- In patients with hepatocellular carcinoma (HCC) undergoing liver resection, many patients have chronic liver disease and impaired liver function. The development of portal hypertension is one of the most serious complications of chronic liver disease.
- Compared with patients with low portal venous pressure (PVP) (<11 mm Hg), patients with high PVP (>11 mm Hg) had lower platelet counts, lower serum albumin levels, higher ALT concentration, higher International Normalized Ratio (INR), higher Model for End-Stage Liver Disease score, and increased blood loss and blood transfusion during liver resection.
- Overall and disease-free survival rates in the high PVP group were significantly lower than in the low PVP group.
- For patients with high PVP, close follow-up and early salvage liver transplants for recurrent disease may be necessary to improve long-term prognosis after surgery.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally1. Hepatic resection remains the main treatment strategy for patients with early disease, providing the chance for a cure2 and offering long-term survival3. In HCC resection, many of the patients have chronic liver disease and impaired liver function4,5. The development of portal hypertension (PH) is one of the most serious complications of chronic liver disease. The elevated portal pressure in these patients usually reflects the degree of fibrosis and is closely related to the degree of liver function damage6.
Currently, the use of hepatectomy for the treatment of HCC involving PH is still controversial7. The American Association for the Study of Liver Diseases (AASLD)/Barcelona Clinic8,9 recommends that only liver transplantation can be regarded as curative treatment for early-stage HCC (single nodule or up to 3 nodules measuring 3 cm) with PH. However, some studies have shown that patients with PH undergoing hepatectomy have the same postoperative complications and survival rates as patients without PH10–12.
In this study, patients were divided into groups with or without PH using portal venous pressure (PVP) data determined directly before hepatectomy. We studied the long-term outcomes of patients with or without PH after curative resection of HCC.
Materials and methods
We carried out a prospective study including 68 patients with HCC who underwent liver curative resection at Taipei Veterans General Hospital, Taipei, Taiwan, between May 2001 and April 2005. Patient exclusion criteria were as follows: previous history of hepatectomy, chronic renal insufficiency, preoperative ascites, and concurrent major surgery during hepatectomy, including splenectomy, bowel resection, and adrenalectomy. The research protocol was approved by the ethics committee of the Taipei Veterans General Hospital. The work has been reported in line with the STROCSS criteria13. Curative resection was defined as surgery in which all tumors were macroscopically removed.
Preoperative images included chest x-ray, abdominal ultrasound, computed tomography and/or magnetic resonance images. Preoperative liver function tests included measurement of serum biochemistry, prothrombin time, and indocyanine green retention rate at 15 minutes (ICG-15). Three preoperative laboratory data were used to calculate the Model for End-Stage Liver Disease (MELD) score, International Normalized Ratio (INR), serum total bilirubin and serum creatinine. The MELD score was calculated using the formula14: MELD=9.57 × loge(creatinine mg/dL)+3.78×loge(total bilirubin mg/dL)+11.20×loge(INR)+6.43. Subsegmentectomy was defined as complete anatomic resection of the corresponding area fed by the portal branches15. Segmentectomy was defined as resection of one, the 4 segments; that is, anterior segment, posterior segment, lateral segment, and medial segment16. Major resection was defined as resection of 3 or more Couinaud segments. The Milan criteria involves tumors up to 3 lesions <3 cm or a single lesion <5 cm and no extrahepatic manifestations or vascular invasion17.
Liver resection techniques
The operative procedures have been described elsewhere16,18. During parenchymal transection, attempts were made to keep a surgical margin of 1 cm or more19. Liver transaction was performed using either the ultrasonic dissector or the tissue-fracture technique, according to the surgeon’s preference. The techniques of inflow occlusion (either the hemihepatic vascular occlusion or the Pringle maneuver) were applied20. Resection procedures were either anatomic or nonanatomic resection. Drains were placed routinely before wound closure. The pathologic features of the tumor, including the size, number, tumor vascular invasion, and liver fibrosis graded using the Hepatic Activity Index (HAI)21 were recorded.
Intraoperative measurement of PVP
For PVP measurements, before hepatectomy, we inserted a 23-G cannula into the portal vein and connected to the pressure sensor. The pressure was expressed as millimeters of mercury. All measurements were repeated twice.
After operation, patients were followed up every 3 months with serum α-fetoprotein assays, ultrasound examination, computed tomography or magnetic resonance imaging (or a combination of tests). Tumor recurrence was diagnosed by the combination of these examination results.
The main outcome measures were disease-free and overall survival. Statistical calculations were carried out using commercially available computer software (SPSS/PC+ 13.0; SPSS Inc, Chicago, IL). Data of continuous variables are expressed as mean±SD and were compared using Student t test, or Pearson correlation. Categorical data were compared with Fisher exact test. Survival rates were calculated with the Kaplan-Meier method and survival curves were compared with the log-rank test. Variables which were significant in univariate analysis (P<0.05) were included in multivariate regression analyses to identify predictive factors for high (>11 mm Hg) PVP. P<0.05 was considered statistically significant.
There were 58 men (85%) and 10 women (15%) with a mean age of 59 years old (SD=14) (27-85 y). Twenty-four patients (35.3%) underwent major resection (resection ≥3 segments), including extended right lobectomy (n=2), right lobectomy (n=5), left lobectomy (n=8), other ≥3 segments resection (n=9). Forty-four (64.7%) patients underwent minor resection, including segmentectomy (n=20), subsegmentectomy (n=8), and partial resection (n=16). There were no hospital deaths after operation.
Correlation of PVP with clinicopathologic factors
The median PVP was 10.7 mm Hg, ranging from 2.9 to 23.5 mm Hg, with a mean (SD) of 10.8 (3.4) mm Hg (Fig. 1). PVP was significantly associated with the preoperative value of ICG-15, MELD score, serum albumin, platelet count, and INR (Table 1).
Table 1 -
Relationship between the portal venous pressure and variables.
|Portal Venous Pressure
|Serum total bilirubin
ALT indicates alanine aminotransferase; ICG-15, indocyanine green dye retention at 15 minutes; INR, international normalized ratio; MELD, model for end-stage liver disease.
The mean patient follow-up time was 101 months (range: 5–231 mo). During the follow-up period, 54 patients (79.4%) had tumor recurrence (Fig. 2) and 50 patients (73.5%) died (Fig. 3). Twenty-six patients (48.1%) had recurrences occurred within 2 years after undergoing surgery. Nine patients (18.0%) died without tumor recurrences.
Patients were divided into high (>11 mm Hg) (n=33) and low (≤11 mm Hg) (n=35) PVP groups. Survival analysis showed that the 5-, 10-, and 15-year overall survival rates of the high PVP group were: 48.5%, 30.3%, and 21.2%; respectively. These were significantly lower than the corresponding rates of 77.1%, 53.4%, and 47.5% in the low PVP group (P=0.029). The 5-, 10-, and 15-year disease-free survival rates of the high PVP group were: 30.0%, 20.0%, and 6.7%; respectively. These were also significantly lower than the corresponding rates of 55.9%, 35.3%, and 19.9% in the low PVP group (P=0.035). Subgroup analysis showed that for patients with tumor staging within Milan criteria, those in the high PVP group had lower overall survival (P=0.032) (Fig. 4) and disease-free survival (P=0.016) (Fig. 5) than those in the low PVP group. For patients with tumor staging outside the Milan criteria, no difference in survival was found when comparing the overall survival (P=0.473) (Fig. 6) and disease-free survival (P=0.461) (Fig. 7) of the high and low PVP groups.
Comparison of clinicopathologic factors between low and high PVP groups
The clinicopathologic characteristics of HCC patients were compared according to PVP (Table 2). Compared with patients with a low PVP (≤11 mm Hg), patients with a high PVP (>11 mm Hg) had lower platelet counts, lower serum albumin levels, higher ALT concentrations, higher INR, higher MELD score, and higher volume of blood loss and blood transfusion during liver resection, and higher Ishak fibrosis scores. Fourteen patients (42.4%) in the high PVP group had complications after hepatectomy, including postoperative hyperbilirubinemia (n=6), massive ascites (n=5), massive pleural effusion (n=3), intra-abdominal fluid accumulation (n=3), bile leakage (n=3), bile duct injury (n=1), and wound infection (n=2). Eleven patients (31.4%) in the low PVP group had complications, including postoperative hyperbilirubinemia (n=5), massive ascites (n=4), massive pleural effusion (n=2), intra-abdominal fluid accumulation (n=3), delirium (n=1), intestinal obstruction (n=1), bile leakage (n=2), and wound infection (n=2). There was no significant difference in morbidity between the 2 groups (P=0.347). In multivariate logistic regression analysis, the preoperative factors associated with high PVP were: serum albumin level <3.6 g/dL (odd ratio: 5.532, 95% confidence interval: 1.286–23.79, P=0.022), and MELD score >6 (odd ratio: 5.585; 95% confidence interval: 1.638–19.040, P=0.006).
Table 2 -
Comparison of clinicopathological characteristics according to portal venous pressure.
||PVP ≤11 mm Hg (n=35), n (%)
||PVP >11 mm Hg (n=33), n (%)
|With family history of HCC
|Alcohol intake (+)
|Blood loss (mL)
|Blood transfused (mL)
|Operative time (min)
|Tumor size >5 cm
|Specimen weight (g)
|Within Milan criteria
|Ishak fibrosis score
|Surgical margin (cm)
|Drain amount (mL)
|Postoperative hospital stay (d)
Continuous data are expressed as mean±SD.
AFP indicates α-fetoprotein; ALT, alanine aminotransferase; Anti-HCV, anti-hepatitis C virus antibody; AST, aspartate aminotransferase; BMI, body mass index; DM, diabetes mellitus; HBsAg, hepatitis B virus surface antigen; HCC, hepatocellular carcinoma; ICG-15, indocyanine green dye retention at 15 minutes (reference range, 0%–10%); INR, international normalized ratio; MELD, model for end-stage liver disease; PVP, portal venous pressure; T-Bil, total bilirubin.
Whether there are differences in the long-term prognosis of HCC patients with or without PH undergoing hepatic resection remains controversial. Our study shows that, in patients with tumor stage within Milan criteria, those with PVP >11 mm Hg had a worse long-term survival than patients with PVP ≤11 mm Hg.
PVP measurement in patients with PH has long been considered to have relevant prognostic and therapeutic significance22,23. A normal PVP is generally considered to be between 5 and 10 mm Hg. PH is defined as a portal pressure higher than 10 or 12 mm Hg13,24,25. Once the PVP rises to 12 mm Hg or higher, complications such as varices and ascites may occur.
The PVP can be directly acquired from transhepatic or transvenous catheterization of hepatic portal vein26, or from portal vein puncture or catheterization during abdominal surgery27–30. Salman et al27 suggested that direct measurement of PVP during surgery can be used as an indicator of mortality in patients with cirrhotic disease undergoing emergency surgery. Allard et al29 reported that in patients without severe fibrosis or cirrhosis who underwent a major liver resection (≥3 segments), posthepatectomy PVP >20 mm Hg is an independent predictive factor of liver failure. In study by Bogner et al30, results indicated that increase in intraoperative PVP is an independent predictor of posthepatectomy liver failure. In our study, using Pearson correlation analysis, we found PVP to be significantly correlated with the preoperative value of ICG-15, MELD score, serum albumin, platelet count, and INR. Patients with high PVP had higher blood loss and higher blood transfusion during hepatectomy. However, no significant difference was found when comparing complication rates between the 2 groups. This may be due to the fact that in our cohort, in patients who already have clinical signs of PH, we restrict the extent of liver resection to avoid a small remnant liver, and thus reduce the occurrence of postoperative liver decompensation and prevent postoperative liver failure and its lethal outcome. There was no surgical mortality in our entire cohort.
In our study, the cut-off value of 11 mm Hg of PVP is based on the median value of PVP of our cohort and is also consistent with the definition of PH in the literature13,24,25. A high PVP (>11 mm Hg) is associated with liver inflammation and fibrosis, as evidenced by lower albumin levels, higher ALT concentrations, higher INR, higher MELD score, and higher Ishak fibrosis score.
The impact of PH on long-term survival after hepatectomy for HCC is still controversial11,30,31. In a study reported by Hidaka et al32, 177 HCC patients underwent direct measurement of PVP immediately after laparotomy. These patients were divided into 2 groups with high (>15 mm Hg) and low (<15 mm Hg) PVP. High PVP was associated with poor long-term overall survival, but not disease-free survival. In our study, patients with early disease (tumor staging that meets Milan criteria), the presence of PH had a detrimental effect on long-term survival after surgery. The better prognosis of patients with early disease without PH may be due to a variety of factors, and can be attributed to differences in tumor-related factors and surgical factors between the 2 groups. In our study, the main cause of death in patients with and without PH was cancer recurrence, and 48.1% of recurrences occurred within 2 years after surgery (Fig. 2). The presumably higher frequency of occult nodules in patients with cirrhosis and PH may be a possible reason for the poor prognosis of these patients. In the later stages of the disease, patients with and without PH are most likely to have intrahepatic metastasis, and the prognosis of both groups is expected to be equally dismal. In the early stages of the disease, the probability of intrahepatic metastasis is low and effective control of local cancer is effective to avoid tumor recurrence33,34. Only feasible in patients without PH, more extensive resection with tumor clearance can lead to a better prognosis for this group of patients. In addition to these factors, in patients with chronic liver disease, the residual liver after hepatectomy still has malignant potential and may be associated with a higher recurrence rate after resection34. In a prospective follow up of a total of 213 patients with compensated cirrhosis, Ripoll et al35 indicated that HVPG was an independent predictor of HCC on multivariate analysis.
In general, the results of liver transplantation are better than those of resection for HCC patients with PH and cirrhosis, particularly in patients who meet the Milan criteria36,37. However, due to the scarcity of organ donation, the mortality rate among patients on the transplant waiting list is as high as 25%38,39. Our results showed that hepatic resection of HCC in patients with PH can be performed safely, and patients who have tumor staging within the Milan criteria have a 5-year overall survival rate/disease-free survival rate of 55.6/33.3%, and a 10-year overall survival rate/disease-free survival rate of 33.3/19.7%, respectively. This is better than in patients receiving other treatment modalities (including RFA and TACE for small HCC)40,41. From the perspective of overall treatment results, at present, hepatic resection can be justified as the first-line of treatment for early-stage HCC with or without high PVP. In patients with a high PVP (>11 mm Hg) undergoing hepatic resection, a close postresectional follow-up is necessary, and early liver transplantation can be adopted as salvage treatment for patients with HCC who have recurrent disease after hepatic resection, as reported by Poon et al42 and Wen et al43.
Our study has strengths and limitations. A major strength is that it is based on a prospective cohort of patients with long-term follow-up. In addition, the stratification of patients with or without PH is based on the measurement of PVP directly before hepatectomy. Among the limitations, this is a single institutional study, and that the sample size is relatively small. Second, our study was mainly based on the cohort of patients with HCC and predominant hepatitis B virus infection. From this study we cannot extrapolate whether the prognostic value of a high PVP would extend to patients with HCV infection or with history of alcohol abuse. The clinical significance of PVP in these patients needs further investigation.
In summary, we have shown that for HCC patients with tumor staging within the Milan criteria, patients with a high PVP (>11 mm Hg) had lower postresectional survival rates than patients with a lower (<11 mm Hg) PVP during long-term follow-up. For patients with PH undergoing hepatectomy, close follow-up and early salvage transplantation may be necessary to improve postoperative long-term outcomes. Our findings may help to provide patients with accurate information and make further therapeutic decisions based on expected outcomes and risk stratification.
The research protocol was approved by the ethics committee of the Taipei Veterans General Hospital.
Sources of funding
This study was supported by grants from Taipei Veterans General Hospital (V99C1-080), (V109C-187).
S.-Y.W. and I.Y.C.: concepturation. S.-Y.W., I.Y.C., C.-Y.H., H.-J.L., S.-C.C., Y.-C.K., and G.-Y.C.: data curation. S.-Y.W. and I.Y.C.: data analysis and interpretation. S.-Y.W., I.Y.C., and G.-Y.C.: manuscript writing.
Conflict of interest disclosures
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
1. Yang JD, Hainaut P, Gores GJ, et al. Global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019;16:589–604.
2. Cucchetti A, Zhong J, Berhane S, et al. The chances of hepatic resection curing hepatocellular carcinoma. J Hepatol 2020;72:711–7.
3. Tsai TJ, Chau GY, Lui WY, et al. Clinical significance of microscopic tumor venous invasion in patients with resectable hepatocellular carcinoma. Surgery 2000;127:603–8.
4. Chang WT, Kao WY, Chau GY, et al. Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: extending the indication for resection. Surgery 2012;152:809–20.
5. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol 2015;33:550–8.
6. Karagiannakis DS, Voulgaris T, Siakavellas SI, et al. Evaluation of portal hypertension in the cirrhotic patient: hepatic vein pressure gradient and beyond. Scand J Gastroenterol 2018;53:1153–64.
7. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–22.
8. Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet 2009;373:614–6.
9. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–2.
10. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908–16.
11. Cucchetti A, Ercolani G, Vivarelli M, et al. Is portal hypertension a contraindication to hepatic resection. Ann Surg 2009;250:922–8.
12. Capussotti L, Ferrero A, Viganò L, et al. Portal hypertension: contraindication to liver surgery. World J Surg 2006;30:992–9.
13. Agha R, Abdall-Razak A, Crossley E, et al. For the STROCSS Group. The STROCSS 2019 Guideline: Strengthening the reporting of cohort studies in surgery. Int J Surg 2019;72:156–65.
14. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464–70.
15. Chau GY. Resection of hepatitis B virus-related hepatocellular carcinoma: evolving strategies and emerging therapies to improve outcome. World J Gastroenterol 2014;20:12473–84.
16. Lui WY, Chau GY, Loong CC, et al. Hepatic segmentectomy for curative resection of primary hepatocellular carcinoma. Arch Surg 1995;130:1090–7.
17. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9.
18. Lui WY, Chau GYWanebo HJ. Operative approaches to hepatocellular carcinoma in the cirrhotic patient. Surgery for Gastrointestinal Cancer: A Multidisciplinary Approach. Philadelphia, PA: Lippincott-Raven; 1997:533–9.
19. Chau GY, Lui WY, Tsay SH, et al. Prognostic significance of surgical margin in hepatocellular carcinoma resection: an analysis of 165 Childs’ A patients. J Surg Oncol 1997;66:122–6.
20. Chau GY, Lui WY, King KL, et al. Evaluation of effect of hemihepatic vascular occlusion and the Pringle maneuver during hepatic resection for patients with hepatocellular carcinoma and impaired liver function. World J Surg 2005;29:1374–83.
21. Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696–9.
22. Merkel C, Bolognesi M, Sacerdoti D, et al. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000;32:930–4.
23. Silva-Junior G, Baiges A, Turon F, et al. The prognostic value of hepatic venous pressure gradient in patients with cirrhosis is highly dependent on the accuracy of the technique. Hepatology 2015;62:1584–92.
24. Berzigotti A, Rossi V, Tiani C, et al. Prognostic value of a single HVPG measurement and Doppler-ultrasound evaluation in patients with cirrhosis and portal hypertension. J Gastroenterol 2011;46:687–95.
25. Asrani SK, Kamath PS. Natural history of cirrhosis. Curr Gastroenterol Rep 2013;15:308.
26. Xu G, Li F, Mao Y. Portal pressure monitoring-state-of-the-art and future perspective. Ann Transl Med 2019;7:583–97.
27. Salman MA, Mansour DA, Balamoun HA, et al. Portal venous pressure as a predictor of mortality in cirrhotic patients undergoing emergency surgery. Asian J Surg 2019;42:338–42.
28. Kanematsu T, Takenaka K, Furuta T, et al. Acute portal hypertension associated with liver resection. Analysis of early postoperative death. Arch Surg 1985;120:1303–5.
29. Allard MA, Adam R, Bucur PO, et al. Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. Ann Surg 2013;258:822–30.
30. Bogner A, Reissfelder C, Striebel F, et al. Intraoperative increase of portal venous pressure is an immediate predictor of posthepatectomy liver failure after major hepatectomy: a prospective study. Ann Surg 2019. doi: 10.1097/SLA.0000000000003496. [Epub ahead of print].
31. Cucchetti A, Cescon M, Golfieri R, et al. Hepatic venous pressure gradient in the preoperative assessment of patients with resectable hepatocellular carcinoma. J Hepatol 2016;64:79–86.
32. Hidaka M, Takatsuki M, Soyama A, et al. Intraoperative portal venous pressure and long-term outcome after curative resection for hepatocellular carcinoma. Br J Surg 2012;99:1284–19.
33. Chau GY, Lui WY, Wu CW. Spectrum and significance of microscopic vascular invasion in hepatocellular carcinoma. Surg Oncol Clin N Am 2003;12:25–34.
34. Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009;51:890–7.
35. Ripoll C, Groszmann RJ, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol 2009;50:923–8.
36. Clavien PA, Lesurtel M, Bossuyt PM, et al. OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13:e11–22.
37. Chang CH, Chau GY, Lui WY, et al. Long-term results of hepatic resection for hepatocellular carcinoma originating from the noncirrhotic liver. Arch Surg 2004;139:320–5.
38. Merion RM, Wolfe RA, Dykstra DM, et al. Longitudinal assessment of mortality risk among candidates for liver transplantation. Liver Transpl 2003;9:12–8.
39. Mehta N, Dodge JL, Hirose R, et al. Increasing liver transplantation wait-list dropout for hepatocellular carcinoma with widening geographical disparities: implications for organ allocation. Liver Transpl 2018;24:1346–56.
40. Liu PH, Hsu CY, Hsia CY, et al. Surgical resection versus radiofrequency ablation for single hepatocellular carcinoma ≤2 cm in a propensity score model. Ann Surg 2016;263:538–45.
41. Cucchetti A, Mazzaferro V, Pinna AD, et al. Average treatment effect of hepatic resection versus locoregional therapies for hepatocellular carcinoma. Br J Surg 2017;104:1704–12.
42. Poon RTP, Fan ST, Lo CM, et al. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002;235:373–82.
43. Wen T, Jin C, Facciorusso A, et al. Multidisciplinary management of recurrent and metastatic hepatocellular carcinoma after resection: an international expert consensus. Hepatobiliary Surg Nutr 2018;7:353–71.