Abstract
Background and aim
Previous studies have shown that microscopic vessel invasion (MVI) occurs in hepatocellular carcinoma (HCC) with a treatment history due to its poorer malignant behavior in comparison with primary HCC. The aim of the present study was to determine the predictors of MVI and overall survival in HCC patients with a treatment history.
Methods
This retrospective study included 580 patients who underwent hepatectomy and whose preoperative imaging showed no evidence of macroscopic vessel invasion. The patients were classified into two groups: primary HCC (n = 425) and HCC with a treatment history (n = 155). MVI was defined as the presence of either microscopic portal vein invasion or venous invasion, which was invisible on preoperative imaging.
Results
MVI was identified in 34 (21.9%) patients with a treatment history. A multivariate analysis showed that a high des-gamma-carboxy prothrombin (odds ratio [OR] 5.16, P = 0.002) and a large tumor diameter (OR 2.57, P = 0.030) were the significant predictor of MVI in HCC with a treatment history. Moreover, the presence of MVI (hazard ratio [HR] 2.27, P = 0.001) and tumor diameter >27 mm (HR 2.04, P = 0.006) remained significant predictors of the overall survival in HCC with a treatment history. The tumor diameter cutoff value for predicting MVI (27 mm) in HCC with a treatment history was smaller than in primary HCC (37 mm).
Conclusions
The presence of MVI was a significant predictor in the HCC patients with a treatment history. The tumor diameter is an important factor that can be used to predict the presence of MVI, especially in HCC with a treatment history.
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Introduction
Recent advances in diagnostic imaging technology have made possible to identify early-stage hepatocellular carcinoma (HCC), and multidisciplinary treatment has improved the survival rate in patients with the disease. However, HCC is still difficult to cure due to its high recurrence rate [1, 2]. Microscopic vessel invasion (MVI) is regarded as an independent predictor of early recurrence and poor overall survival after the surgical treatment of HCC [3,4,5,6]. However, in the absence of macrovascular invasion, MVI is difficult to detect on preoperative imagings [7, 8]. Thus, the diagnosis of MVI has limited impact on preoperative decision making.
HCC is characterized by an insidious onset at an early stage, followed by MVI with tumor growth [9,10,11]. Numerous studies have shown that the tumor diameter is a significant predictor of the presence of MVI [7, 11,12,13,14,15]. However, no studies have shown the correlation between the tumor diameter and the presence of MVI while taking into account the difference of tumor behavior in primary HCC and HCC with a treatment history. Moreover, many recent studies have shown that the outcomes of repeat or salvage hepatectomy for recurrent HCC are acceptable and the procedure seems to be justified [16,17,18,19,20,21,22,23,24], while some have shown that the tumor behavior of HCC with a treatment history is worse than that of primary HCC [19,20,21,22,23,24]. These results suggest that predictors of MVI are likely to differ between the primary HCC and HCC with a treatment history, especially after therapeutic interventions therapy such as radiofrequency ablation (RFA) [19,20,21,22,23,24]. Based on the results of previous studies [12,13,14,15,16,17,18,19,20,21,22,23,24], we hypothesized that the predictors of MVI would differ in patients with a particular focus on simple factors such as the tumor diameter. If this hypothesis was correct, then it would become possible to determine appropriate treatment strategies for primary HCC and HCC with a treatment history based on the risk of the presence of MVI—which is invisible on the preoperative imaging. The aim of the present study was to determine the predictors of MVI and prognostic factors in patients with primary HCC and HCC with a treatment history.
Methods
Patients and methods
A total of 631 patients underwent hepatectomy with curative intent at the Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, in the period between September 2002 and December 2015. Based on the predictors of MVI in clinical setting, the patients were excluded from the analysis due to the presence of macroscopic vessel invasion on preoperative imaging.
All of the patients who were included in the study had undergone computed tomography (CT), abdominal ultrasonography and magnetic resonance imaging (MRI) before surgery. All preoperative imaging studies were reviewed by radiologists. Based on the radiologists’ report, the presence of macroscopic vessel invasion was judged, and the diameter of tumor was generally measured by enhanced CT before surgery in the present study. In patients with multiple tumors, the diameter of the largest tumor was applied, and the differentiation between multicentric tumors and intrametastatic tumors was performed based on the pathological report in the present study. Subsequently, the patients were classified into two groups: the primary HCC group and HCC with a treatment history group.
All of the patients underwent preoperative viral serological testing, the measurement of tumor markers such as alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), and a laboratory assessment of the liver function. The liver function was assessed according to the Child–Pugh classification [25]. HCC had been pathologically diagnosed in all cases. The tumor stage was assessed based on the seventh edition of the Union Internationale Contra le Cancer classification [26].
The surgical procedure and the extent of hepatectomy in each patient were decided in a weekly joint conference with surgeons, oncologists and radiologists. The details of the surgical strategy and procedure have been reported previously [27].
The patients underwent physical examinations and blood tests every 3 months after surgery. Serial CT or liver ultrasonography was performed for each patient every 3–6 months. When a recurrence of HCC was found, the most appropriate therapy (i.e., repeat hepatectomy, transcatheter arterial chemoembolization [TACE], RFA or sorafenib) was applied, after considering the patient’s liver function and tumor factors. For the analysis of overall survival, the follow-up period ended at the time of all the death including any other reasons than HCC. The remaining patients were censored at the last follow-up visit. The study period ended in December 2016.
In the present study, MVI was defined as the presence of either microscopic portal vein invasion or venous invasion, which was difficult to recognize on preoperative imaging. The recurrence form was divided into two groups: local recurrence (residual tumor from the most recent treatment) and distant recurrence (new tumor different from the most recently treated tumor). This study was a retrospective study, and we got the Institutional Review Board of Shizuoka Cancer Center approval for the exception of patients’ consent.
Statistical analyses
Continuous variables were presented as the median and range and were compared using the Mann–Whitney U test. Categorical variables were compared using the Chi-squared test or Fisher’s exact test, as appropriate. All factors that were found to be significantly associated with the presence or absence of MVI (P < 0.05) in a univariate analysis were entered into a multivariate analysis. When converting continuous variables to categorical variables, a receiver operating characteristic (ROC) curve and Youden’s index were used to determine the cutoff values. The cumulative recurrence-free and overall survival curves were analyzed using the Kaplan–Meier method. A Cox proportional hazards model was used for the univariate and multivariate analyses, and all factors found to be significant predictors of the recurrence-free and overall survival (P < 0.05) in the univariate analysis were entered into the multivariate analysis. The multivariate analysis was performed using the logistic regression method with a backward stepwise selection model. All of the statistical analyses were performed using the SPSS 24.0 software package (SPSS, Inc., Chicago, IL). Two-tailed P values of <0.05 were considered to indicate statistical significance.
Results
Patient characteristics
Among 631 patients, 49 patients were excluded from the analysis due to the presence of macroscopic vessel invasion, while 2 patients were excluded because an exact pathological result was obtained. The remaining 580 patients with HCC were included in the analysis. The patient characteristics are shown in Table 1. There were 425 primary HCC patients and 155 HCC patients with a treatment history. The treatments that the 155 HCC patients with a treatment history had most recently undergone were as follows: surgical resection (n = 61), RFA (n = 29), TACE (n = 53) and the other treatments (n = 12). The rate of local recurrence was higher in the patients who underwent TACE and other treatments than in those who underwent surgical resection and RFA. The median period of follow-up was 42.2 months (range, 0.1–164.1 months). The 1-, 3- and 5-year overall survival rates were 93.9, 81.0 and 68.0%, respectively. The 1-, 3- and 5-year recurrence-free survival rates were 72.8, 40.5 and 30.7%, respectively. MVI was identified in 110 of the 580 patients (19.0%).
The preoperative factors of the primary HCC patients with and without MVI
MVI was identified in 76 of the 425 (17.9%) patients with primary HCC (Table 2). The cumulative overall survival rate in patients with MVI was significantly poorer than in patients without MVI (Fig. 1a, P = 0.034). The rate of poorly differentiated HCC of the patients with MVI was significantly higher than that of the patients without MVI (11.8 vs. 1.7%, P < 0.001). The tumor diameter of the patients with MVI was significantly larger than that of the patients without MVI (median diameter: 51 vs. 34 mm, P < 0.001). With regard to the preoperative blood examination results of the patients with and without MVI, significant differences were observed in five factors: the platelet count (P < 0.001), the prothrombin time (PT) (P = 0.002), the aspartate aminotransferase (AST) (P = 0.001), AFP (P < 0.001) and DCP (P < 0.001) levels.
The univariate and multivariate analyses to identify the predictors of MVI in primary HCC patients
Seven preoperative factors were identified as the candidate predictors of the presence of MVI. After converting the continuous variables to categorical variables, an ROC curve analysis was performed to determine the cutoff values for the AST level (55 IU/L), the platelet count (15.1 × 104/μL), the PT (85%), the AFP (17.0 ng/mL) and DCP (55 mAL/mL) levels and the tumor diameter (37 mm) (Fig. 2a). The odds ratios (ORs) for possible determinants of the presence of MVI, which were determined in the univariate logistic regression analyses, are shown in Table 3. In the multivariate analysis, the following factors remained as significant independent predictors of MVI in the primary HCC patients: DCP > 55 mAL/mL (OR 9.74, 95% confidence interval [CI] 3.40–27.9, P < 0.001), poorly tumor differentiation (OR 5.41, 95% CI 1.70–17.2, P = 0.004), AST > 55 IU/L (OR 2.62, 95% CI 1.44–4.78, P = 0.002), PT < 85% (OR 2.52, 95% CI 1.44–4.42, P = 0.001) and platelet count > 15.1 × 104/μL (OR 2.42, 95% CI 1.33–4.41, P = 0.004) (Table 3).
Univariate and multivariate analyses of the prognostic factors for the overall survival in primary HCC patients
In the multivariate analysis, AFP > 17.0 ng/mL (hazard ratio [HR] 1.78, 95% CI 1.26–2.51, P = 0.001), tumor diameter > 37 mm (HR 1.75, 95% CI 1.25–2.44, P = 0.001), age ≥ 70 years (HR 1.58, 95% CI 1.13–2.44, P = 0.008), AST > 55 IU/L (HR 1.57, 95% CI 1.09–2.26, P = 0.015) and PT < 85% (HR 1.42, 95% CI 1.02–2.26, P = 0.040) remained significant independent predictors of the overall survival (Table 4).
The preoperative factors of HCC patients with a treatment history with and without MVI
MVI was identified in 34 of 155 (21.9%) HCC patients with a treatment history (Table 5). The cumulative overall survival rate in patients with MVI was significantly poorer than in patients without MVI (Fig. 1b, P < 0.001). Although there were no significant differences in the most recent treatments of the patients with and without MVI (P = 0.177), MVI was frequently identified in patients with local recurrence (31.1%). In contrast, MVI was identified in only 15 of 94 (16.0%) HCC patients with distant recurrence. Significant differences were observed in four factors: the recurrence form, time after the most recent treatment >24 months, the serum level of DCP and the tumor diameter (P = 0.030, P = 0.049, P = 0.002 and P < 0.001, respectively).
The univariate and multivariate analyses to identify the predictor of MVI in HCC patients with a treatment history
After converting the continuous variables to categorical variables, an ROC analysis was performed to determine the cutoff values for DCP (48 mAL/mL) and the tumor diameter (27 mm) (Fig. 2b). The results of the univariate logistic regression analyses, which were performed to calculate the ORs for possible determinants of MVI, are shown in Table 6. In the multivariate analysis, DCP > 48 mAL/mL (OR 5.16, 95% CI 1.80–14.8, P = 0.002) and tumor diameter >27 mm (OR 2.57, 95% CI 1.10–6.04, P = 0.030) were the significant independent predictor of the presence of MVI in the HCC patients with a treatment history (Table 6).
The preoperative DCP level and tumor diameter on imaging, which could be easily evaluated prior to hepatectomy, were selected as the independent predictors for MVI to establish the preoperative scoring system. Scoring was performed considering with each risk factor taken as 1 point. There were 57, 52 and 46 patients with scores of 0, 1 and 2, respectively. The rate of MVI in the patients with a score of 0 was 5.3%, whereas that in patients with a score of 2 was 43.5% (Fig. 3).
Univariate and multivariate analyses of the prognostic factors for overall survival in HCC patients with a treatment history
In the multivariate analysis, the presence of MVI (HR 2.27, 95% CI 1.30–3.97, P = 0.001) and tumor diameter >27 mm (HR 2.04, 95% CI 1.22–3.40, P = 0.006) remained significant independent predictors of the overall survival (Table 7).
Discussion
The present study showed that the predictors of MVI were different in primary HCC and HCC with a treatment history and that the tumor diameter cutoff value for predicting MVI in HCC with a treatment history was smaller in comparison with that in primary HCC.
The present study reveals some interesting results. First, the present study is the first report to show the predictors of MVI in HCC with a treatment history though several studies have shown the predictors of MVI in patients with primary HCC alone or in populations that included patients with primary and treatment history. We found that a tumor diameter of >27 mm was the significant predictor in this subgroup of patients. Many studies have shown the frequency of MVI after repeat hepatectomy or salvage hepatectomy after RFA [16,17,18, 23, 24]. The results of the present study suggest that MVI is likely to occur in HCC with a treatment history even if the tumors are still small—as previous studies have reported [19,20,21,22]. In local recurrence cases in particular, MVI tended to occur at a high rate, whereas the rate of MVI in distant recurrence cases was almost the same as that of primary HCC. This suggests that most distant recurrence cases were considered as multicentric recurrence in the present study, and such tumors may need to be handled in the same way as primary HCC.
Furthermore, the present study revealed that the tumor diameter cutoff value for predicting the presence of MVI in HCC with a treatment history (27 mm) was smaller than that in the primary HCC (37 mm). Although the multivariate analysis did not show that the tumor diameter was a predictor of MVI in patients with primary HCC, previous studies have reported the tumor diameter to be an important factor for predicting MVI [7, 11,12,13,14,15]. In terms of primary HCC patients, Zhong et al. [11] reviewed the frequency of MVI in the literature series and found that the frequency of MVI in patients with a tumor diameter of >5 cm (64.1%) was markedly increased in comparison with patients with a tumor diameter of ≤5 cm. Several other studies have reported a tumor diameter cutoff value of 5 cm [13, 15]. In contrast, the rate of MVI was high in the patients with a high DCP level, even in those with primary HCC ≤2 cm [28], results that were partially consistent with our own; DCP was a significant independent predictor of the presence of MVI in both primary HCC and HCC patients with a treatment history.
Regarding the HCC with a treatment history, the studies related to third or more repeat hepatectomy from Japan showed that the median tumor diameter was <2 cm in cases treated with repeat hepatectomy [17, 18]. Yamashita et al. [17] reported that, despite the small tumor diameter, the frequency of MVI was very high (>60%). In contrast, Mise et al. [18] reported that the frequency of MVI was relatively low, and concluded that third or more repeat hepatectomy offers favorable survival that is similar to second hepatectomy, in spite of the low rate of anatomical resection (the procedure that they recommended for HCC) [29]. Our established scoring system is useful for deciding on the operative procedure (anatomical resection or non-anatomical resection) following the prediction of the presence of MVI which is invisible on preoperative imaging because the two factors constituting the scoring system can be easily evaluated prior to hepatectomy. In particular, the preoperative DCP level reflects the biological behavior of HCC more strongly than does the tumor diameter, as the DCP level was found to be an independent predictor of the presence of MVI in both primary HCC and HCC patients with a treatment history. Given the results of these studies, a favorable prognosis might be achieved by not performing anatomical resection for HCC patients with a treatment history with a score of 0.
With regard to the image findings, MRI findings, non-smooth tumor margins, peritumoral enhancement [30], a macroscopic appearance on CT [12] and intraoperative ultrasound findings [31], have recently been reported as predictors of MVI. The image findings are important, especially in primary HCC patients. In contrast, objective predictors such as tumor diameter are desirable for HCC with a treatment history because macroscopic appearance after treatment is strongly affected by recent treatment and is difficult to recognize based on imaging features. Although it is not denied that the tumor diameter is also affected by recent treatment, the results of the present study were reliable in terms of showing the association between the tumor diameter on preoperative images and the presence of MVI.
The present study is associated with several limitations. First, this study was retrospective in nature and was performed at a single center; thus, the influence of a selection bias cannot be ruled out. Further prospective multi-institutional studies are therefore needed to objectively validate the results of the present study. However, the results of the present study, which were based on a relatively large study population (>500 patients) and a long follow-up period (median, 42.2 months), were reliable. Second, the rate of MVI in the present study (19.0%) was relatively low in comparison with other studies [12,13,14]. However, the prevalence of MVI in the review article varied widely (15.0–57.1%) [6]. Patients with macroscopic invasion were initially excluded from the present study. If these patients had been included, the rate of MVI would increase to 25.6%.
In conclusion, the predictors of MVI differ between primary HCC and HCC with a treatment history and the tumor diameter should be considered when predicting MVI—especially in HCC with a treatment history. This is especially important for determining the treatment strategy because primary HCC and HCC with a treatment history show different levels of malignant potential.
References
Zimmerman MA, Ghobrial RM, Tong MJ et al (2008) Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg 143:182–188 (Discussion 188)
Bruix J, Gores GJ, Mazzaferro V (2014) Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 63:844–855
Lim KC, Chow PK, Allen JC et al (2011) Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. Ann Surg 254:108–113
Tsai TJ, Chau GY, Lui WY et al (2000) Clinical significance of microscopic tumor venous invasion in patients with resectable hepatocellular carcinoma. Surgery 127:603–608
Clavien PA, Lesurtel M, Bossuyt PM, OLT for HCC Consensus Group et al (2012) Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 13:e11–e22
Rodríguez-Perálvarez M, Luong TV et al (2013) A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability. Ann Surg Oncol 20:325–339
Cucchetti A, Piscaglia F, Grigioni AD et al (2010) Preoperative prediction of hepatocellular carcinoma tumour grade and microvascular invasion by means of artificial neural network: a pilot study. J Hepatol 52:880–888
Hirokawa F, Hayashi M, Miyamoto Y et al (2014) Outcomes and predictors of microvascular invasion of solitary hepatocellular carcinoma. Hepatol Res 44:846–853
Wang MH, Ji Y, Zeng ZC et al (2010) Impact factors for microinvasion in patients with hepatocellular carcinoma: possible application to the definition of clinical tumor. Int J Radiat Oncol Biol Phys 76:467–476
Lu XY, Xi T, Lau WY et al (2011) Pathobiological features of small hepatocellular carcinoma: correlation between tumor size and biological behavior. J Cancer Res Clin Oncol 137:567–575
Zhong Y, Deng M, Xu R (2015) Reappraisal of evidence of microscopic portal vein involvement by hepatocellular carcinoma cells with stratification of tumor size. World J Surg 39:1142–1149. https://doi.org/10.1007/s00268-014-2807-5
Renzulli M, Brocchi S, Cucchetti A et al (2016) Can current preoperative imaging be used to detect microvascular invasion of hepatocellular carcinoma? Radiology 279:432–442
Kaibori M, Ishizaki M, Matsui K et al (2010) Predictors of microvascular invasion before hepatectomy for hepatocellular carcinoma. J Surg Oncol 102:462–468
Eguchi S, Takatsuki M, Hidaka M et al (2010) Predictor for histological microvascular invasion of hepatocellular carcinoma: a lesson from 229 consecutive cases of curative liver resection. World J Surg 34:1034–1038. https://doi.org/10.1007/s00268-010-0424-5
Kim BK, Han KH, Park YN et al (2008) Prediction of microvascular invasion before curative resection of hepatocellular carcinoma. J Surg Oncol 97:246–252
Wu CC, Cheng SB, Yeh DC et al (2009) Second and third hepatectomies for recurrent hepatocellular carcinoma are justified. Br J Surg 96:1049–1057
Yamashita Y, Shirabe K, Tsuijita E et al (2013) Third or more repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery 154:1038–1045
Mise Y, Hasegawa K, Shindoh J et al (2015) The feasibility of third or more repeat hepatectomy for recurrent hepatocellular carcinoma. Ann Surg 262:347–357
Takada Y, Kurata M, Ohkohchi N (2003) Rapid and aggressive recurrence accompanied by portal tumor thrombus after radiofrequency ablation for hepatocellular carcinoma. Int J Clin Oncol 8:332–335
Nicoli N, Casaril A, Abu Hilal M et al (2004) A case of rapid intrahepatic dissemination of hepatocellular carcinoma after radiofrequency thermal ablation. Am J Surg 188:165–167
Livraghi T, Lazzaroni S, Meloni F et al (2005) Risk of tumour seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma. Br J Surg 92:856–858
Koda M, Maeda Y, Matsunaga Y et al (2003) Hepatocellular carcinoma with sarcomatous change arising after radiofrequency ablation for well-differentiated hepatocellular carcinoma. Hepatol Res 27:163–167
Sugo H, Ishizaki Y, Yoshimoto J et al (2012) Salvage hepatectomy for local recurrent hepatocellular carcinoma after ablation therapy. Ann Surg Oncol 19:2238–2245
Yamashita S, Aoki T, Inoue Y et al (2015) Outcome of salvage hepatic resection for recurrent hepatocellular carcinoma after radiofrequency ablation therapy. Surgery 157:463–472
Pugh RN, Murray-Lyon IM, Dawson JL et al (1973) Transection of the esophagus for bleeding oesophageal varices. Br J Surg 60:646–649
Sobin LH, Gospodarowicz MK, Wittekind CH (eds) (2009) TNM classification of malignant tumours, 7th edn. Wiley-Liss, New York
Okamura Y, Ito T, Sugiura T et al (2014) Anatomic versus nonanatomic hepatectomy for a solitary hepatocellular carcinoma: a case–controlled study with propensity score matching. J Gastrointest Surg 18:1994–2002
Yamashita Y, Tsujita E, Takeishi K et al (2012) Predictors for microinvasion of small hepatocellular carcinoma. Ann Surg Oncol 19:2027–2034
Hasegawa K, Kokudo N, Imamura H et al (2005) Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 242:252–259
Yang C, Wang H, Sheng R et al (2017) Microvascular invasion in hepatocellular carcinoma: is it predictable with a new, preoperative application of diffusion-weighted imaging? Clin Imaging 41:101–105
Santambrogio R, Cigala C, Barabino M et al (2018) Intraoperative ultrasound for prediction of hepatocellular carcinoma biological behaviour: prospective comparison with pathology. Liver Int 38:312–320
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Okamura, Y., Sugiura, T., Ito, T. et al. The Predictors of Microscopic Vessel Invasion Differ Between Primary Hepatocellular Carcinoma and Hepatocellular Carcinoma with a Treatment History. World J Surg 42, 3694–3704 (2018). https://doi.org/10.1007/s00268-018-4658-y
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DOI: https://doi.org/10.1007/s00268-018-4658-y