Abstract
Background/Aim: Diabetes mellitus (DM) is known as an important risk factor for hepatocellular carcinoma (HCC). However, surgical outcomes in patients with DM and HCC have not been evaluated in detail. Patients and Methods: We retrospectively studied 177 patients with type 2 DM who underwent curative hepatectomy for HCC. Surgical outcomes after curative hepatectomy and prognostic factors were evaluated among 75 patients with DM and/or nonalcoholic steatohepatitis (NASH)-related HCC and 102 patients with DM and viral or alcoholic hepatitis (VAH)-related HCC. Results: The 5-year survival rate and 5-year recurrence-free survival rate were significantly higher in the DM and/or NASH-related HCC group (87% and 51%) than in the DM and VAH-related HCC group (68%: p=0.0001 and 26%: p=0.0002). Multivariate analysis showed DM and/or NASH-related HCC to be significant independent prognostic factors for overall survival and recurrence-free survival. Conclusion: Patients with DM and/or NASH-related HCC showed more favorable surgical outcomes after hepatectomy in patients with DM and HCC.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with an estimated annual mortality of 7 million worldwide (1). Viral hepatitis B and C are common risk factors for HCC. Diabetes mellitus (DM) is a common disease and is known to be another risk factor for HCC (2). Several studies have shown that patients with DM had a more than two-fold incidence of HCC, and that patients with DM showed an increased risk for HCC worldwide (2-6). Although HCC is often associated with DM, there have been no previous reports on surgical outcomes in patients with HCC and DM. In this study, we evaluated the surgical outcomes and prognostic factors of patients with HCC and DM.
Patients and Methods
Between 2002 and 2015, 924 patients with HCC underwent curative hepatectomy at Tokyo Women's Medical University Hospital, Tokyo, Japan. Of these patients, 177 were enrolled in this study because they had HCC and were receiving treatments for type 2 DM (118 patients with insulin therapy and 59 patients with oral hypoglycemic agents). Of these, 102 patients (23 patients with hepatitis B virus, 51 patients with hepatitis C virus, and 28 patients with alcoholic hepatitis) constituted the DM and viral or alcoholic hepatitis (VAH)-related HCC group. The remaining 75 patients (42 patients with DM and nonalcoholic steatohepatitis (NASH) and 33 patients with DM without NASH) constituted the DM and/or NASH-related HCC group. The hemoglobin A1c (HbA1c), Child-Pugh class, indocyanine green retention rate at 15 min (ICGR15), serum levels of alpha-fetoprotein (AFP), and serum levels of protein induced by vitamin K absence and antagonist II (PIVKA-II) were evaluated preoperatively. Patients who had a HCC with major portal or hepatic vein invasion were excluded from this study. This study was approved by the ethics committee of Tokyo Women's Medical University (approval number: 4512).
Surgery and pathological examination. All patients underwent curative hepatectomy, and the choice of resection was made on the basis of tumor size, tumor location, and liver function (ICGR15). Anatomical hepatectomy with the Glissonean pedicle transection method was performed in 153 patients and non-anatomical partial resection was performed in 24 patients (7-9). Pathologically, tumor size, vascular (portal or hepatic vein) invasion, intrahepatic metastasis, and cirrhosis were examined. Pathological findings of HCC were examined according to the General Rules for the Clinical and Pathological Study of Primary Liver Cancer of the Liver Cancer Study Group of Japan (10). Steatohepatitis was confirmed by the following pathological findings: steatosis, portal and lobular inflammation or both, hepatocyte ballooning, pericellular fibrosis by silver staining and the Mallory body (11).
Patient characteristics.
Follow-up and treatment of patients with recurrence. After surgery, patients were followed up every 4-12 weeks at the outpatient Department of our Institution. Ultrasonography or computed tomography was performed once every 3-4 months. Survival duration was defined as the time from hepatic resection to the date of death or last contact. When a solitary HCC had recurred in the liver, repeat hepatic resection or radiofrequency ablation was performed. When multiple HCCs had recurred in the liver, transarterial chemoembolization (TACE) was performed. When HCCs had recurred in the liver and/or other organs including lymph nodes, systemic chemotherapy or best supportive care was performed.
Statistical analysis. All values are expressed as median with range. The overall survival (OS) rate and recurrence-free survival (RFS) rate were calculated using the Kaplan–Meier method and compared with the log-rank test. Cox's proportional hazard model identified independent predictors of survival or recurrence. p-Values <0.05 were taken to indicate statistical significance. The JMP software was used (version 14.0; SAS Institute, Inc., Cary, NC, USA) for statistical analysis.
Results
Patient characteristics are shown in Table I. The median HbA1c (%) was 7.9%. The median HbA1c (%), median ICGR15 and median AFP showed no significant differences between groups. The number of patients with anatomical hepatectomy did not differ between groups, nor did the number of patients with vascular invasion or the number of patients with intrahepatic metastasis. The median tumor size was significantly larger in the DM and/or NASH-related HCC group than in the DM and VAH-related HCC group. The number of patients with cirrhosis was significantly lower in the DM and/or NASH-related HCC group than in the DM and VAH-related HCC group.
The median patient follow-up period was 52 months. One patient died within 30 days after surgery in the DM and VAH-related HCC group. The survival rate of 177 patients with DM was 77% at 5 years, and median survival was 140 months (ranging from 0.1 to 183 months). Tumor recurrence after curative surgery occurred in 108 of 177 patients (61%), and the 5-year RFS rate was 37%. The 5-year OS and RFS rates were significantly higher in the DM and/or NASH-related HCC group (87% and 51%) than in the DM and VAH-related HCC group (68%: p=0.0001, Figure 1a and 26%: p=0.0002, Figure 1b).
The univariate analysis of prognostic factors for OS and RFS with 16 variables in patients with DM and HCC is summarized in Table II. The univariate prognostic factors were entered into a multivariate model to identify independent predictors of survival. Multivariate analysis showed that DM and/or NASH-related HCC, PIVKA-II, and intrahepatic metastasis were significant independent prognostic factors for OS (Table III). Multivariate analysis showed that DM and/or NASH-related HCC, cirrhosis, portal invasion, and intrahepatic metastasis were significant independent prognostic factors for RFS (Table III).
Overall survival (a) and recurrence-free survival curves (b) between 75 patients with DM and/or NASH-related HCC and 102 patients with DM and viral or alcoholic hepatitis (VAH)-related HCC.
Discussion
Viral hepatitis B and C are common risk factors for HCC. DM is known to be an important risk factor for HCC. A more than two-fold incidence of HCC has been reported in patients with DM compared to those with no-DM (2-6, 12, 13). Furthermore, malignant neoplasm has been reported to be the most frequent cause of death in patients with DM, and liver cancer the most frequent malignant neoplasm (13). Although patients with HCC often have DM, there have been no previous reports on surgical outcomes in patients with HCC and DM. In our present study, 5-year OS and 5-year RFS rates were significantly higher in the DM and/or NASH-related HCC group than in the DM and VAH-related HCC group. Furthermore, multivariate analysis showed DM and/or NASH-related HCC to be an independent prognostic factor for survival and RFS in patients with DM and HCC.
The synergistic effects of DM and virus hepatitis may promote development of HCC (14, 15). Reddy et al. have reported that patients with HCC and hepatitis C virus and/or ASH have more severe liver dysfunction and poorer survival rates after curative treatment compared with patients with HCC and NASH (16). In our present study, the number of patients with cirrhosis was significantly lower in the DM and/or NASH-related HCC group than in the DM and VAH -related HCC group. Cirrhosis is an independent prognostic factor for RFS on multivariate analysis. Therefore, lower risk of recurrence and longer survival were seen in patients with DM and/or NASH-related HCC.
NASH is known to be a risk factor for HCC, and a high prevalence of NASH in patients with DM is also known (17). In our present study, 42 of 177 patients with HCC showed DM with NASH, and 32 of 177 patients with HCC showed DM without NASH. Smaller HCC tended to be detected in patients with NASH, which were followed-up regularly. On the other hand, more progressed HCC, larger tumor size (median tumor diameter of 10 cm), was often observed in patients without NASH. However, the majority patients without NASH showed no cirrhosis (only 1 patient showed cirrhosis). Better surgical outcomes after hepatectomy, even for HCCs that are 10 cm or more in diameter, have been reported (18). Therefore, hepatectomy is recommended for patients with DM with or without NASH-related HCC since favorable surgical outcomes were achieved.
In conclusion, patients with DM and/or NASH-related HCC showed more favorable surgical outcomes after hepatectomy in patients with DM and HCC.
The univariate analysis of prognostic factors of survival and recurrence-free survival.
Multivariate analysis of survival and recurrence-free survival.
Acknowledgements
The Authors are indebted to Associate Professor Raoul Breugelmans of the Department of English of Tokyo Medical University for his review of this manuscript.
Footnotes
Authors' Contributions
All Authors participated in conferences to plan and discuss about this manuscript. JL and SA: collected the date. SA and MY: treated and operated patients. JL, SA and MN: examined the pathological findings. All Authors contributed and agreed with the content of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest regarding this study.
- Received August 26, 2019.
- Revision received September 8, 2019.
- Accepted September 10, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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