CHC is an uncommon liver tumor with distinctive biological behavior and clinicopathological features. Due to its rarity, the clinical information is limited, especially for the patients’ survival and recurrence. In the present study, we developed and externally validated a novel prognostic score for postoperative CHC patients. This final model was based on 5 independent predictors with C-index of 0.651 (95%CI, 0.593–0.710) and presented better performance in recurrence prediction than AJCC 7th TNM staging system.

Growing evidences document CHC as an aggressive cancer with dismal prognosis, and the tumor recurred frequently at the liver.16,25,26 Previously, we demonstrated that CHC had a median prognosis between HCC and ICC.4 Further, we observed that the CHC patients had a short OS (18.1 months) and DFS (11.0 months) similar to previous studies.5,27 CHC was thought to be derived from hepatic progenitor cells with the biopotential to differentiate into both hepatocytes and cholangiocytes.6,28Aoki et al20 reported that the prognosis of CHC might be like that of mass-forming ICC, though the clinical characteristics of CHC are similar to those of HCC. However, several studies indicated that there was no relationship between poor outcome and the predominance of ICC cells (or HCC cells).29,30 Further studies are needed to investigate the intrinsic mechanism of CHC.

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Definitive evaluation of recurrent predictors in resected CHC patients has not been well established. Previous studies found that tumor number, vascular invasion, radical resection, lymphoid metastasis and tumor stage were prognostic factors for CHC patients.1,3,4,25 Kim et al also reported that CA19-9 was a risk predictor for CHC patients.1 In our present study, five risk factors (sex, GGT, macrovascular invasion, lymphoid metastasis and adjuvant TACE) were identified as independent factors associated with recurrence. Interestingly, sex was selected as an independent risk factor related to CHC recurrence in our model, unlike tumor markers (serum AFP, CA19-9 or CEA). Previous studies indicated that CHC was more prevalent in male population, particularly in the endemic area of chronic hepatitis.25,31,32 The causative association between sex and recurrence of CHC patients is required to be confirmed in future studies. Consistent with previous studies,5,33 GGT, a risk factor of liver cancer, was found to be associated with RFS in our study. Macroscopic vascular invasion, the essential causes of intrahepatic recurrence and long-term survival, was also identified as an independent predictor of CHC recurrence in accordance with previous studies in HCC34,35 and ICC.36 In liver cancer, Wang et al37 revealed that the prognosis of patients with lymph node metastasis or direct invasion and local metastasis was significantly poor. Also, lymphoid metastasis was found to be an independent predictor of recurrence with a HR of 2.443 (95% CI, 1.341–4.450) in the present study. Extrahepatic recurrence was reported mainly in lymph nodes of CHC patients,5 suggesting that regional nodal groups need to be resected during operation.

Different from HCC, the pathological pattern of CHC is less vascular and much more fibrotic tissues, resulting in poor uptake of chemotherapeutic agents. Retrospective studies have shown that TACE could improve survival outcomes in recurrent or unresectable CHC patients,38,39 especially for hypervascular lesions. However, in patients with peripherally enhancing lesions, the prognosis was worse than HCC or globally enhancing CHC patients.39 In our study, we found that adjuvant TACE did not have a preventive effect, but may increase the risk of recurrence for resected CHC patients. The explanations may be as follows: first, patients benefiting from adjuvant TACE were mainly combined with an intermediate or high risk of recurrence;17 second, CHC is an uncommon tumor with significant heterogeneity and aggressive biological behavior, patients with residual tumor may not respond to postoperative TACE; third, in our study, nearly 60% of patients combined with chronic HBV infection, the injury derived from TACE may promote local recurrence of CHC. Further investigation will be needed to verify the clinical efficacy of adjuvant TACE in CHC patients after hepatectomy.

How does our constructed model potentially influence clinical practice for CHC patients? First, it could help clinicians predict the likelihood of recurrence in postoperative CHC patients. In the present study, the probability of recurrence in patients with score 0, 1, 2, 3 and 4 at 1 year was 11.1%, 20.0%, 29.9%, 45.9% and 72.7%, respectively. Second, the PECAR score will help us to determine whether CHC surveillance after resection is warranted. Previous studies indicated that the prognosis of CHC may be worse than HCC or ICC patients, implying that the surveillance should be modified and fitted for CHC patients in clinical practice. Currently, the clinical efficacy of therapeutic strategies on CHC after surgery remains unclear, and our PECAR score may facilitate the improvement of postoperative management of patients with intermediate or high risk of recurrence in the future.

This study is not devoid of limitations. First, the study is based on a retrospective cohort in China, with over 60% of patients having HBV infection; prospective studies in different populations are required to further validate our model. Second, our predictive model is used for postoperative decision-making. Third, genomic analyses were not performed for resected tumor specimens. Genomic classification has been shown to provide unique prognostic information, except for clinical parameters, and may help to identify patients at higher risk for subsequent metastatic tumor formation.

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