence time and pattern, tumor recurrences within 1 year after resection were more frequent in AR   after resection (Table 4). In the aspect of overall recurrence after resection for HCC smaller than 3 cm, satel-lite nodule (HR 6.21; p=0.005) and background liver cirrhosis (HR 1.96; p=0.032) were revealed as independent risk factors in multivariate analysis (Table 5).

Relation between safety margin, microvascular invasion and recurrence
In terms of recurrence, width of safety margin (margin ＜1 cm) was not correlated with HCC recurrence after surgery in single HCC smaller than 3 cm (Fig. 3A).
Although MVI was the independent prognostic factors for early recurrence (within 1 year), overall recurrence was not significantly affected by MVI (Fig. 3B) (Fig. 3C).

DISCUSSION
Liver resection has been accepted as the gold standard treatment for solitary HCC in patients with well-preserved liver function. 22 However, the superiority of AR has been still controversial. Recently, with the technical improvement, laparoscopic liver resection has been widely applied for the treatment of HCC and NAR can be performed more easily than AR with laparoscopy especially in cases of small HCC which is protruded or located peripherally.
For this reason, the proportion of laparoscopic resection was significantly higher in NAR group than AR group in this study.
Previously several retrospective studies reported the superiority of AR for HCC in the aspect of recurrence and survival. 9,[11][12][13]23 However, most of these studies have significant selection bias of patients, the difference of reserved liver function which is a significant postoperative Our results showed that the outcomes of NAR in terms of recurrence pattern, recurrence-free survival, and overall survival were not different from those in AR ( The limitations of this study include its retrospective nature, small volume cohort from single center and selected population. Furthermore, most of patients in this study showed favorable biologic behavior and some factors which accepted as powerful prognostic factors were observed in very few patients. this could raise the possibility of statistical error. However, similar liver function in all patients (well-preserved liver function) and no difference in clinical and pathologic findings between groups can minimize the risk of selection bias. In addition, when considering the less aggressive biologic nature of early HCC, our results might be accepted as a meaningful data.
In conclusion, the outcomes of NAR were comparable with those of AR in patients with single HCC smaller than 3 cm and well-preserved liver function. Although MVI was not correlated with overall survival and recurrence, early recurrence was significantly affected by MVI, and the outcome of resection with safety margin ＜1 cm was shown worse than safety margin ≥1 cm. Therefore, wide resection with adequate safety margin is recommended in patients with single HCC smaller than 3 cm. In terms of overall recurrence, back ground liver status such as cirrhosis and viral activity has more significant impact on prognosis rather than pathobiologic behavior in single HCC smaller than 3 cm.