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Hepatology Research 2016; 46: 298–305
doi: 10.1111/hepr.12540
Original Article
Gross classification of solitary small hepatocellular carcinoma on preoperative computed tomography: Prognostic significance after radiofrequency ablation Xu Fu,1 Liang Mao,1 Min Tang,2 Xiaopeng Yan,1 Yudong Qiu,1 Jian He2 and Tie Zhou1 Department of 1Hepatopancreatobiliary Surgery and 2Radiology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
Aim: The prognostic significance of the gross classification of hepatocellular carcinoma (HCC) has been confirmed in both hepatectomy and living donor liver transplantation. However, the role of this type of classification in HCC treated with radiofrequency ablation (RFA) has rarely been reported. The aim of this study was to investigate the role of preoperative gross classification in cases of solitary small HCC treated with RFA.
Methods: From January 2007 to September 2013, 103 patients with solitary small HCC treated with RFA were retrospectively reviewed. The lesions were classified into three types according to gross appearance in preoperative contrast-enhanced computed tomography (CT) scans. Clinicopathological variables and survival information were compared among these three types. Univariate and multivariate analyses were performed to clarify the long-term prognostic factors. Results: The group of 103 tumors comprised 34 type 1, 49 type 2 and 20 type 3 tumors. The level of preoperative serum
INTRODUCTION
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EPATOCELLULAR CARCINOMA (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide.1 More than 50% of new cases occur in China.2 With the progress in imaging techniques, increasing numbers of small HCC can be detected. Treatment options for small HCC include resection, liver transplantation and radiofrequency ablation (RFA).3 The
Correspondence: Dr Jian He, Department of Radiology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu Province 210008, China. Email: [email protected], Xx Tie Zhou, Department of Hepatopancreatobiliary Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu Province 210008, China. Email: [email protected] Conflict of interest: There are no conflicts of interest. Received 5 March 2015; revision 4 May 2015; accepted 1 June 2015.
© 2015 The Japan Society of Hepatology
α-fetoprotein in the type 3 tumors was significantly higher than that in types 1 and 2 (P < 0.05). The overall survival of the patients with type 3 HCC was the poorest among the three types. The tumor-free survival of the patients with types 3 and 2 HCC were significantly poorer than those with type 1 (P < 0.05). The univariate analysis showed that gross classification, α-fetoprotein level, tumor size and degree of enhancement were poor prognostic factors. The multivariate analysis indicated that the gross classification was the only independent prognostic indicator.
Conclusion: The preoperative gross classification was of great prognostic significance in solitary small HCC treated with RFA. Key words: ablation techniques, carcinoma, classification, hepatocellular carcinoma, multidetector computed tomography, prognosis
long-term effectiveness of RFA is comparable with hepatectomy for patients with small HCC,4–6 and RFA is associated with a lower complication rate and shorter hospital stay.5 However, we found that patients with small HCC after RFA had different prognoses, which is similar to what is observed in patients with HCC after surgery. The optimal candidates for treatment with RFA among patients with small HCC remain unknown. The prognostic significance of the gross classification of HCC based on specimens has been confirmed in patients after hepatectomy and living donor liver transplantation (LDLT).7–11 However, the role of gross classification in HCC treated with RFA has rarely been reported. The concept of gross classification for HCC was first put forward in 1901 by Eggel et al.12 based on autopsy data. In 1987, based on an analysis of surgically resected HCC, Kanai et al.7 proposed a new gross classification (single nodular type, single nodular type with extranodular growth,
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confluent multinodular type and infiltrative type), which was accepted by the Liver Cancer Study Group of Japan8 and has been widely used. A recent study reported that even for HCC of 2 cm or less, the gross type was significantly associated with local recurrence after RFA.13 However, the survival significance of gross classification in single small HCC treated with RFA has not been previously reported. The aim of this study was to investigate the distribution, clinicopathological features and prognostic role of gross classification based on preoperative computed tomography (CT) imaging of solitary small HCC treated with RFA.
METHODS Patients
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HE LOCAL ETHICS committee approved the study protocol. From January 2007 to July 2013, a total of 316 patients with clinically diagnosed HCC received RFA at our institution. The diagnosis of HCC was based on the clinical diagnostic criteria for HCC used by our country and the European Association for the Study of the Liver.14 Ablation therapy was used when patients were considered not to be suitable for resection because of liver function impairment, number and distribution of the tumors, and cardiopulmonary dysfunction, or because they voluntarily preferred ablation with informed consent despite surgery also being valuable. Inclusion criteria for this study were as follows: (i) pathologically confirmed HCC with a maximum diameter of 5 cm or less; (ii) a solitary lesion without evidence of intra- or extrahepatic metastasis; (iii) the preoperative CT imaging scans, clinicopathological records and survival information could be obtained; and (iv) RFA was an initial treatment. Among the 316 patients, 21 without a definite pathologic diagnosis, 43 patients underwent a combination therapy of transcatheter arterial chemoembolization (TACE) or systemic therapy, 128 patients who had more than one but less than three lesions and 21 patients who were lost to follow up were excluded. A total of 103 patients thus served as subjects in this retrospective study.
Preoperative CT examination All the 103 patients underwent plain and contrastenhanced (CE)-CT examinations using a multidetector CT scanner (LightSpeed VCT; GE Healthcare, Pittsburgh, PA, USA) with a 5.0-mm slice thickness at 30, 60 and 180 s to obtain hepatic arterial, portal venous and equilibrium phase images after the injection of contrast media (Omnipaque 350 mg I/mL; GE Healthcare) at a rate of 3.0 mL/s with a dose of 1.5 mL/kg bodyweight. Other
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parameters of the abdominal CT scan included a tube voltage of 120 kVp, tube current of 240 mA, rotation time of 0.6 s, helical pitch of 1.375, field of view of 35–40 cm and matrix of 512 × 512. The length of time between the preoperative CT examination and the RFA treatment ranged 3–5 days.
Gross classification of HCC based on CT imaging The preoperative CT images were reviewed independently by three blinded readers (two radiologists and one surgeon) who were unaware of the patients’ clinical and survival information. By referring to previous studies,8,9,15 and based on the readers’ own experience, the gross appearance of the tumors on the CT images was designated as one of three types (Fig. 1): type 1, round or oval-shaped tumor with a clear margin, especially in the arterial and portal phases, sometimes with a pseudocapsule in the equilibrium phase; type 2, round or oval-shaped tumor with a clear margin, and focally protruding areas at any slice in any phase image, or a lobulated tumor with multinodular enhancement especially in the arterial phase, and sometimes with intratumoral separations in the portal and equilibrium phases, excluding a lesion with any satellite nodule; and type 3, was an irregular tumor with a clear margin or a blurred tumor without a clear margin at any slice in any phase. The readers made their classifications independently and reached a consensus by discussion if there were disagreements. In addition, the HCC lesions were described as remarkably (>30 HU) or moderately– slightly enhanced (≤30 HU) based on the degree of enhancement in the arterial phase.
RFA treatment procedures All the RFA procedures were performed by a surgeon with 15 years of experience in ultrasonography (US)- or CTguided interventional procedures and RFA. The treatments were performed under general anesthesia with a commercially available system (Cool-tip; Valleylab, Burlington, MA, USA). Each patient underwent a tumor biopsy with an 18-G needle before the ablation. The treatment was initiated with 10 W of power and was increased at 10 W/min to 90 W for approximately 15 min. The frequency of ablation was dependent on the tumor size and the position at which the needle was introduced. The aim was to create a safe margin of approximately 1 cm if possible. The patients received abdominal bag compression and remained in bed for 12 h to prevent internal bleeding after the procedure.
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Figure 1 Dynamic contrast-enhanced computed tomography images of solitary small hepatocellular carcinomas. (a) Type 1, a round tumor with a clear margin and a pseudocapsule in the portal venous phase. (b) Type 2, a round tumor with a clear margin, as well as focally protruding areas in the hepatic arterial phase. (c) Type 2, a lobulated tumor with multinodular enhancement. (d) Type 3, an irregular tumor with a blurred margin in the portal venous phase.
Follow up One month after the RFA therapy, each patient underwent abdominal CE-CT to evaluate the treatment efficacy. The patients were then followed up regularly. Follow up was arranged monthly for the first 6 months, then every 3 months from one-half to 2 years and every 6 months until the time of death or 30 October 2014. During each follow up, an ultrasonography examination and liver function and α-fetoprotein (AFP) tests were ordered. If a relapse or progression of the disease was suspected, CE-CT, magnetic resonance imaging (MRI) or hepatic angiography was performed. Once a diagnosis of recurrence was confirmed, local ablation, surgical resection, TACE or molecular-targeted therapy was adopted according to the total status of each patient. Recurrence times and patterns and the causes of death of the involved cases were recorded.
Statistical analysis Demographic characteristics and clinicopathological variables were compared among the three types of solitary small HCC. The continuous data were presented as the means ± standard deviation and were compared by oneway ANOVA. The categorical variables were compared using a χ 2-test. The disease-free and overall survival curves of the patients with each type of HCC were calculated using the
© 2015 The Japan Society of Hepatology
Kaplan–Meier method and compared using the log–rank test. The Cox proportional hazards model was used to determine the factors most related to survival. All the statistical analyses were performed with SPSS version 19.0 software (SPSS, Chicago, IL, USA). P-values less than 0.05 were considered statistically significant.
RESULTS General information
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HE CLINICOPATHOLOGICAL VARIABLES of the 103 patients with solitary small HCC are summarized in Table 1. There were 82 men and 21 women, with a mean age of 57 ± 11 years (range, 34–77 years). There were 34 patients with type 1 HCC (33.0%), 49 patients with type 2 HCC (47.6%) and 20 patients with type 3 HCC (19.4%). The preoperative serum AFP value was significantly higher in the patients with type 3 HCC than in those with types 1 and 2 (P < 0.05). The proportion of remarkable enhancement in type 3 HCC was significantly lower than that in types 1 and 2 (P < 0.05).
Survival information The overall survival rates of all the patients who underwent RFA at 1, 3 and 5 years were 97.0%, 75.9% and 59.7%, respectively (Fig. 2). For types 1, 2 and 3 HCC, the 3-year survival rates were 94.7%, 71.9% and 33.0%, and the 3-year
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Table 1 Comparison of clinicopathological variables of patients with three types of solitary small hepatocellular carcinomas Type 1
Type 2
Type 3
(n = 49)
(n = 20)
F or χ 2
P
Variables
(n = 34)
Age (years) Sex (male/female) HCV positive (%) HBsAg positive (%) WBC (1 × 109/L) Platelet (1 × 109/L) ALT (U/L) AST (U/L) TB (μmol/L) Albumin(g/L) INR ICG-R15 (%) MELD score AFP (ng/mL) Enhancement degree (remarkably/moderately–slightly) Tumor size (cm) Histological grade (well/moderate/poor) Ablative margin (cm)
54.6 ± 12.1 26/8 5.8% 82.3% 8.4 ± 18.6 93 ± 69 36.7 ± 18.6 39.3 ± 13.5 21.9 ± 9.4 40.3 ± 4.4 0.93 ± 0.42 8.3 ± 6.4 7.8 ± 2.7 43.4 ± 139.9 17/17
58.9 ± 11.6 38/11 4.1% 81.6% 6.2 ± 12.3 95 ± 49 46.4 ± 38.7 42.6 ± 31.1 20.7 ± 12.4 40.6 ± 5.0 1.05 ± 0.28 8.2 ± 3.0 8.6 ± 3.0 161.0 ± 297.9 20/29
58.5 ± 9.8 18/2 5% 85% 6.9 ± 14.5 94 ± 56 47.5 ± 36.5 45.7 ± 28.3 25.1 ± 14.3 39.5 ± 5.9 0.98 ± 0.42 9.3 ± 3.0 8.6 ± 3.1 414.1 ± 834.2 3/17
1.096 1.665 0.142 0.113 0.333 0.200 0.689 0.253 0.632 0.256 0.850 1.135 0.770 3.414 6.649
0.340 0.435 0.931 0.945 0.632 0.392 0.506 0.777 0.535 0.775 0.432 0.313 0.467 0.038 0.036
2.7 ± 1.0 7/24/3 1.2 ± 0.3
2.6 ± 1.0 7/38/4 1.0 ± 0.3
2.6 ± 1.3 3/15/2 1.1 ± 0.3
0.006 0.703 0.938
0.994 0.951 0.395
Enhancement degree was defined as remarkably (>30 HU) or moderately–slightly enhanced (≤30 HU) based on enhancement degree in the arterial phase. AFP, α-fetoprotein; ALT, alanine aminotransferase; AST, aspartate transaminase; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCV, antibody against hepatitis C virus; ICG-R15, indocyanine green retention rate at 15 min; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; TB, total bilirubin; WBC, white blood cell.
disease-free survival rates were 70.6%, 16.3% and 20.0%, respectively. The overall survival rates and disease-free survival of the patients with types 3 and 2 HCC were significantly poorer than those of patients with type 1 HCC (P < 0.05; Figs 3,4). The overall survival rate of the patients with tumors that were moderately–slightly enhanced was poorer than those with remarkably enhanced tumors (P < 0.05; Fig. 5). The univariate analysis revealed that gross classification, AFP, enhancement degree and tumor size were predictors associated with survival. However, the multivariate analysis showed that the gross classification was the only independent prognostic factor (P = 0.013) (Table 2).
DISCUSSION
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Figure 2 Kaplan–Meier curve for overall survival of the patients with solitary small hepatocellular carcinoma after radiofrequency ablation. The 1-, 3- and 5-year overall survival rates were 97.0%, 75.9% and 59.7%, respectively.
HE PROPORTIONS AND prognostic significance of gross classification have been reported in patients with HCC after hepatectomy and LDLT.7–11 Most of these studies were from Japan and Western countries, in which the dominant risk factor is hepatitis C virus infection, together with alcohol abuse.2,16 However, Chinese patients with HCC have primarily been infected with the hepatitis B
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Figure 3 Kaplan–Meier curves for overall survival of patients with different gross types of solitary small hepatocellular carcinomas after radiofrequency ablation. Type 1 versus 2, P = 0.013; type 1 versus 3, P = 0.000; type 2 versus 3, P = 0.009.
Figure 5 Kaplan–Meier curves for overall survival of patients with solitary small hepatocellular carcinomas with different enhancement degrees in the arterial phase of contrast-enhanced computed tomography, P = 0.023.
virus, and the incidence of each gross type in Chinese patients with HCC may be different from previous reports. The classification reported in previous studies was based
on postoperative specimens. However, the preoperative assessment of the gross appearance of tumors using imaging modalities seems to be more important for the management of patients with HCC. To our knowledge, this is the first study focusing on the role of preoperative gross classification in solitary small HCC treated with RFA. Our study finds that the preoperative gross classification of the tumors is of great prognostic significance in solitary small HCC treated with RFA. The overall survival of patients with type 3 was the poorest among the three types. The tumor-free of patients with types 3 and 2 were significantly poorer than type 1. The univariate analysis showed that the level of AFP, gross classification, enhancement degree and tumor size were all risk factors influencing the overall survival time of patients with solitary small HCC after RFA. Recent studies have reported that tumor size, tumor location, tumor number, AFP level and an insufficient safety margin, among others, are risk factors for local tumor progression of HCC after RFA.17–19 Most of these factors were considered in our study, including the preoperative gross classification of HCC. The multivariate analysis indicated that the preoperative gross classification was the only independent prognostic factor in patients with solitary small HCC after RFA. The serum AFP level in type 3 was significantly higher than that in the other types, and the serum AFP level was
Figure 4 Kaplan–Meier curves for disease-free survival of patients with different gross types of solitary small hepatocellular carcinomas after radiofrequency ablation. Type 1 versus 2, P = 0.006; type 1 versus 3, P = 0.002; type 2 versus 3, P = 0.562.
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Table 2 Univariate and multivariate analysis of prognostic factors of patients with solitary small hepatocellular carcinoma after radiofrequency ablation
Variables Age Sex HBsAg positive WBC (1 × 109/L) Platelets (1 × 109) ALT (U/L) AST (U/L) TB (μmol/L) Albumin (g/L) INR ICG-R15 (%) MELD score Histological grade (well/moderate/poor) Gross classification AFP (ng/mL) Tumor size (cm) Enhancement degree
Univariate analysis (P)
Multivariate analysis RR 95% CI p-value
0.688 0.852 0.557 0.343 0.707 0.733 0.445 0.493 0.455 0.517 0.486 0.599 0.573 0.000 0.001 0.010 0.025
3.443 1.000 1.565 3.084
1.301–9.113 0.999–1.001 0.930–1.053 0.504–18.873
0.013 0.826 0.738 0.223
AFP, α-fetoprotein; ALT, alanine aminotransferase; AST, aspartate transaminase; CI, confidence interval; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; ICG-R15, indocyanine green retention rate at 15 min; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; RR, relative risk; TB, total bilirubin; WBC, white blood cell.
the lowest in type 1 in our study. Farinati et al.20 reported that a high AFP level was associated with the tumor size, tumor number and tumor staging. In our study, all the lesions were solitary and at an early stage, and the tumor sizes of the three types were not significantly different. We hypothesized that the difference in serum AFP levels among the different types may be due to different biological characteristics and molecular mechanisms. For example, HCC with a low expression of BCL2 have been correlated with higher AFP levels.20 Most of the type 3 HCC (85.7%) in our study lacked the rapid “wash-in and wash-out” characteristic commonly seen on enhanced CT imaging. Rosenkrantz et al.21 confirmed that infiltrative HCC is an aggressive form of HCC that is often less conspicuous on arterial phase images compared with the typical mass-forming HCC. It has been reported that imaging features and gross classification were independent prognostic factors for patients with HCC. Nakayama et al.22 reported that preoperative morphological classification appeared to provide a promising additional criterion for the prognostic categorization of
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patients with HCC via a new CT-based morphological classification system. Kawamura et al.23 reported that the heterogeneity of dynamic CT images correlated with the malignant characteristics of HCC and could be potentially used to predict the malignant potential of HCC before treatment. Types 1, 2 and 3 HCC accounted for 33.0%, 47.6% and 19.4% of the cases in this study, respectively. Based on previous studies and our own experience,8–10 type 1 in this study corresponded pathologically to the single nodular type; type 2 primarily corresponded to the single nodular type with extranodular growth and sometimes to the confluent multinodular type; and type 3 generally indicated the infiltrating HCC and the confluent multinodular type. However, the proportion of tumors with a pathological single nodular type has been reported as 73–77%, while those with a single nodular type with extranodular growth was 23–27%, and the incidence of infiltrating HCC has been reported to be extremely low.9,24,25 This discrepancy may be due to the high rate of hepatitis B infection in this cohort, and the features of HCC may vary among different areas worldwide.2 Patients with hepatitis C virus show multicentric carcinogenesis, but patients with hepatitis B do not. The overall survival of the patients with type 3 was the poorest among the three types. The tumor-free survival rates of the patients with types 3 and 2 were significantly poorer than those of the patients with type 1. The recurrence of HCC after treatment is classified as local and distant recurrence. Local recurrence is defined as a reappearance of tumor progression adjacent to the treated site and distant recurrence as the emergence of one or several tumor(s) not adjacent to the ablation zone. In our study, the 3-year overall recurrence rate was 64.1% and the 3-year recurrence rate of the three types was 29.4%, 83.7% and 80.0%, respectively. The local recurrence rate of the three types was 3.0%, 12.2% and 15%, respectively. The local recurrence rates of the patients with types 3 and 2 were significantly higher than those of the patients with type 1. Ariizumi et al.26 reported that HCC with nonsmooth margins had greater involvement of microscopic portal vein invasion and intrahepatic metastasis than those with smooth margins. Okusaka et al.27 found that the macroscopic type of HCC was significantly associated with the prevalence of satellite lesions, even in small HCC. Small satellite nodules were detected within 0.5-1.0 cm from the main lesion. The poor prognosis of the patients with type 3 HCC may be due to the high incidence of intrahepatic metastases and microinvasion with this type of HCC, and RFA was apparently insufficient to eliminate all of these small lesions.
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The 1-, 3- and 5-year survival rates of the patients in our study were 97.0%, 75.9% and 59.7%, respectively. The survival rates in our study are comparable with previous reports. Shiina et al.28 reported that the 5-year survival rate of patients with HCC after RFA was 60.2% based on a large sample size. Chen et al.6 compared RFA and partial hepatectomy for the treatment of small HCC and the 1-, 2-, 3and 4-year overall survival rates were 95.8%, 82.1%, 71.4% and 67.9%, and 93.3%, 82.3%, 73.4% and 64.0%, respectively. In our study, the 3-year survival rate for the patients with type 1 HCC after RFA was superior to that after hepatectomy (94.7% vs 73.4%), suggesting that patients with type 1 HCC on preoperative CT imaging are optimal candidates for RFA. The 3-year survival rates for the patients with type 2 and 3 HCC were poorer than those for the patients treated with hepatectomy (71.9%, 33.0% vs 73.4%), indicating that patients with irregularly shaped HCC are more suitable for surgical resection. Therefore, it is important to assess the gross type of small HCC through preoperative imaging to determine the optimal treatment method. There were some limitations in this study. First, this was a single-center retrospective study with a relatively small sample size. Second, only CT imaging was used for the preoperative assessment of the HCC lesions. Hatanaka et al.29 reported that CE-US is a more reliable tool than CE-CT to evaluate the gross type of HCC. Tada et al.30 reported that gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI was equal or superior to angiography-assisted CT. Third, no gross specimens could serve as the reference for imaging classification and there was a risk of dissemination with tumor biopsy. Finally, the treatment after recurrence could affect the outcomes of patients with HCC. Nevertheless, the disease-free survival rates of the patients with different types of HCC were significantly different, indicating the great prognostic significance of the gross classification of solitary small HCC treated with RFA. In summary, this study demonstrated that the preoperative gross classification of the tumors is of great prognostic significance in solitary small HCC treated with RFA. Not all of the patients with small HCC are suitable for RFA treatment. The gross classification should be considered before treating patients with small HCC. Surgical resection is strongly recommended for the management of irregular types, such as types 2 and 3, even in small HCC.
ACKNOWLEDGMENTS
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HE AUTHORS THANK Professor Fan Yimei for help with the statistics, and for guidance from the
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multidisciplinary hepatobiliary cancer teams of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School. This work was funded by a grant from Fundamental Research Funds for the Central Universities (no. 20620140664) and Nanjing City Young Health Personnel Training Project (third level) (no. QRX11178).
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15 Nakayama H, Takayama T, Okubo T et al. Proposal of objective morphological classification system for hepatocellular carcinoma using preoperative multiphase computed tomography. J Gastroenterol 2014; 49: 1430–37. 16 Shiratori Y, Shiina S, Imamura M et al. Characteristic difference of hepatocellular carcinoma between hepatitis B- and C-viral infection in Japan. Hepatology 1995; 22: 1027–33. 17 Hori T, Nagata K, Hasuike S et al. Risk factors for the local recurrence of hepatocellular carcinoma after a single session of percutaneous radiofrequency ablation. J Gastroenterol 2003; 38: 977–81. 18 Kim YS, Rhim H, Cho OK, Koh BH, Kim Y. Intrahepatic recurrence after percutaneous radiofrequency ablation of hepatocellular carcinoma: analysis of the pattern and risk factors. Eur J Radiol 2006; 59: 432–41. 19 Izumi N, Asahina Y, Noguchi O et al. Risk factors for distant recurrence of hepatocellular carcinoma in the liver after complete coagulation by microwave or radiofrequency ablation. Cancer 2001; 91: 949–56. 20 Farinati F, Marino D, De Giorgio M et al. Diagnostic and prognostic role of α-fetoprotein in hepatocellular carcinoma: Both or neither? Am J Gastroenterol 2006; 101: 524–32. 21 Rosenkrantz AB, Lee L, Matza BW, Kim S. Infiltrative hepatocellular carcinoma: Comparison of MRI sequences for lesion conspicuity. Clin Radiol 2012; 67: e105–11. 22 Nakayama H, Takayama T, Okubo T et al. Proposal of objective morphological classification system for hepatocellular carcinoma using preoperative multiphase computed tomography. J Gastroenterol 2014; 49: 1430–7. 23 Kawamura Y, Ikeda K, Hirakawa M et al. New classification of dynamic computed tomography images predictive of
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doi: 10.1111/hepr.12540
Original Article
Gross classification of solitary small hepatocellular carcinoma on preoperative computed tomography: Prognostic significance after radiofrequency ablation Xu Fu,1 Liang Mao,1 Min Tang,2 Xiaopeng Yan,1 Yudong Qiu,1 Jian He2 and Tie Zhou1 Department of 1Hepatopancreatobiliary Surgery and 2Radiology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
Aim: The prognostic significance of the gross classification of hepatocellular carcinoma (HCC) has been confirmed in both hepatectomy and living donor liver transplantation. However, the role of this type of classification in HCC treated with radiofrequency ablation (RFA) has rarely been reported. The aim of this study was to investigate the role of preoperative gross classification in cases of solitary small HCC treated with RFA.
Methods: From January 2007 to September 2013, 103 patients with solitary small HCC treated with RFA were retrospectively reviewed. The lesions were classified into three types according to gross appearance in preoperative contrast-enhanced computed tomography (CT) scans. Clinicopathological variables and survival information were compared among these three types. Univariate and multivariate analyses were performed to clarify the long-term prognostic factors. Results: The group of 103 tumors comprised 34 type 1, 49 type 2 and 20 type 3 tumors. The level of preoperative serum
INTRODUCTION
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EPATOCELLULAR CARCINOMA (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide.1 More than 50% of new cases occur in China.2 With the progress in imaging techniques, increasing numbers of small HCC can be detected. Treatment options for small HCC include resection, liver transplantation and radiofrequency ablation (RFA).3 The
Correspondence: Dr Jian He, Department of Radiology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu Province 210008, China. Email: [email protected], Xx Tie Zhou, Department of Hepatopancreatobiliary Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu Province 210008, China. Email: [email protected] Conflict of interest: There are no conflicts of interest. Received 5 March 2015; revision 4 May 2015; accepted 1 June 2015.
© 2015 The Japan Society of Hepatology
α-fetoprotein in the type 3 tumors was significantly higher than that in types 1 and 2 (P < 0.05). The overall survival of the patients with type 3 HCC was the poorest among the three types. The tumor-free survival of the patients with types 3 and 2 HCC were significantly poorer than those with type 1 (P < 0.05). The univariate analysis showed that gross classification, α-fetoprotein level, tumor size and degree of enhancement were poor prognostic factors. The multivariate analysis indicated that the gross classification was the only independent prognostic indicator.
Conclusion: The preoperative gross classification was of great prognostic significance in solitary small HCC treated with RFA. Key words: ablation techniques, carcinoma, classification, hepatocellular carcinoma, multidetector computed tomography, prognosis
long-term effectiveness of RFA is comparable with hepatectomy for patients with small HCC,4–6 and RFA is associated with a lower complication rate and shorter hospital stay.5 However, we found that patients with small HCC after RFA had different prognoses, which is similar to what is observed in patients with HCC after surgery. The optimal candidates for treatment with RFA among patients with small HCC remain unknown. The prognostic significance of the gross classification of HCC based on specimens has been confirmed in patients after hepatectomy and living donor liver transplantation (LDLT).7–11 However, the role of gross classification in HCC treated with RFA has rarely been reported. The concept of gross classification for HCC was first put forward in 1901 by Eggel et al.12 based on autopsy data. In 1987, based on an analysis of surgically resected HCC, Kanai et al.7 proposed a new gross classification (single nodular type, single nodular type with extranodular growth,
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confluent multinodular type and infiltrative type), which was accepted by the Liver Cancer Study Group of Japan8 and has been widely used. A recent study reported that even for HCC of 2 cm or less, the gross type was significantly associated with local recurrence after RFA.13 However, the survival significance of gross classification in single small HCC treated with RFA has not been previously reported. The aim of this study was to investigate the distribution, clinicopathological features and prognostic role of gross classification based on preoperative computed tomography (CT) imaging of solitary small HCC treated with RFA.
METHODS Patients
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HE LOCAL ETHICS committee approved the study protocol. From January 2007 to July 2013, a total of 316 patients with clinically diagnosed HCC received RFA at our institution. The diagnosis of HCC was based on the clinical diagnostic criteria for HCC used by our country and the European Association for the Study of the Liver.14 Ablation therapy was used when patients were considered not to be suitable for resection because of liver function impairment, number and distribution of the tumors, and cardiopulmonary dysfunction, or because they voluntarily preferred ablation with informed consent despite surgery also being valuable. Inclusion criteria for this study were as follows: (i) pathologically confirmed HCC with a maximum diameter of 5 cm or less; (ii) a solitary lesion without evidence of intra- or extrahepatic metastasis; (iii) the preoperative CT imaging scans, clinicopathological records and survival information could be obtained; and (iv) RFA was an initial treatment. Among the 316 patients, 21 without a definite pathologic diagnosis, 43 patients underwent a combination therapy of transcatheter arterial chemoembolization (TACE) or systemic therapy, 128 patients who had more than one but less than three lesions and 21 patients who were lost to follow up were excluded. A total of 103 patients thus served as subjects in this retrospective study.
Preoperative CT examination All the 103 patients underwent plain and contrastenhanced (CE)-CT examinations using a multidetector CT scanner (LightSpeed VCT; GE Healthcare, Pittsburgh, PA, USA) with a 5.0-mm slice thickness at 30, 60 and 180 s to obtain hepatic arterial, portal venous and equilibrium phase images after the injection of contrast media (Omnipaque 350 mg I/mL; GE Healthcare) at a rate of 3.0 mL/s with a dose of 1.5 mL/kg bodyweight. Other
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parameters of the abdominal CT scan included a tube voltage of 120 kVp, tube current of 240 mA, rotation time of 0.6 s, helical pitch of 1.375, field of view of 35–40 cm and matrix of 512 × 512. The length of time between the preoperative CT examination and the RFA treatment ranged 3–5 days.
Gross classification of HCC based on CT imaging The preoperative CT images were reviewed independently by three blinded readers (two radiologists and one surgeon) who were unaware of the patients’ clinical and survival information. By referring to previous studies,8,9,15 and based on the readers’ own experience, the gross appearance of the tumors on the CT images was designated as one of three types (Fig. 1): type 1, round or oval-shaped tumor with a clear margin, especially in the arterial and portal phases, sometimes with a pseudocapsule in the equilibrium phase; type 2, round or oval-shaped tumor with a clear margin, and focally protruding areas at any slice in any phase image, or a lobulated tumor with multinodular enhancement especially in the arterial phase, and sometimes with intratumoral separations in the portal and equilibrium phases, excluding a lesion with any satellite nodule; and type 3, was an irregular tumor with a clear margin or a blurred tumor without a clear margin at any slice in any phase. The readers made their classifications independently and reached a consensus by discussion if there were disagreements. In addition, the HCC lesions were described as remarkably (>30 HU) or moderately– slightly enhanced (≤30 HU) based on the degree of enhancement in the arterial phase.
RFA treatment procedures All the RFA procedures were performed by a surgeon with 15 years of experience in ultrasonography (US)- or CTguided interventional procedures and RFA. The treatments were performed under general anesthesia with a commercially available system (Cool-tip; Valleylab, Burlington, MA, USA). Each patient underwent a tumor biopsy with an 18-G needle before the ablation. The treatment was initiated with 10 W of power and was increased at 10 W/min to 90 W for approximately 15 min. The frequency of ablation was dependent on the tumor size and the position at which the needle was introduced. The aim was to create a safe margin of approximately 1 cm if possible. The patients received abdominal bag compression and remained in bed for 12 h to prevent internal bleeding after the procedure.
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Figure 1 Dynamic contrast-enhanced computed tomography images of solitary small hepatocellular carcinomas. (a) Type 1, a round tumor with a clear margin and a pseudocapsule in the portal venous phase. (b) Type 2, a round tumor with a clear margin, as well as focally protruding areas in the hepatic arterial phase. (c) Type 2, a lobulated tumor with multinodular enhancement. (d) Type 3, an irregular tumor with a blurred margin in the portal venous phase.
Follow up One month after the RFA therapy, each patient underwent abdominal CE-CT to evaluate the treatment efficacy. The patients were then followed up regularly. Follow up was arranged monthly for the first 6 months, then every 3 months from one-half to 2 years and every 6 months until the time of death or 30 October 2014. During each follow up, an ultrasonography examination and liver function and α-fetoprotein (AFP) tests were ordered. If a relapse or progression of the disease was suspected, CE-CT, magnetic resonance imaging (MRI) or hepatic angiography was performed. Once a diagnosis of recurrence was confirmed, local ablation, surgical resection, TACE or molecular-targeted therapy was adopted according to the total status of each patient. Recurrence times and patterns and the causes of death of the involved cases were recorded.
Statistical analysis Demographic characteristics and clinicopathological variables were compared among the three types of solitary small HCC. The continuous data were presented as the means ± standard deviation and were compared by oneway ANOVA. The categorical variables were compared using a χ 2-test. The disease-free and overall survival curves of the patients with each type of HCC were calculated using the
© 2015 The Japan Society of Hepatology
Kaplan–Meier method and compared using the log–rank test. The Cox proportional hazards model was used to determine the factors most related to survival. All the statistical analyses were performed with SPSS version 19.0 software (SPSS, Chicago, IL, USA). P-values less than 0.05 were considered statistically significant.
RESULTS General information
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HE CLINICOPATHOLOGICAL VARIABLES of the 103 patients with solitary small HCC are summarized in Table 1. There were 82 men and 21 women, with a mean age of 57 ± 11 years (range, 34–77 years). There were 34 patients with type 1 HCC (33.0%), 49 patients with type 2 HCC (47.6%) and 20 patients with type 3 HCC (19.4%). The preoperative serum AFP value was significantly higher in the patients with type 3 HCC than in those with types 1 and 2 (P < 0.05). The proportion of remarkable enhancement in type 3 HCC was significantly lower than that in types 1 and 2 (P < 0.05).
Survival information The overall survival rates of all the patients who underwent RFA at 1, 3 and 5 years were 97.0%, 75.9% and 59.7%, respectively (Fig. 2). For types 1, 2 and 3 HCC, the 3-year survival rates were 94.7%, 71.9% and 33.0%, and the 3-year
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Table 1 Comparison of clinicopathological variables of patients with three types of solitary small hepatocellular carcinomas Type 1
Type 2
Type 3
(n = 49)
(n = 20)
F or χ 2
P
Variables
(n = 34)
Age (years) Sex (male/female) HCV positive (%) HBsAg positive (%) WBC (1 × 109/L) Platelet (1 × 109/L) ALT (U/L) AST (U/L) TB (μmol/L) Albumin(g/L) INR ICG-R15 (%) MELD score AFP (ng/mL) Enhancement degree (remarkably/moderately–slightly) Tumor size (cm) Histological grade (well/moderate/poor) Ablative margin (cm)
54.6 ± 12.1 26/8 5.8% 82.3% 8.4 ± 18.6 93 ± 69 36.7 ± 18.6 39.3 ± 13.5 21.9 ± 9.4 40.3 ± 4.4 0.93 ± 0.42 8.3 ± 6.4 7.8 ± 2.7 43.4 ± 139.9 17/17
58.9 ± 11.6 38/11 4.1% 81.6% 6.2 ± 12.3 95 ± 49 46.4 ± 38.7 42.6 ± 31.1 20.7 ± 12.4 40.6 ± 5.0 1.05 ± 0.28 8.2 ± 3.0 8.6 ± 3.0 161.0 ± 297.9 20/29
58.5 ± 9.8 18/2 5% 85% 6.9 ± 14.5 94 ± 56 47.5 ± 36.5 45.7 ± 28.3 25.1 ± 14.3 39.5 ± 5.9 0.98 ± 0.42 9.3 ± 3.0 8.6 ± 3.1 414.1 ± 834.2 3/17
1.096 1.665 0.142 0.113 0.333 0.200 0.689 0.253 0.632 0.256 0.850 1.135 0.770 3.414 6.649
0.340 0.435 0.931 0.945 0.632 0.392 0.506 0.777 0.535 0.775 0.432 0.313 0.467 0.038 0.036
2.7 ± 1.0 7/24/3 1.2 ± 0.3
2.6 ± 1.0 7/38/4 1.0 ± 0.3
2.6 ± 1.3 3/15/2 1.1 ± 0.3
0.006 0.703 0.938
0.994 0.951 0.395
Enhancement degree was defined as remarkably (>30 HU) or moderately–slightly enhanced (≤30 HU) based on enhancement degree in the arterial phase. AFP, α-fetoprotein; ALT, alanine aminotransferase; AST, aspartate transaminase; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCV, antibody against hepatitis C virus; ICG-R15, indocyanine green retention rate at 15 min; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; TB, total bilirubin; WBC, white blood cell.
disease-free survival rates were 70.6%, 16.3% and 20.0%, respectively. The overall survival rates and disease-free survival of the patients with types 3 and 2 HCC were significantly poorer than those of patients with type 1 HCC (P < 0.05; Figs 3,4). The overall survival rate of the patients with tumors that were moderately–slightly enhanced was poorer than those with remarkably enhanced tumors (P < 0.05; Fig. 5). The univariate analysis revealed that gross classification, AFP, enhancement degree and tumor size were predictors associated with survival. However, the multivariate analysis showed that the gross classification was the only independent prognostic factor (P = 0.013) (Table 2).
DISCUSSION
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Figure 2 Kaplan–Meier curve for overall survival of the patients with solitary small hepatocellular carcinoma after radiofrequency ablation. The 1-, 3- and 5-year overall survival rates were 97.0%, 75.9% and 59.7%, respectively.
HE PROPORTIONS AND prognostic significance of gross classification have been reported in patients with HCC after hepatectomy and LDLT.7–11 Most of these studies were from Japan and Western countries, in which the dominant risk factor is hepatitis C virus infection, together with alcohol abuse.2,16 However, Chinese patients with HCC have primarily been infected with the hepatitis B
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Figure 3 Kaplan–Meier curves for overall survival of patients with different gross types of solitary small hepatocellular carcinomas after radiofrequency ablation. Type 1 versus 2, P = 0.013; type 1 versus 3, P = 0.000; type 2 versus 3, P = 0.009.
Figure 5 Kaplan–Meier curves for overall survival of patients with solitary small hepatocellular carcinomas with different enhancement degrees in the arterial phase of contrast-enhanced computed tomography, P = 0.023.
virus, and the incidence of each gross type in Chinese patients with HCC may be different from previous reports. The classification reported in previous studies was based
on postoperative specimens. However, the preoperative assessment of the gross appearance of tumors using imaging modalities seems to be more important for the management of patients with HCC. To our knowledge, this is the first study focusing on the role of preoperative gross classification in solitary small HCC treated with RFA. Our study finds that the preoperative gross classification of the tumors is of great prognostic significance in solitary small HCC treated with RFA. The overall survival of patients with type 3 was the poorest among the three types. The tumor-free of patients with types 3 and 2 were significantly poorer than type 1. The univariate analysis showed that the level of AFP, gross classification, enhancement degree and tumor size were all risk factors influencing the overall survival time of patients with solitary small HCC after RFA. Recent studies have reported that tumor size, tumor location, tumor number, AFP level and an insufficient safety margin, among others, are risk factors for local tumor progression of HCC after RFA.17–19 Most of these factors were considered in our study, including the preoperative gross classification of HCC. The multivariate analysis indicated that the preoperative gross classification was the only independent prognostic factor in patients with solitary small HCC after RFA. The serum AFP level in type 3 was significantly higher than that in the other types, and the serum AFP level was
Figure 4 Kaplan–Meier curves for disease-free survival of patients with different gross types of solitary small hepatocellular carcinomas after radiofrequency ablation. Type 1 versus 2, P = 0.006; type 1 versus 3, P = 0.002; type 2 versus 3, P = 0.562.
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Table 2 Univariate and multivariate analysis of prognostic factors of patients with solitary small hepatocellular carcinoma after radiofrequency ablation
Variables Age Sex HBsAg positive WBC (1 × 109/L) Platelets (1 × 109) ALT (U/L) AST (U/L) TB (μmol/L) Albumin (g/L) INR ICG-R15 (%) MELD score Histological grade (well/moderate/poor) Gross classification AFP (ng/mL) Tumor size (cm) Enhancement degree
Univariate analysis (P)
Multivariate analysis RR 95% CI p-value
0.688 0.852 0.557 0.343 0.707 0.733 0.445 0.493 0.455 0.517 0.486 0.599 0.573 0.000 0.001 0.010 0.025
3.443 1.000 1.565 3.084
1.301–9.113 0.999–1.001 0.930–1.053 0.504–18.873
0.013 0.826 0.738 0.223
AFP, α-fetoprotein; ALT, alanine aminotransferase; AST, aspartate transaminase; CI, confidence interval; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; ICG-R15, indocyanine green retention rate at 15 min; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; RR, relative risk; TB, total bilirubin; WBC, white blood cell.
the lowest in type 1 in our study. Farinati et al.20 reported that a high AFP level was associated with the tumor size, tumor number and tumor staging. In our study, all the lesions were solitary and at an early stage, and the tumor sizes of the three types were not significantly different. We hypothesized that the difference in serum AFP levels among the different types may be due to different biological characteristics and molecular mechanisms. For example, HCC with a low expression of BCL2 have been correlated with higher AFP levels.20 Most of the type 3 HCC (85.7%) in our study lacked the rapid “wash-in and wash-out” characteristic commonly seen on enhanced CT imaging. Rosenkrantz et al.21 confirmed that infiltrative HCC is an aggressive form of HCC that is often less conspicuous on arterial phase images compared with the typical mass-forming HCC. It has been reported that imaging features and gross classification were independent prognostic factors for patients with HCC. Nakayama et al.22 reported that preoperative morphological classification appeared to provide a promising additional criterion for the prognostic categorization of
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patients with HCC via a new CT-based morphological classification system. Kawamura et al.23 reported that the heterogeneity of dynamic CT images correlated with the malignant characteristics of HCC and could be potentially used to predict the malignant potential of HCC before treatment. Types 1, 2 and 3 HCC accounted for 33.0%, 47.6% and 19.4% of the cases in this study, respectively. Based on previous studies and our own experience,8–10 type 1 in this study corresponded pathologically to the single nodular type; type 2 primarily corresponded to the single nodular type with extranodular growth and sometimes to the confluent multinodular type; and type 3 generally indicated the infiltrating HCC and the confluent multinodular type. However, the proportion of tumors with a pathological single nodular type has been reported as 73–77%, while those with a single nodular type with extranodular growth was 23–27%, and the incidence of infiltrating HCC has been reported to be extremely low.9,24,25 This discrepancy may be due to the high rate of hepatitis B infection in this cohort, and the features of HCC may vary among different areas worldwide.2 Patients with hepatitis C virus show multicentric carcinogenesis, but patients with hepatitis B do not. The overall survival of the patients with type 3 was the poorest among the three types. The tumor-free survival rates of the patients with types 3 and 2 were significantly poorer than those of the patients with type 1. The recurrence of HCC after treatment is classified as local and distant recurrence. Local recurrence is defined as a reappearance of tumor progression adjacent to the treated site and distant recurrence as the emergence of one or several tumor(s) not adjacent to the ablation zone. In our study, the 3-year overall recurrence rate was 64.1% and the 3-year recurrence rate of the three types was 29.4%, 83.7% and 80.0%, respectively. The local recurrence rate of the three types was 3.0%, 12.2% and 15%, respectively. The local recurrence rates of the patients with types 3 and 2 were significantly higher than those of the patients with type 1. Ariizumi et al.26 reported that HCC with nonsmooth margins had greater involvement of microscopic portal vein invasion and intrahepatic metastasis than those with smooth margins. Okusaka et al.27 found that the macroscopic type of HCC was significantly associated with the prevalence of satellite lesions, even in small HCC. Small satellite nodules were detected within 0.5-1.0 cm from the main lesion. The poor prognosis of the patients with type 3 HCC may be due to the high incidence of intrahepatic metastases and microinvasion with this type of HCC, and RFA was apparently insufficient to eliminate all of these small lesions.
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The 1-, 3- and 5-year survival rates of the patients in our study were 97.0%, 75.9% and 59.7%, respectively. The survival rates in our study are comparable with previous reports. Shiina et al.28 reported that the 5-year survival rate of patients with HCC after RFA was 60.2% based on a large sample size. Chen et al.6 compared RFA and partial hepatectomy for the treatment of small HCC and the 1-, 2-, 3and 4-year overall survival rates were 95.8%, 82.1%, 71.4% and 67.9%, and 93.3%, 82.3%, 73.4% and 64.0%, respectively. In our study, the 3-year survival rate for the patients with type 1 HCC after RFA was superior to that after hepatectomy (94.7% vs 73.4%), suggesting that patients with type 1 HCC on preoperative CT imaging are optimal candidates for RFA. The 3-year survival rates for the patients with type 2 and 3 HCC were poorer than those for the patients treated with hepatectomy (71.9%, 33.0% vs 73.4%), indicating that patients with irregularly shaped HCC are more suitable for surgical resection. Therefore, it is important to assess the gross type of small HCC through preoperative imaging to determine the optimal treatment method. There were some limitations in this study. First, this was a single-center retrospective study with a relatively small sample size. Second, only CT imaging was used for the preoperative assessment of the HCC lesions. Hatanaka et al.29 reported that CE-US is a more reliable tool than CE-CT to evaluate the gross type of HCC. Tada et al.30 reported that gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI was equal or superior to angiography-assisted CT. Third, no gross specimens could serve as the reference for imaging classification and there was a risk of dissemination with tumor biopsy. Finally, the treatment after recurrence could affect the outcomes of patients with HCC. Nevertheless, the disease-free survival rates of the patients with different types of HCC were significantly different, indicating the great prognostic significance of the gross classification of solitary small HCC treated with RFA. In summary, this study demonstrated that the preoperative gross classification of the tumors is of great prognostic significance in solitary small HCC treated with RFA. Not all of the patients with small HCC are suitable for RFA treatment. The gross classification should be considered before treating patients with small HCC. Surgical resection is strongly recommended for the management of irregular types, such as types 2 and 3, even in small HCC.
ACKNOWLEDGMENTS
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HE AUTHORS THANK Professor Fan Yimei for help with the statistics, and for guidance from the
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multidisciplinary hepatobiliary cancer teams of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School. This work was funded by a grant from Fundamental Research Funds for the Central Universities (no. 20620140664) and Nanjing City Young Health Personnel Training Project (third level) (no. QRX11178).
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