Postoperative complications affect early recurrence of hepatocellular carcinoma after curative resection

Hepatocellular carcinoma (HCC) is the 5th most common malignancy and ranks the 3rd cause of cancer-related death worldwide. Although hepatic resection is an effective treatment option for HCC, the long-term prognosis remains poor in most series mainly because of the high tumor recurrence in the remnant liver [1].

With improvements in careful patient selection, surgical techniques and perioperative care, hepatectomy for HCC has become a safe procedure with a reported operative mortality rate lower than 5 % at high-volume centers. However, the incidence of complications is as high as 30.9–42.6 % [2‐4]. Several studies have assessed the impact of postoperative complications on long-term survival in patients with HCC [2, 5‐7], but few data are available in the literature regarding its impact on the risk of tumor recurrence. To clarify this issue, we conducted a retrospective study of 274 consecutive patients who underwent curative resection for HCC.

Complications after hepatectomy for HCC are common with morbidity rates between 30.9 and 42.6 % [2‐4]. In line with literature, a morbidity rate of 37.6 % was observed in the present study. The most common were ascites or pleural effusion. The high incidence of ascites was probably related to high portal pressure after liver resection, which can trigger massive ascites by stimulating neurohormonal systems to promote renal water and sodium resorption [10]. The changes generated by vascular clamping and instruments working close to the diaphragm during hepatectomy may increase the risk of pleural effusion [11].

There is no doubt that postoperative complications may lead to prolonged hospital stay and higher medical costs. Recent evidence has suggested that postoperative complications also have negative impact on long-term survival in patients with gastric cancer [12], esophageal cancer [13], pancreatic cancer [14], hilar cholangiocarcinoma [15], and colorectal liver metastasis [16, 17]. To the best of our knowledge, there have been four studies on the effect of postoperative complications on the survival and prognosis of HCC patients. In a study of 863 HCC patients undergoing curative resection, Chok et al. [5] found that the presence of postoperative complications was independently associated with poor OS. In another study of 291 patients, Kusano et al. [2] reported that the 5-year OS rate was significantly lower in patients with perioperative complications than that in those without these complications (34.3 % vs.48.7 %). Their multivariate analysis showed that the presence of perioperative complications was an independent predictor of poor OS. A study of 100 patients by Mizuguchi et al. [6], and a study of 376 patients by Okamura et al. [7] also reported the similar results. Consistent with previous investigations, our study reconfirmed the prognostic value of postoperative complications.

Few data are available in the literature regarding the potential impact of complications on HCC recurrence. It was found in this study that postoperative complications were associated with a higher HCC recurrence after hepatectomy, and identified as an independent risk factor for early recurrence. This finding is consistent with the finding of Okamura et al. [7], who reported that the recurrence-free survival curve for patients with postoperative complications was steeper than that for the group without, especially from 12 to 24 months. Early recurrence might reflect residual micrometastasis in the liver [9]. In the field of periampullary cancer surgery, the negative impact of postoperative complications on survival is even more prominent in patients with microscopically residual disease [18]. An explanation for negative impact of postoperative complications on cancer recurrence remains unclear. One possible factor promoting metastatic growth and early recurrence is immunosuppression resulting from systemic inflammatory responses [16]. It has been demonstrated that surgical trauma and septic inflammation may promote T-cell commitment toward a T-helper 2-type lymphocyte pattern [19]. The T-helper 2-type cytokines (interleukin-10 in particular) were shown to down-modulate tumor-specific immune response probably through several mechanisms: (i) directly suppressing interferon γ and interleukin-12 production, thereby preventing the activation of cytotoxic T lymphocytes and natural killer cells; (ii) reducing major histocompatibility complex expression on the surface of tumor cells, thus preventing the optimal expression of binary complexes formed by tumor antigen in association with major histocompatibility complex molecules on the surface of such cells; and (iii) inhibiting tumor antigen presentation by antigen-presenting cells [20]. In fact, serum interleukin-10 level was found to be associated with a worse disease-free survival in patients with resectable HCC [21]. As late recurrence is considered as the most significant factor attributable to hepatitis related multicentric carcinogenesis, it is therefore reasonable to conclude that postoperative complications have no effect on late recurrence.

Conventional aggressive biological behaviors of HCC such as vascular invasion, poor tumor differentiation and multiple tumors have been reported to affect recurrence. Our finding presented additional data that the surgeon’s performance is also an important determinant. Similar to other series [2], our study also found that increased intraoperative blood loss was an independent predictor of complications occurrence after hepatic resection for HCC. Various methods of vascular occlusion (such as Pringle’s maneuver, total or selective hepatic vascular exclusion, combination of Pringle’s maneuver and infrahepatic inferior vena cava clamping, and hanging maneuver) and new surgical devices (such as Harmonic Scalpel, radiofrequency electrodes, and staplers) have been suggested for reducing blood loss during liver parenchymal transaction. Some recent studies [22] have suggested that laparoscopic surgery for HCC can reduce intraoperative blood loss without compromising the oncologic outcome. Hepatic surgeons should know how to use these surgical strategies appropriately according to the actual situation in clinical practice.

Unlike previous findings [7], this study failed to show that the use of Pringle’s maneuver is a risk factor for postoperative complications. The main drawback related to Pringle’s maneuver is the hepatic ischemia-reperfusion injury. However, there is ample evidence that liver parenchyma tolerates prolonged ischemic injury better than the effect of massive bleeding and blood transfusion [23]. More importantly, there is no clinical evidence that Pringle’s maneuver adversely affects the oncologic outcome [24]. To avoid irreversible injury to the liver, Pringle’s maneuver should be done with intermittent clamping with an upper limit of 120 min [23].

It was also found in our study that old age was a significant risk factor for postoperative complications occurrence, probably because elderly patients are more likely to have co-morbidities. This emphasizes the need of multidisciplinary preoperative evaluation and postoperative management of elderly patients undergoing hepatic resection [25].

There are several limitations in this study. First, its retrospective nature may inherently incur selection bias. In addition, as this is a single-center study, the generalizability of our findings awaits further investigation. Finally, the effect of classification of postoperative morbidity by the Clavien-Dindo stratification was not analyzed because of the limited number of patients [26]. Farid et al. [16] reported a negative relationship between postoperative morbidity and the oncologic outcome in 750 patients undergoing hepatic resection for colorectal metastases. Interestingly, the severity of complications was found to be irrelevant to the oncologic outcome. A similar observation was also noted by Correa-Gallego et al. [17]. Therefore, any postoperative complications (even minor ones) need to be prevented for the sake of improving the cancer-specific outcome [17].

The results of the present study indicate that the occurrence of postoperative complications is a predictive factor for HCC recurrence after curative hepatectomy, especially for early recurrence. To improve the patients’ oncological outcome, surgeons should do their best to minimize the occurrence of postoperative complications wherever possible. Further large prospective multicenter clinical trials are necessary to confirm our results.