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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 7  |  Page : 2021-2026

Preoperative tumor abnormal protein is a promising biomarker for predicting hepatocellular carcinoma oncological outcome following curative resection


1 Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
2 Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China

Date of Submission09-Jan-2022
Date of Decision10-Sep-2022
Date of Acceptance23-Sep-2022
Date of Web Publication11-Jan-2023

Correspondence Address:
Xiangdong Hua
Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_58_22

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 > Abstract 


Introduction and Objectives: The objective of this study was to explore the potential relationship between tumor abnormal protein (TAP) and the prognosis of hepatocellular carcinoma (HCC) after a radical hepatectomy.
Patients or Materials and Methods: This retrospective study included 168 HCC patients (tumor recurrence in 78 patients) who underwent a curative resection from January 2018 to June 2020. The whole population was categorized into a TAP high (≥224.6 μm2) or a TAP low group (<224.6 μm2).
Results: There was no correlation between maximum tumor size and TAP. In the whole population or subgroups stratified by maximum tumor size, the recurrence-free survival (RFS) rate of the TAP low group was significantly higher than TAP high group (P < 0.05 for all). The multivariate analysis revealed that TAP (hazard ratio [HR], 3.47; 95% confidence interval [CI], 2.18–5.51; P < 0.001), large tumor size (HR, 2.18; 95% CI, 1.36–3.49; P < 0.001), poor tumor differentiation (HR, 0.53; 95% CI, 0.33–0.84; P = 0.007), and presence of microvascular invasion (MVI) (HR, 2.03; 95% CI, 1.28–3.22; P = 0.003) were independently associated with RFS. The prognostic implication of the nomogram incorporating TAP, maximum tumor diameter, tumor differentiation, and MVI was stronger than the model without TAP.
Conclusion: The present study suggests that higher preoperative TAP is correlated with undesirable prognosis in HCC patients who underwent a radical hepatectomy. Our study provides a robust nomogram for RFS of postoperative HCC patients.

Keywords: HCC, nomogram, recurrence-free survival, tumor abnormal protein


How to cite this article:
Cai H, Li W, Zhang Y, Hua X. Preoperative tumor abnormal protein is a promising biomarker for predicting hepatocellular carcinoma oncological outcome following curative resection. J Can Res Ther 2022;18:2021-6

How to cite this URL:
Cai H, Li W, Zhang Y, Hua X. Preoperative tumor abnormal protein is a promising biomarker for predicting hepatocellular carcinoma oncological outcome following curative resection. J Can Res Ther [serial online] 2022 [cited 2023 Jan 27];18:2021-6. Available from: https://www.cancerjournal.net/text.asp?2022/18/7/2021/367473

Authors Huayong Cai and Wenxin contributed equally to this work.





 > Introduction Top


Although there have been some recent treatment advances,[1],[2],[3] curative resection is still the predominant treatment for hepatocellular carcinoma (HCC).[4] However, the high recurrence risk (>50% at 5 years) is a substantial challenge for HCC patients who underwent a radical hepatectomy.[5]

In almost all kinds of cancer, abnormal glycosylation is found in many proteins and is correlated with tumor development, metastasis, and the clinical outcome of patients.[6],[7],[8],[9],[10],[11] Glycoproteins produced by various malignant tumors are collectively referred to as TAP, and it had been proven as an important diagnostic and prognostic marker of various cancers.[12],[13],[14],[15],[16]

This study aimed to explore the potential relationship between tumor abnormal protein (TAP) and the prognosis of HCC after radical hepatectomy.


 > Materials and Methods Top


Patients

The study included 168 patients who underwent curative surgery performed by the same surgeon from January 2018 to June 2020 at the Department of Hepatopancreatobiliary Surgery of Liaoning Cancer Hospital and Institute. The recurrence group included 78 relapsed HCC patients, and the nonrecurrence group incorporated the remaining 90 patients. The patient inclusion criteria were: (1) 18-70 years old; (2) had a single HCC; (3) received a radical hepatectomy that was performed by the same surgical team and no other treatments, such as ablation therapy and immunotherapy; (4) had full clinicopathologic, TAP measure, and follow-up information. Patients who underwent postoperatively adjuvant treatments aimed at preventing tumor recurrence were excluded. We also excluded patients who had other kinds of cancer history. The Liaoning Cancer Hospital and Institute medical ethics committee authorized this study and procedures were followed in accordance with the Helsinki Declaration of 1975.

Data collection and TAP detection

We retrospectively collected the following clinical data from our institute's medical records: Demographic characteristics (such as age, body mass index, and sex), biochemical variable (such as alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, and hepatitis B surface antigen [HBsAg]), and operative parameters (such as operative procedure, pringle maneuver, operation time, and estimated blood loss). We collected information regarding maximum tumor diameter, tumor differentiation (poor or well), microvascular invasion (MVI) (presence or not), and cirrhosis (yes or no) from the histopathological reports.

When TAP presents in blood, it will react with the detection reagent (abnormal sugar chain structure of glycoproteins) and generate a crystal-like condensation product. According to the cut-off value determined by receiver operator characteristic (ROC) curve analysis, TAP-positive (high expression group) was defined as condensation particle area ≥224.6 μm2 and TAP-negative (low expression group) was defined as condensation particle area <224.6 μm2.

Follow-up and outcome

According to clinical guidelines,[17] all HCC patients who undergo a radical hepatectomy should attend regular outpatient visits. Patients were recommended to be seen every 3 months during the first year post-hepatectomy, and at least every 6 months after the first year. All patients received biochemical tests (such as serum alpha-fetoprotein, ALT, and AST) and imaging examinations (such as contrast computerized tomography or magnetic resonance imaging examination) during each follow-up. We followed up on the oncology outcome by phone calls for patients who did not receive outpatient care at our hospital. The deadline was April 2021. The nonrecurrence group and recurrence group had the same median follow-up time, 21.5 months (interquartile range [IQR], 15.0–26.3) and 21.5 months (IQR, 15.0–28.0), respectively.

The primary aim of this study was to investigate whether there was a correlation between TAP and the prognosis of HCC after radical hepatectomy. Additionally, we aimed to identify independent prognostic factors of recurrence-free survival (RFS), defined as the interval time between radical resection and time to relapse, death, or cut-off time (April 2021), and to construct a robustly predictive nomogram for postoperative HCC patients based on TAP and other prognostic variables.

Statistical analysis

Continuous variables were described as median (IQR), and the difference between groups was tested by the Mann-Whitney U-test. Dichotomous variables were summarized by frequency (percentage), and the difference between groups was tested by Fisher's exact test or the Chi-square test. Pearson r analysis was used to determine whether there was a correlation between maximum tumor size and TAP. ROC curve analysis with the calculation of the Youden index (defined as the sum of sensitivity and specificity minus 1) was used to determine the optimal cut-off value of TAP to predict recurrence. Kaplan–Meier method was applied to calculate RFS, and the difference between groups was tested by a log-rank test. The prognostic factors of RFS were determined by univariate and multivariate Cox regression models. All statistical analyses were performed by SPSS 22.0 software, and two-sided, P < 0.05 was considered statistically significant. We used EmpowerStats software to construct a nomogram and tested its performance with internal validation. A calibration plot was used to calculate the calibration of this nomogram. The clinical value of this predictive model was evaluated by decision curve analysis.


 > Results Top


Patient characteristics

We retrospectively incorporated 168 patients with a single HCC, who underwent a radical hepatectomy by the same surgeon from January 2018 to June 2020. The study population was divided into a nonrecurrence group and a recurrence group, incorporating 90 and 78 patients, respectively, based on the oncology status found during follow-up. Recurrence group had significantly higher TAP (204.5(154.1, 228.1) vs. 165.1(134.9, 203.0) μm2, respectively; P = 0.002) and distinctly bigger tumor size (5.0 [3.5, 6.0] vs. 4.5 [3.0, 5.0] cm, respectively; P = 0.003) than patients in nonrecurrence group [Table 1]. However, demographic characteristics such as HBsAg status, MVI, cirrhosis, liver function level, degree of differentiation, operative parameters, and Child-Pugh score had no statistical difference between groups (P > 0.05 for all) [Table 1].
Table 1: Baseline characteristics in the recurrence group and nonrecurrence group

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Pearson r analysis determined no significant correlation between TAP and maximum tumor size (r = 0.122; P = 0.117) as shown in [Figure 1].
Figure 1: The correlations between TAP and maximum tumor size. There is no correlation between TAP and maximum tumor size. TAP tumor abnormal protein

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Survival and risk factor

According to the cut-off value of TAP level determined by ROC curve analysis (cut-off value, 224.6; sensitivity, 44.9%; specificity, 88.9%; area under the curve [AUC] = 0.64, 95% confidence interval [CI] 0.554–0.726) [Figure 2]a, the whole population was categorized into the TAP high expression group (TAP condensation particle area ≥224.6 μm2) and TAP low expression group (TAP condensation particle area <224.6 μm2). As shown in [Figure 2]b, the RFS rate was distinctly higher in the TAP low group than the TAP high group for the whole population (P < 0.001). Furthermore, in the stratification analysis according to maximum tumor diameter (≤5 or >5 cm), the RFS rate of the TAP high group was distinctly different from that of the TAP low group (P < 0.001 and P = 0.001, respectively; [Figure 2]c and [Figure 2]d). In univariate analysis, TAP (P < 0.001), presence of MVI (P = 0.008), large tumor size (P < 0.001), and degree of tumor differentiation (P = 0.042) were distinctly associated with RFS in HCC patients who underwent a radical surgery [Table 2]. In addition, the multivariate analysis suggested that TAP (hazard ratio [HR], 3.47; 95% CI, 2.18–5.51; P < 0.001), large tumor size (HR, 2.18; 95% CI, 1.36–3.49; P < 0.001), poor tumor differentiation (HR, 0.53; 95% CI, 0.33–0.84; P = 0.007), and presence of MVI (HR, 2.03; 95% CI, 1.28–3.22; P = 0.003) were also independently correlated with RFS [Table 2].
Figure 2: Kaplan–Meier curves of RFS. (a) ROC curve of TAP to predict the presence of recurrence. (b) Kaplan–Meier curves of RFS in the whole population by TAP. (c and d) Kaplan–Meier curves of RFS in patients with maximum tumor size ≤5 cm or >5 cm by TAP. TAP: tumor abnormal protein, RFS: recurrence-free survival

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Table 2: Independent prognostic factors predicting RFS in the whole population

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Construction of a robust nomogram

According to the previously mentioned independent prognostic variables, we constructed a robust nomogram [Figure 3]a. The calibration curves of this nomogram, which indicated favorable consistency between the predicted and observed relapse risk in the whole population, and the result of the Hosmer–Lemeshow test suggested an excellent fit (P = 0.519) [Figure 3]b. [Table 3] lists the statistical parameters of this predictive model, such as accuracy, specificity, and sensitivity.
Figure 3: (a) A reliable nomogram for recurrence-free survival in HCC patients who had received radical hepatectomy. (b) Calibration curves of the nomogram in the whole cohort. The 45° black line indicates optimal prediction. The red line represents the nomogram's predictive performance. The region between two blue dotted lines represent 95% confidence interval of the nomogram. (c) Receiver operating characteristic curves of the combined model (integrate TAP, tumor differentiation, tumor diameter, and MVI) and model without TAP. (d) Decision curve analysis for recurrence-free survival. Black line: No patient recurrence. Gray line: All patients recurrence. Red line: Model without TAP. Blue line: Combined model. TAP: tumor abnormal protein, MVI: microvascular invasion

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Table 3: The predictive performance of prognostic models

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To emphasize the contribution of TAP in the nomogram, we used ROC curve analysis to compare the prognostic performance of the model incorporating TAP, MVI, maximum tumor diameter, and degree of tumor differentiation with the model that only integrated maximum tumor diameter, degree of tumor differentiation, and MVI. With regard to RFS, the area under the ROC curve (AUC) of the model without TAP and the combined model was 0.68 and 0.77 (P = 0.022; [Figure 3]c and [Table 3]), respectively, which indicated that the predictive performance of the conjunctive model was better than the model that did not incorporate TAP.

The clinical value of this nomogram was evaluated by decision curve analysis [Figure 3]d. When the clinical decision determined the high-risk threshold was greater than 25%, both nomogram models were better at predicting RFS than the no-patient relapse pattern or all-patients relapse pattern. Furthermore, the nomogram incorporating TAP, MVI, degree of tumor differentiation, and maximum tumor diameter was a better predictor for RFS than the model that only incorporated MVI, degree of tumor differentiation, and maximum tumor diameter in this range.


 > Discussion Top


The majority of previously reported studies have concentrated on the clinical utility of TAP in the early diagnosis of malignancies, such as digestive tract precancerous lesions, bladder cancer, endometrial cancer, colorectal cancer, papillary thyroid cancer, and breast cancer.[12],[13],[18],[19],[20],[21] However, as far as we know, no reported data have indicated a correlation between TAP and the oncological outcome of HCC after radical hepatectomy. This study suggested a positive correlation between higher preoperative TAP and prognosis of HCC after curative resection, and multivariate analysis confirmed that it was a significant prognostic factor of RFS.

It is well known that MVI and tumor size are distinctly associated with HCC recurrence risk after radical hepatectomy.[22],[23],[24] In addition, Yang et al. indicated that there was a negative correlation between tumor differentiation and the survival of patients with solitary Hepatitis B Virus-associated HCC after curative surgery.[25] Consistent with previous studies, our results demonstrated that tumor differentiation, MVI, and tumor size were independent predictors of RFS in HCC patients who had received a radical treatment. As mentioned earlier, the median maximum tumor size was smaller in the nonrecurrence group than that in the recurrence group, but the maximum tumor diameter was not correlated with TAP, as determined by Kaplan—Meier analysis and Pearson r analysis. In addition, the predictive capability of the nomogram model that integrated TAP, tumor differentiation, MVI, and maximum tumor size was a better predictor than the model only incorporating tumor differentiation, MVI, and maximum tumor size.

As far as we know, this was the first study to demonstrate the correlation between TAP and the prognosis of HCC patients who underwent a radical hepatectomy, with the poor prognosis being correlated to higher TAP. In addition, the multivariate analysis revealed that MVI, tumor differentiation, and maximum tumor size were independently associated with RFS. According to these prognostic variables, we constructed a robustly predictive nomogram for RFS of postoperative HCC patients.

It is worth noting that the present study had several limitations. First, this study retrospectively included patients from a single center which has inevitable shortcomings. Second, our study population was relatively small, which might reduce the credibility of our findings, and we only focused on short-term survival. Therefore, a prospective, multicenter study should be done to verify the results of our study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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