Risk Factors of Peritoneal Recurrence and Outcome of Resected Peritoneal Recurrence After Liver Resection in Hepatocellular Carcinoma: Review of 1222 Cases of Hepatectomy in a Tertiary Institution

After resection, tumor recurrence rate is exceedingly high in HCC, reaching about 70% at 5 years.7,25‐27 Most of the recurrences occur within the liver. Common sites of systemic metastasis of HCC after resection are lungs, bones, and brain. Other systemic sites such as adrenal glands, spleen, pancreas, and ovaries are usually not detected until autopsy.28‐30 PR in HCC is uncommon. The reported incidence ranged 2–16%.11‐14,31 In our series, the PR rate was 3.0%. The rate of unresectable PR was 1.9%, while another 1.1% underwent resection of PR after liver resection.

Because PRs after hepatectomy for HCC are rare, many previous reports related to PRs were included in studies focusing on extrahepatic recurrences. In comparison, our study solely examined the risk factors of PR in the cohort of patients. Cha et al. from Memorial Sloan-Kettering Cancer Center reported that tumor size of >5 cm and presence of vascular invasion were significant predictors of extrahepatic recurrences in HCC after resection. These two factors were similarly found to be significant predictors for PR in our cohort. Furthermore, a positive resection margins was not found to be a significant factor as a result of its low frequency in their study.32 In contrast, we found that positive resection margin was a significant predictor of PR, whereas presence or portal vein/hepatic vein invasion was not. Furthermore, the presence of bile duct invasion was found to increase the risk of PR in our study. In terms of the pattern of distribution of PR, we noted that the omentum was the most common site (47.2%), followed by the posterior peritoneal lining (inclusive of parietal peritoneal surface of diaphragm). This was consistent with the pattern observed in the study by Yeh et al., in which omental nodules constituted 50% of all cases.23 However, it is important to emphasize that our series included both resectable and unresectable PR, whereas Yeh et al. studied only resected PR patients.

Ruptured tumor has commonly been postulated to increase the risk of PR in HCC. Most of the reports on peritoneal metastasis after ruptured HCC were case reports. Many of the reports note that peritoneal metastases occurred 8 months after tumor rupture, although some occurred as early as 3–4 months after ruptured HCC.33,34 In our study, there were only two patients in the PR group with a history of ruptured HCC. One of them developed four isolated peritoneal lesions 1 month after hepatectomy and underwent resection of those lesions (because no other distant metastasis was noted). Another patient developed seven disseminated peritoneal nodules with multiple intrahepatic lesions at 6 months after liver resection after ruptured HCC and was treated conservatively. This differs greatly from many reports suggesting that a single metastatic nodule is the most common presentation for PR after ruptured HCC.33,34 Shin et al. reported a patient who survived a long time with recurred HCC after three bouts of repeated hepatic resection for intrahepatic recurrences and one bout of right hemicolectomy for an omental recurrence.35 In the current study, ruptured HCC was a significant factor for PR by univariate analysis but did not show significance on multivariate analysis, probably as a result of the low incidence of ruptured HCC in our cohort (n = 14, 1.2%).

Tumor markers levels, such as prehepatectomy PIVKA-II, AFP, and PIVKA-II level at detection of PR, were all significantly higher in patients with unresectable PR. This could indicate that the higher tumor load and the disseminated nature of the disease could preclude them from undergoing potentially curative surgical resection of PR. Indeed, most of the patients with unresectable PR had concomitant intrahepatic tumor recurrence and/or other systemic metastases. We also found that patients with smaller HCC (≤50 mm) and lower T stage of tumor at primary hepatectomy were more likely to undergo resection of PR. In addition, they also had significantly fewer lesions (median 1.0, range 1.0–4.0) compared to those resectable disease (median 2.0, range 1.0–7.0). In this regard, Yeh and Chen reported that tumor capsule invasion and elevated AFP level >400 ng/ml were significant predictors of peritoneal implantation after hepatectomy.13

Reports on the long-term survival outcome of patients with peritoneal metastasis after hepatectomy are scarce in the literature, leading to a lack of recommendations in the management of PR in HCC. In general, when PR occurs in HCC, surgical resection with curative intent would not be considered. In one rare report of 20 year data by Lin et al., patients with metachronous peritoneal metastasis experienced a median survival of 12.5 months—significantly longer than those who did not undergo PR resection (2.1 months).14 In addition, Nakayama et al. reported that resection of peritoneal metastases arising from HCC is justified because patients experienced disease-free survival and OS of 11.8 to 81.6 months after salvage therapy.12 In our series, the median OS for resected PR was 33.0 months, which was significantly longer than patients with unresectable PR (median OS 15.0 months). The 5 year survival for resectable PR was 48.0%, compared to 6.0% in patients with unresectable PR.

Some patients with PR after resection of HCC may experience good long-term survival if the peritoneal metastasis was resected. In the current study, in addition to resection of the peritoneal lesions, longer interval between hepatectomy and detection of PR > 6 months was a positive prognostic factor for OS. On the other hand, presence of serosal involvement and high AFP levels of >200 ng/dl at detection of PR were significant negative predictors of survival in PR. Indeed, a long disease-free interval suggested that there was a subset of patients with better tumor biology, and thus the peritoneal metastasis took a much longer time to become clinically evident. This group of patients would certainly experience better long-term survival after peritoneal metastasectomy. There were a few long-term survivors in our series with disease-free intervals of more than 48 months and an OS of more than 5 years. Two were still alive at the time of last follow-up.

Although resection of HCC was associated with a high incidence of recurrence, aggressive therapy for the recurrence is a key strategy in prolonging survival. On the basis of our analysis, we strongly recommend that surgical resection of PR be offered as an option as part of a multimodality therapy in HCC after hepatectomy in selected patients. Suitable candidates include patients with small tumor size (HCC ≤ 50 mm), low T stage of tumor, prehepatectomy PIVKA-II level of <200 mg/dl, low AFP level at detection of PR (<200 ng/dl), and long interval between hepatectomy and PR (>6 months).

Finally, we acknowledge that the retrospective nature of this analysis is a limitation of the study. The study could potentially underestimate the real incidence of PR, which was the reason why we reviewed such a large series of patients and went through their post-HCC resection scans in such detail. Further prospective studies would result in a better understanding of this condition. However, we recognize that this would be a difficult task because of the low incidence of PR in HCC.

In conclusion, peritoneal metastases of HCC are rare. Risk factors that we identified as predictors of PR after hepatectomy for HCC included tumor size >50 mm, presence of MVI, bile duct invasion, and positive resection margins. Selected patients with small tumor size (HCC ≤ 50 mm), low T stage of tumor, prehepatectomy PIVKA-II level <200 mg/dl, low AFP level at detection of PR (<200 ng/dl), and long interval between hepatectomy and resected PR (>6 months) would be suitable candidates for resection of PR.