No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Early hepatocellular carcinoma as an entity with a high rate of surgical cure
Abstract
Early hepatocellular carcinoma (HCC) has been defined as a well-differentiated cancer containing Glisson's triad, but it remains unknown whether this lesion is curable. We prospectively studied 70 patients (enrolled from 1,172 referrals between 1982 and 1991) who had a diagnosis of a single HCC 2 cm or less in diameter (Stage T1) and who underwent curative hepatectomy and long-term follow-up (range, 0.2 to 14.3 years). Patients were eligible for surgery if they had a tumor that met the diagnostic criteria for HCC and were in Child-Pugh class A (n = 59) or B (n = 11) status. Among the 70 patients, there was 1 operative death. Based on our typing system, the tumors were assigned as early HCC (n = 15), overt HCC (n = 52), and non-HCC tumor (n = 3). The rate of microscopic regional spread was lower in early HCCs than in overt HCCs (7% vs. 42%; P = .01). The early HCC group had a longer time to recurrence than did the overt HCC group (3.9 vs. 1.7 years; P < .001) and had no local recurrence. After a median follow-up of 6.3 years, both overall survival and recurrence-free survival in the early HCC group were significantly better than those in the overt HCC group (P = .01; P = .001). In these two groups, the 5-year rates of overall survival were 93% and 54% (P = .01), and those of recurrence-free survival were 47% and 16% (P = .05), respectively; a significant survival benefit persisted over a decade (57% vs. 21%; P = .05). The early HCC group was at a lower risk of recurrence (relative risk, 0.31; 95% CI, 0.15 to 0.65; P = .002) and death (relative risk, 0.26; 95% CI, 0.09 to 0.73; P = .01) than was the overt HCC group. Early HCC is a distinct clinical entity with a high rate of surgical cure, thereby justifying its definition. It can be a lesion that corresponds to "Stage 0" cancer in other organs.
... Takayama et al. [72] compared the overall survival (OS) and recurrence-free survival (RFS) rates of patients undergoing surgery for solitary early and overt HCCs measuring ≤2 cm in size; the OS and RFS rates of early HCC cases were significantly longer than those of overt HCC cases. Pathologically, early HCCs do not undergo intrahepatic metastasis, whereas typical hypervascular HCCs, even those <2 cm, are associated with portal vein involvement and intrahepatic metastasis, providing a rationale for initiating therapeutic intervention at the stage of early HCC [19]. ...
... The 2017 revised edition of JSH Clinical Practice Guidelines for HCC published in October 2017 recommends hepatectomy in all Child-Pugh A/B cases with no >3 tumors regardless of tumor size [9]. [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84] than in the PEIT group (57%, 95% CI: 45-71; p = 0.01). Similarly, the RFA group had significantly better RFS and local recurrence rates, with no significant differences in complications between the 2 groups. ...
The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other’s work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
... Anatomical resection of a subsegment, Couinaud's segment, sector, or hemiliver was the preferred surgical procedure (21). All liver resections were performed using the clamp crushing method (22). ...
... After discharge, all patients were examined for recurrence by dynamic computed tomography every 3 to 4 months. Recurrence was defined as the appearance of a new lesion with radiological features typical of HCC (21). The disease-free survival period was defined as the interval between surgery for HCC and the date of diagnosis of the first recurrence or the last follow-up visit. ...
There is little information on the impact of aging on liver resection of hepatocellular carcinoma (HCC). The aim of study was to evaluate the prognostic impact of the patient's age on the long-term survival after resection of HCC. The postoperative outcomes of the 291 elderly (≥ 70 years) and 340 younger (< 70 years) patients underwent curative liver resection for HCC were analyzed using multivariate and propensity-score matching. Risk score were calculated from the results of Cox regression analysis. The overall survival rate was significantly lower in the elderly group than that in the younger group (p = 0.01). Factors related to overall survival were vascular invasion (absent vs. present, HR 2.25; 95% CI 1.52-3.33, p = 0.0001), albumin level (< 3.0 vs. ≥ 3.0 g/dl, HR 2.23; 95% CI 1.31-3.79, p = 0.003), and number of tumors (solitary vs. multiple, HR 1.68; 95% CI 1.24-2.27, p = 0.001). The results of risk-score analysis with a Cox proportional-hazards model indicated that the proportion of poor-risk patients was significantly higher in the elderly than in the younger group. Propensity-score matching analysis yielded 234 pairs of patients. There were no significant differences in baseline profiles or risk scores between the two groups (p = 0.43). There were also no significant differences in the overall survival between the two groups (p = 0.23). Advanced age does not have a significant impact on the outcomes of patients after resection of HCC.
... Tumour size was the only continuous variable, and the 3-cm cut-off would be best suited as threshold based on evidencebased guidelines 6,7 , whereas the 2-cm value led to overestimation of the prognostic forecast because such small tumours are frequently (25 per cent) precursor lesions of HCC 18,19 . As regards surgical factors, tumour residue was selected as the most important determinant, and surgical margin was not included because of its collinearity with tumour residue. ...
... If these conditions are not met, the tumour falls into the grade A2 group. In grade A as a whole, 5-year survival rates of around 70 per cent indicate a potential surgical cure 18,19,24 for the target HCC, unless multicentre recurrence develops in the remnant liver. ...
Background
Surgical treatment for hepatocellular carcinoma (HCC) is advancing, but a robust prediction model for survival after resection is not available. The aim of this study was to propose a prognostic grading system for resection of HCC.
Methods
This was a retrospective, multicentre study of patients who underwent first resection of HCC with curative intent between 2000 and 2007. Patients were divided randomly by a cross-validation method into training and validation sets. Prognostic factors were identified using a Cox proportional hazards model. The predictive model was built by decision-tree analysis to define the resection grades, and subsequently validated.
Results
A total of 16 931 patients from 795 hospitals were included. In the training set (8465 patients), four surgical grades were classified based on prognosis: grade A1 (1236 patients, 14.6 per cent; single tumour 3 cm or smaller and anatomical R0 resection); grade A2 (3614, 42.7 per cent; single tumour larger than 3 cm, or non-anatomical R0 resection); grade B (2277, 26.9 per cent; multiple tumours, or vascular invasion, and R0 resection); and grade C (1338, 15.8 per cent; multiple tumours with vascular invasion and R0 resection, or R1 resection). Five-year survival rates were 73.9 per cent (hazard ratio (HR) 1.00), 64.7 per cent (HR 1.51, 95 per cent c.i. 1.29 to 1.78), 50.6 per cent (HR 2.53, 2.15 to 2.98), and 34.8 per cent (HR 4.60, 3.90 to 5.42) for grades A1, A2, B, and C respectively. In the validation set (8466 patients), the grades had equivalent reproducibility for both overall and recurrence-free survival (all P < 0.001).
Conclusion
This grade is used to predict prognosis of patients undergoing resection of HCC.
... Differences in stage at diagnosis might also impact survival considerably. Patients with early stage HCC who receive surgical resections or transplantation can achieve a 90% of 5-year survival [14]; in contrast, the 1-year survival rate for advanced HCC is only 12% [15]. In the USA, HCC surveillance in clinical practice is underused because no standardized HCC screening/prevention program exists [16]. ...
... Given the absence of universally accepted guidelines for HCC management, variation in treatment strategies between the USA and Taiwan is expected. However, it is concerning that relatively few patients with early-stage HCC in the USA received transplantation or surgical resection, which have potential to cure the disease [14]. In prior research, patients receiving curative treatments (resection and transplantation) had better survival compared to those undergoing ablation or palliative treatments [33][34][35]. ...
Background
Survival in hepatocellular carcinoma (HCC) is lower in the USA than in Taiwan. Little is known about the extent to which differences in stage at diagnosis and treatment contribute to this difference. We examined treatment patterns and survival in HCC and analyzed factors driving the difference.
Methods
Using a uniform methodology, we identified patients aged 66 years and older with newly diagnosed HCC between 2004 and 2011 in the USA and Taiwan. We compared treatment within 6 months after HCC diagnosis and 2-year stage-specific survival between the two countries.
Results
Compared with patients in Taiwan (n = 32,987), patients in the USA (n = 7,003) were less likely to be diagnosed as stage IA (4% vs 8%) and II (13% vs 22%), or receive cancer-directed treatments (41% vs 58%; all p < .001). Stage-specific 2-year survival rates were lower in the USA than in Taiwan (stage IA: 57% vs 77%; stage IB: 38% vs 63%; stage II: 40% vs 57%, stage III: 14% vs 18%; stage IV: 4% vs 5%, respectively; all p < .001 except p = .018 for stage IV). Differences in age and sex (combined), stage, and receipt of treatment accounted for 3.8%, 17.0%, and 16.8% of the survival difference, respectively, leaving 62.5% unexplained.
Conclusions
Differential stage at diagnosis and treatment were substantially associated with the survival difference, but approximately two-thirds of the difference remained unexplained. Identifying the main drivers of the difference could help improve HCC survival in the USA.
... In the United States, liver cancer incidence rates have more than tripled since 1980, with death rates doubling during this time, associated with a significant socioeconomic burden [3]. Advances in imaging procedures and close monitoring have led to an increase in early detection and better treatment outcomes [4,5]. However, despite potential curative therapy with surgical resection, liver transplant, and locoregional therapies, HCC recurrence remains elevated at 70% within 5 years [6]. ...
Background:
Hepatocellular carcinoma (HCC) is a leading cause of cancer morbidity and mortality. Findings of microvascular invasion (MVI) in patients with HCC have emerged as an important prognostic factor for poor survival after tumor resection.
Aim:
This study evaluated the relation between MVI and HCC within various anatomical Couinaud's segments of the liver.
Method:
A multicenter retrospective review of HCC records was conducted from 2012 to 2017. HCC cases were identified using ICD-9 and 10 codes 155, C22.0, and C22.8. HCC patients who underwent liver transplants were included in this study. Liver segment of the location of HCC was obtained from radiographic records, and MVI information was obtained from pathology reports. Segmental distributions of HCC in MVI versus non-MVI groups were compared using Wilcoxon rank sum tests. p value was set at <0.05.
Results:
We analyzed 120 HCC patients who underwent liver transplantation. The mean age of our cohort was 57 years, and the most common etiology of liver disease was hepatitis C at 58.3%. The median HCC size was 3.1 cm, and MVI was present in 23.3% of the explanted specimens. MVI was 2 to 3 times significantly higher in patients with HCC affecting segments 2 and 3 and segments 4b and 5 (p = 0.01). Moreover, median survival was significantly lower in patients with MVI versus those without MVI (50 vs. 137 months, p < 0.05).
Conclusion:
MVI was significantly higher in HCC tumors located in liver segments 2 and 3 and 4b and 5, and survival was lower in patients with MVI compared with those without.
... By contrast, Patients may bene t from life-prolonging, potentially curative treatments in the early development of HCC [8]. Some clinical studies had shown that clinical surgical intervention for S-HCC (≤ 2cm) can reduce the recurrence rate and improve the cure rate of patients [9][10][11]. Therefore, the early detection of S-HCC and differentiation of S-HCC from pre-HCC are of great signi cance for patients. ...
Background: The pre-HCC describe the precancerous condition of HCC, which include regenerative nodule (RN), low-grade dysplastic nodule (LGDN) and high-grade dysplastic nodule (HGDN) [1].
Purpose: To assess the feasibility of radiomics based on precontrast MRI for the distinguish of small hepatocellular carcinoma (S-HCC) (≤2cm) and pre-hepatocellular carcinoma (pre-HCC).
Method: We retrospectively analyzed 146 nodules with pathological confirmed from 78 patients. Each nodule was segment on precontrast MRI sequence (T1WI and fat-suppression T2WI (FS-T2WI) ), retrospectively. 1223 radiomics features were extracted and the optimal features from T1WI, FS-T2WI and T1WI+FS-T2WI were selected by the least absolute shrinkage and selection operator (LASSO). We used the logistic regression classifier to establish the radiomics model.
Result: We applied logistic regression classifier to identify S-HCC and pre-HCC on the basis of valuable radiomics features extracted from T1WI, FS-T2WI, T1WI+FS-T2WI, respectively. The AUC, sensitivity and specificity of the training group and test group based on T1WI were 0.879 (95% CI 0.797 -0.962), 78.9% and 83.1% and 0.796 (95% CI 0.619-0.973), 66.7% and 83.3%, respectively. The AUC, sensitivity and specificity of the training group and test group based on FS-T2WI were 0.911 (95% CI 0.839-0.983), 94.7% , 83.1% and 0.907 (95% CI 0.779-1), 83.3%, 88.9%, respectively. The AUC, sensitivity and specificity of the training group and test group based on T1WI+FS-T2WI were 0.918 (95% CI 0.844-0.991), 84.2% , 87.3% and 0.870 (95% CI 0.728-1), 84.2%, 87.3%, respectively.
Conclusion: This study suggested that radiomics model may serve as an adjunct and noninvasive tool to classify S-HCC and pre-HCC based on precontrast MRI.
... Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide and the 4th leading cause of cancer-related deaths in 2018 [1]. The Barcelona Clinic Liver Cancer staging classification recommends surgery only for patients with stage 0 disease [2] (solitary HCC diameter <2 cm and Child-Pugh score A) and with stage A (solitary HCC) and radiofrequency ablation (RFA) for stage 0 and stage A patients (patients with the largest HCC diameter ≤3 cm and ≤3 nodules) [3]. The Japanese clinical practice guidelines for HCC (4th JSH-HCC guidelines) recommends both surgery and RFA for patients with the largest HCC diameter ≤3 cm, HCC ≤3 nodules, and Child-Pugh grade A or B [4]. ...
Introduction: It remains unclear which of surgery or radiofrequency ablation (RFA) is the more effective treatment for small hepatocellular carcinoma (HCC). We aimed to compare survival between patients undergoing surgery (surgery group) and patients undergoing RFA (RFA group).
Methods: We conducted a randomized controlled trial involving 49 institutions in Japan. Patients with Child-Pugh scores ≤ 7, largest HCC diameter ≤ 3 cm, and ≤ 3 HCC nodules were considered eligible. The co-primary endpoints were recurrence-free survival (RFS) and overall survival (OS). The current study reports the final result of RFS, and the follow-up of OS is still ongoing.
Results: During 2009–2015, 308 patients were registered. After excluding ineligible patients, the surgery and RFA groups included 150 and 151 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range, 1.5–2.2 cm) in the surgery group and 1.8 cm (interquartile range, 1.5–2.3 cm) in the RFA group. The median procedure duration (274 versus 40 minutes, P
... The timing of recurrence is generally associated with biological factors indicative of tumor aggressiveness, with earlier episodes having a more negative prognosis [3][4][5][6][7]. Genetic and molecular studies focused specifically on the clonal origins of recurrent HCCs have identified differences between the characteristics of earlier and later recurrences [8,9]. ...
Introduction:
In spite of the high frequency of recurrence of hepatocellular carcinoma (HCC) after resection, little evidence exists to directly help to plan a reasonable schedule for the frequency and intensity of postoperative surveillance for recurrence.
Methods:
1,918 consecutive patients with Child-Turcott-Pugh class A who had T1- or T2-staged HCCs detected by active surveillance and underwent curative resection for their tumors at 3 teaching hospitals in Korea, followed by recurrence screening at 6-monthly or shorter intervals. To set an evidence-based timetable for postoperative surveillance, we investigated the annual hazard rate of recurrence through postoperative year 10 in patients undergoing hepatectomy for HCC, and the clinical and morphological phenotypes associated with early versus late recurrence.
Results:
The estimated hazard rate for recurrence peaked during year 0-1 (21.7%), with a subsequent gradual decrease through 5 years, followed by stabilization at <7.0% until year 10, except in the case of cirrhotics, who had a rate of 10.5% during year 4-5. Multivariate time-to-recurrence analysis by recurrence period revealed that serum alpha-fetoprotein ≥200 ng/mL, larger size of tumor, tumor multiplicity, microvascular invasion, capsular invasion, and higher METAVIR fibrosis stage were significantly related to disease recurrence within 5 years after resection, while cirrhosis (METAVIR F4) alone was related to disease recurrence beyond 5 years (Ps < 0.05). Post-relapse overall survival was better in the latter group (p = 0.033).
Conclusions:
Our chronological and morphological insights into recurrence after resection of primary HCCs may help implement an optimal intensity of surveillance for recurrence.
... Meanwhile, patients with Por HCCs measuring <2 cm did not have a high risk for early recurrence, early extra- hepatic recurrence, or low OS in our study. Previous studies indicated excellent long-term outcomes in patients with HCCs up to 2 cm in size [24]. The cutoff size of 2 cm has been adopted in the Barcelona Clinic Liver Cancer staging system, and HCCs ≤2 cm in size are categorized as "very early HCC" [5]. ...
Introduction:
The present study aimed to evaluate the effect of poor differentiation and tumor size on survival outcome after hepatic resection of hepatocellular carcinoma (HCC).
Methods:
A total of 1,107 patients who underwent initial and curative hepatic resection for HCC without macroscopic vascular invasion participated in the study. Using the multivariable Cox proportional hazards regression model, we evaluated changes in hazard ratios (HRs) for the association between tumor differentiation and survival based on tumor size.
Results:
In patients with poorly (Por) differentiated HCCs, the adjusted HRs of reduced overall survival (OS), recurrence-free survival (RFS), early RFS, and early extrahepatic RFS were 1.31 (95% confidence interval [CI]; 1.07-1.59), 1.07 (95% CI 0.89-1.28), 1.31 (95% CI 1.06-1.62), and 1.81 (95% CI 1.03-3.17), respectively. Moreover, based on an analysis of the effect modification of tumor differentiation according to tumor size, Por HCC was found to be associated with a reduced OS (p = 0.033). The HRs of Por HCCs sharply increased in patients with tumors measuring up to 5 cm. The adjusted HRs of reduced OS in patients with Por HCCs measuring <2, ≥2 and <5, and ≥5 cm were 1.22 (95% CI 0.69-2.14), 1.33 (95% CI 1.02-1.73), and 1.58 (95% CI 1.04-2.42), respectively. The corresponding adjusted HRs of reduced early RFS were 0.85 (95% CI 0.46-1.57), 1.34 (95% CI 1.01-1.8), and 1.57 (95% CI 1.03-2.39), respectively. The adjusted HRs of reduced early extrahepatic RFS were 1.89 (95% CI 0.83-4.3) in patients with tumors measuring ≥2 and <5 cm and 2.33 (95% CI 0.98-5.54) in those with tumors measuring ≥5 cm.
Conclusions:
Por HCC measuring ≥2 cm was associated with early recurrence. Hence, it had negative effects on OS. After surgery, patients with Por HCC measuring ≥5 cm should be cautiously monitored for early extrahepatic recurrence. These findings will help physicians devise treatment strategies for patients with HCC.
... HCC develops via multistep carcinogenesis in a background of chronic liver disease, where an early HCC (eHCC) develops from a premalignant dysplastic lesion, then eventually to a progressed (moderately or poorly differentiated) HCC (3,4). Early HCCs are histologically defined as vaguely nodular, well-differentiated HCCs with stromal invasion (5,6), and are characterized by a lower risk of recurrence and higher 5-year survival rate than progressed HCCs after treatment (7,8). Therefore, the detection of eHCCs may help decrease mortality associated with HCC, and increase opportunities for curative treatment (9,10). ...
Purpose: To describe the imaging features of histologically defined early hepatocellular carcinoma (eHCC) on gadoxetate disodium-enhanced MRI (EOB-MRI) and diffusion-weighted imaging (DWI).Materials and Methods: We enrolled 173 surgically confirmed eHCCs in 119 patients examined by preoperative EOB-MRI and DWI between January 2006 and September 2017. The imaging features of preoperatively detected eHCCs were retrospectively analyzed by two radiologists. The clinical and imaging characteristics associated with false-negative detection were evaluated.Results: Of the 173 eHCCs, 118 (68%) in 78 patients were prospectively reported on preoperative EOB-MRI. After retrospective review, 17 eHCCs in 13 patients were additionally detected, with a per-lesion detection sensitivity of 78% (135/173). Thus, the imaging features of 135 eHCCs in 91 patients were analyzed. Most eHCCs exhibited hepatobiliary hypointensity (90%, 122/135). Arterial phase hyperenhancement, washout, and capsule appearance were seen in 68 (50%), 79 (59%), and 11 (8%) detected lesions, respectively. Diffusion restriction and fatty change were noted in 30 (22%) and 39 (29%) lesions, respectively; most eHCCs exhibited T1 and T2 isointensity (80 [59%] and 89 [66%], respectively). False-negative detection was associated with small lesion size (< 1 cm), history of HCC treatment (odds ratio, 0.34 [95% confidence interval, 0.13-0.92]), number of HCC lesions (≥ 2; odds ratio, 0.08 [0.01-0.66]), and poor functional liver imaging score (< 4; odds ratio, 0.13 [0.04-0.51]).Conclusions: Histologically defined eHCCs typically appear as hepatobiliary phase hypointensity. Detection sensitivity of eHCC may be affected by lesion size, history of HCC treatment, number of HCCs, and hepatobiliary enhancement.
... Indications for partial resection include unilobar tumors without vascular invasion and metastases in the liver without cirrhosis. The 5 -year survival rate after resection for HCC is 50 % to 68% in experienced centers (4)(5)(6)(7). Impaired hepatic function and/or significant portal hypertension are related to poor tolerability of resection. Regional lymph node metastases are associated with decreased survival (8). ...
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and cirrhosis is a risk factor for HCC. Resection is indicated for those unilobar tumors without vascular invasion and metastases in the liver and preserved liver function. Small HCC (< 2 cm) without microvascular invasion is associated with a 5-year recurrence rate as high as 50% to 60%, whereas liver transplantation is indicated for those within the Milan criteria (solitary tumor ≤ 5 cm or two or three nodules ≤ 3 cm) who have decompensated cirrhosis. The 1-, 3-, and 5-year survival rates of living donor liver transplantation for HCC are 85%, 75%, and 70%, respectively. This review summarizes the scientific evidence supporting the clinical practice recommendations for patients with HCC, and it discusses surgical treatment of HCC.
... chirurgické řešení. Bohužel radikální léčbu stále podstupuje méně než jedna třetina všech nemocných s HCC [27]. AST -aspartátaminotransferáza, CI -interval spolehlivosti, HR -poměr rizik 3S41 nému zhoršení senzitivity celého postupu a zhoršení přežívání (obr. 1) [19]. ...
Hepatocellular carcinoma (HCC) is one of the major complications of chronic liver disease, mostly of liver cirrhosis. Liver diseases from different causes differ in the risks of HCC development. Different mechanisms of carcinogenesis are involved in HCC development in different liver diseases as well. Generally, two main pathways are distinguished: the cause of liver disease itself (e.g. viral infections, accumulation of heavy metals etc.) and chronic liver inflammation and fibrogenesis, including mechanisms of oxidative stress. Rare cases of HCC in liver without underlying cirrhosis are likely the consequences of the mechanisms directly linked with particular etiological factor (e.g. protein X in chronic hepatitis B virus (HBV) infection). The key approach which can lead to significantly better results of any treatment used in HCC cases is HCC screening and surveillance. The appropriate method of HCC surveillance is abdominal ultrasonography in 6-month intervals. There is still one question to be solved: the correct definition of target population which should undergo this method of surveillance. Currently, the target population in the developed world is defined as all patients with liver cirrhosis. Unfortunately, the only method of primary prevention of HCC is available: universal HBV vaccination. Antiviral treatment of hepatitis B or C is considered as a method of secondary prevention. Adjuvant therapy of HCC after its primary therapy (antiviral therapy after HCC resection etc.) and other measures able to reduce HCC recurrence risk are usually mentioned as tertiary prevention approach. The BCLC staging system is the most common system used in Europe for the classification of HCC at the dia-gnosis. This classification combines the stage of HCC itself with other parameters, such as liver disease severity (Child - Pugh classification), portal hypertension etc. BCLC is a system which guides the physicians to optimal treatment options in every HCC stage. The only potentially curable approaches are surgical resection or liver transplantation. These options may be used in 1/3 of all HCC patients. Unfortunately, the vast majority of HCC patients can be treated only by palliative treatment options with transarterial chemoembolisation being the most common one.
... For example, patients with early HCC (eHCC) may have a higher surgical cure rate, a lower recurrence rate, and higher short-and longterm survival rates than those with advanced HCC (adHCC) [2][3] [4]. EHCC can be completely cured [5], but poorly differentiated (diff.) HCC exhibits relatively worse recurrence-free and overall survival rates [6]. ...
Backgrounds: Accurate differential diagnosis regarding histological grades of hepatocellular carcinoma (HCC) is critical for targeted treatment and prognostic evaluation. However, the currently used descriptive diagnosis of histological grading have to observe tedious item of neovascularization, stromal invasion, cellular and structural atypia, which have drawbacks of subjectivity and error-prone. Immunohistochemical (IHC) markers-based diagnosis only needs to determine whether there is staining in the cell membrane, cytoplasm and / or nucleus. Using IHC markers targeted heat shock protein (HSP)70, glypican (GPC)3, glutamine synthetase (GS), and organic anion transport peptide (OATP), we sought to establish an easy method for the diagnosis of the histopathological grades and further explore the best efficacy by their combined or independent application.
Methods: We retrospectively conducted a study of 157 patients with 200 histologically confirmed HCCs, which were classified into early (n= 45), well (n=31), moderately (n=68), and poorly (n=56) differentiated (diff.) HCC. The sensitivity, specificity, accuracy of HSP70, GPC3, GS and OATP on each histological grade were examined.
Results: HSP70 and GPC3 showed difference in most histological grades of HCC ( P < 0.05). GS distinguished early HCC from three other histological grades (p < 0.01). OATP8 only differentiated early HCC from poorly diff. HCC (P=0.019). When any two of the three indicators (HSP, GPC3, and GS) were negatively expressed, the diagnostic efficacy of early HCC was the highest, with an area under the curve (AUC) of 0.802 and accuracy of 80.5%. The optimal efficacy for poorly diff. HCC detection was obtained when both GPC3 and HSP70 were positively expressed (74.4% accuracy; AUC = 0.703). However, for well and moderately diff. HCC, a relative satisfactory AUC value (>0.60) failed to yield either by the independent or combined diagnosis of any IHC indicators.
Conclusion: Using GS, HSP70, and GPC3, early and poorly diff. HCC can be properly diagnosed. IHC markers might be a potential alternative tool for histological differential diagnosis of HCC.
... The outcomes of surgical resection 7,8 and ablation [9][10][11] are closely related to HCC size, with 2 cm suggested as a size cut-off for HCC aggressiveness and invasiveness. 7,12,13 Especially for radiofrequency ablation, the preferable size is smaller than 2 cm 11 as the goal is to obtain a 360-degree, 0.5-1.0 cm ablative margin all around the target tumor. ...
In Asian countries favoring loco-regional treatment such as surgical resection or ablation, very early-stage hepatocellular carcinoma (HCC) should be the main target for surveillance. Even though ultrasound (US) has been accepted as a primary imaging modality for HCC surveillance, its performance in detecting very early-stage HCCs is insufficient. Moreover, in more than 20% of patients at high risk for HCC, visualization of the liver on US may be limited owing to the advanced distortion and heterogeneity of the liver parenchyma. Recently revised HCC clinical guidelines allow the use of alternative surveillance tools including computed tomography or magnetic resonance imaging in patients with inadequate US exams. This paper summarizes the findings of recent studies using imaging modalities other than US as surveillance tools for HCC as well as strengths and limitations of these modalities.
... For HCC, surgical resection is curative, but restricted to patients with unaltered liver function. Thus, the treatment of HCC still requires the development of new therapeutic approaches (Takayama et al., 1998). Therefore there is a need to search for better control and preventive methods in order to reduce cancer mortality and related side effects. ...
... Untreated CLD leads to liver fibrosis, may progress to cirrhosis, which is the most critical risk factor for HCC. 2 However, the advent of newer imaging techniques and surveillance for risk stratification has led to early detection of HCC, resulting in the selection of patients with a value of curative resection. 3,4 Hepatic resection is a potential treatment modality for HCC. 5 But the high frequency of intra and extrahepatic recurrences have led to a poor prognosis. 6,7 Histopathologic features of vascular invasion (VI) by tumor is a poor prognostic factor for patients with HCC who have undergone hepatic resection or liver transplant. ...
Purpose
The objective of our study was to evaluate the value of two-trait predictor of venous invasion (TTPVI) in the prediction of pathological microvascular invasion (pMVI) in patients with hepatocellular carcinoma (HCC) from preoperative computed tomography (CT) and magnetic resonance (MR).
Methods
A total of 128 preoperative patients with findings of HCC were enrolled. Tumor size, tumor margins, tumor capsule, peritumoral enhancement, and TTPVI was assessed on preoperative CT and MRI images. Histopathological features were reviewed: pathological tumor size, tumor differentiation, pMVI along with alpha-fetoprotein level (AFP). Significant imaging findings and histopathological features were determined with univariate and multivariate logistic regression analysis.
Results
Univariate analysis revealed that tumor size (p<0.01), AFP level (p=0.043), tumor differentiation (p<0.01), peritumoral enhancement (p=0.003), pathological tumor size (p<0.01), tumor margins (p<0.01) on CT and MRI, and TTPVI (p<0.01) showed statistically significant associations with pMVI. In multivariate logistic regression analysis, tumor size (odds ratio [OR] = 1.294; 95% confidence interval [CI]: 1.155, 1.451; p < 0.001), tumor differentiation (odds ratio [OR] =1.384; 95% confidence interval [CI]: 1.224, 1.564; p < 0.001), and TTPVI (odds ratio [OR] = 4.802; 95% confidence interval [CI]: 1.037, 22.233; p=0.045) were significant independent predictors of pMVI. Using 5.8 as the threshold for size, one could obtain an area-under-curve (AUC) of 0.793, 95% confidence interval [CI]: 0.715 to 0.857.
Conclusion
Tumor size, tumor differentiation, and TTPVI depicted in preoperative CT and MRI had a statistically significant correlation with pMVI. Hence, TTPVI detected on CT and MRI may be predictive of pMVI in HCC cases.
... Hepatic resection is considered as the first line of curative treatment for hepatocellular carcinoma (HCC). 1 Nevertheless, the recurrence rate after curative hepatectomy is high, with cumulative 5-year recurrence rates >60%. 2 Therefore, we must understand how to manage and treat recurrent HCC for improving survival in patients with HCC after curative hepatectomy. ...
Background
Little evidence exists regarding postrecurrence survival after microwave ablation for recurrent hepatocellular carcinoma (HCC) after curative hepatectomy; we aimed to evaluate the feasibility of surgical microwave ablation.
Methods
In this retrospective review, we enrolled patients who underwent curative hepatectomy for primary HCC in our department and had intrahepatic recurrence. We analyzed overall survival according to treatment modality to clarify the prognostic factors for survival.
Results
Of 257 patients, 119 had intrahepatic recurrence. Three patients underwent repeat hepatectomy; 75 patients underwent surgical microwave ablation, and 34 patients underwent transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy. The median postrecurrence survival time and 5-year postrecurrence survival after surgical microwave ablation were 37.4 months and 55.4%, respectively. The major complication rate (Clavien–Dindo classification IIIa or above) after surgical microwave ablation was 5.3% with no mortality. Multivariate analysis showed that microvascular invasion at primary tumors, and recurrent tumors within 3 cm and 3 nodules were independent prognostic factors for overall survival after surgical microwave ablation for recurrent HCC.
Conclusion
Our results suggested that surgical microwave ablation is safe and feasible for recurrent intrahepatic HCC after curative hepatectomy. Close follow-up and further curative treatment could be important for improving postrecurrence survival.
... intrOductiOn Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer and the third most frequent cause of cancer-related death. 1 Hepatectomy, radiofrequency ablation (RFA), or liver transplantation were considered as the treatment of choice for HCC. [2][3][4][5][6] However, although surveillance programs have reduced the proportion of HCC cases detected at an advanced stage in certain populations, 7,8 only 30-40% of patients with HCC are candidates for curative treatment such as hepatic resection, liver transplantation, or percutaneous radiofrequency ablation. 9 Transcatheter arterial chemoembolization (TACE) has been widely used as a palliative treatment for such patients. ...
Objectives
No previous study has evaluated the risks associated with transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma in patients on hemodialysis (HD) for end stage renal disease (ESRD), because invasive treatment is rarely performed for such patients. We used a nationwide database to investigate in-hospital mortality and complication rates following TACE in patients on HD for ESRD.
Methods
Using the Japanese Diagnosis Procedure Combination database, we enrolled patients on HD for ESRD who underwent TACE for hepatocellular carcinoma. For each patient, we randomly selected up to four non-dialyzed patients using a matched-pair sampling method based on the patient’s age, sex, treatment hospital, and treatment year. In-hospital mortality and complication rates were compared between dialyzed and non-dialyzed patients following TACE.
Results
We compared matched pairs of 1551 dialyzed and 5585 non-dialyzed patients. Although the complication rate did not differ between the dialyzed and non-dialyzed ESRD patients [5.7% vs 5.8%, respectively; odds ratio, 0.99; 95% confidence interval (0.79–1.23); p = 0.90], the in-hospital mortality rate was significantly higher in dialyzed ESRD patients than in non-dialyzed patients [2.2% vs 0.97%, respectively; odds ratio, 2.21; 95% confidence interval (1.44–3.40); p < 0.001]. Among the dialyzed patients, the mortality rate was not significantly associated with sex, age, Charlson comorbidity index, or hospital volume.
Conclusions
The in-hospital mortality rate following TACE was 2.2 % and was significantly higher in dialyzed than in non-dialyzed ESRD patients. The indications for TACE in HD-dependent patients should be considered carefully with respect to the therapeutic benefits v s risks.
Advances in knowledge
In hospital mortality rate following TACE in dialyzed patients was more than twice compared to non-dialyzed patients. Post-procedural complication following TAE in ESRD onHD patients was 5.7%, and did not differ from that in non dialyzed patients.
... The international consensus group for HCC (17) and the World Health Organization (32) defines an "early HCC" as a cancer composed of well-differentiated tumor cells < 2 cm in size, with poorly defined margins, and of the vaguely nodular type. Early HCCs also show more favorable biologic features at pathologic examination and have a lower risk for recurrence after treatment than small progressed HCCs (13,33). Therefore, it is imperative to detect and treat early HCCs in at-risk patients before they become progressed HCCs (34). ...
Hepatocellular carcinoma (HCC) can be diagnosed noninvasively with contrast-enhanced dynamic computed tomography, magnetic resonance imaging, or ultrasonography on the basis of its hallmark imaging features of arterial phase hyperenhancement and washout on portal or delayed phase images. However, approximately 40% of HCCs show atypical imaging features, posing a significant diagnostic challenge for radiologists. Another challenge for radiologists in clinical practice is the presentation of many HCC mimickers such as intrahepatic cholangiocarcinoma, combined HCC-cholangiocarcinoma, arterioportal shunt, and hemangioma in the cirrhotic liver. The differentiation of HCCs from these mimickers on preoperative imaging studies is of critical importance. Hence, we will review the typical and atypical imaging features of HCCs and the imaging features of its common mimickers. In addition, we will discuss how to solve these challenges in practice.
Various hepatic pathologies, including primary hepatocellular carcinoma, metastases, and symptomatic simple cysts, may be treated with liver ablation therapy. There are a variety of Food Drug Administration (FDA)-approved ablation devices such as radiofrequency ablation, microwave ablation, cryoablation, irreversible electroporation, alcohol ablation, and upcoming ablation technologies including pulse electric fields (PEFs), high focused ultrasound (HIFU), and histotripsy. This chapter will discuss the current clinical indications, outcomes, and potential complications of interventional treatment for these hepatic pathologies, with particular emphasis on hepatocellular carcinoma and colorectal metastasis based on inclusion in the National Comprehensive Cancer Network guidelines. Alternative therapies, including recent molecular-based therapies, will also be discussed. Finally, a brief guide will be provided for a typical ablation procedure.
The purpose of this study was to evaluate the proper position of single large hepatocellular carcinoma (HCC) in the Barcelona Clinic Liver Cancer (BCLC) staging system. The data were collected from the nationwide multicentre database of the Korean Liver Cancer Association. Patients with single large (≥5 cm) HCC were separated from BCLC stage A patients and designated as Group X. The remaining BCLC stage A and stage B patients were classified as Group A and Group B, respectively. The survival outcomes of propensity score-matched groups were compared. Among the 3965 randomly selected patients, the number of patients in Group X, Group A, and Group B was 414, 2787, and 760, respectively. TriMatch analysis allowed us to obtain 116 well-balanced triplets. The 1-, 3-, and 5-year overall survival rates in Group X were worse than in Group A (91%, 71%, and 48% vs 90%, 78%, and 64%, respectively; P < .000). However, the rates were not different compared with those in Group B (91%, 71%, and 48% vs 90%, 69%, and 48%, respectively; P < .09). In multivariate analysis, Group X, Group B, age over 60 years, prothrombin time-international normalized ratio, and creatinine level were independent predictors of worse overall survival. Our findings suggest that Group X should be relocated to BCLC stage B rather than BCLC stage A.
The aim of this study was to evaluate liver resection techniques, increase regeneration and to predict complication after hepatectomies. Results of liver resection in the 165 patients and of the different treatment modalities in the 70 rabbits were analysed. Indication for liver resection was hepatocellulary carcinoma (87), metastasis (27), living-related liver transplantation, hemangioma (17), hydatid cysts (4) and others. Of these 165 patients 59 had concomitant cirrhosis and 54 had chronic hepatitis. A comparative studies of the methods of parenchyma dissection, such as clamp-crashing- CC (in the 45 patients), ultrasonic dissector – CUSA (in the 64 patients) and combined use of the CUSA and argon beam coagulation –CUSA+AC (in the 56 patients) were carried out. Results showed that in patients with associated parenchyma disease the CUSA have no advantage over the CC technique in terms of resection time. CUSA+AC decreased blood loss, operation time, transfusion requirements, portal clamping time and morbidity (from 51,7% to 19,5%) in comparison to the CC and CUSA. So, CUSA+AC seemed to be an effective technique for parenchyma dissection in the both normal and fibrotic livers. Comparative study of the different modalities of the He-Ne laser irradiation (irradiation of the liver, portal blood and intravascular blood) and dalargin in the hepatecomized animals showed that combined use of the intravascular blood laser irradiation and dalargin (BLI+D) increase liver regeneration, decrease hepatocyte injury and restore hepatic function abnormalities. The BLI+D method was used in the 76 hepatectomized patients. Results showed that BLI+D increase regeneration rate, decrease time for restoration of the postresectional functional abnormalities, hepatocyte injury and morbidity from 39,6% to 25,4%. Multivariate analyses showed that four of the 58 studied values have independent prognostic significance only: cirrhosis, preoperative bilirubin, parenchyma resection rate, and intraoperative indocyanin green index (ICG). The ICG test was designed for measurement of functional capacity of the remnant liver before resection. This test showed high sensitivity (91,3%) and specificity (77,8%) rate in the prediction of postoperative complications.
Backgrounds and AIMS
Hepatocellular carcinoma (HCC) is the most common cancer with a poor prognosis. Identification of an alternative biomarker that can detect early-stage and conventional tumor marker-negative HCC is urgently needed. We found that protein kinase C delta (PKCδ) is specifically secreted from HCC cell lines into extracellular space and contributes to tumor development, and that its serum levels were elevated in HCC patients. This study aimed to assess the practical usefulness of serum PKCδ for detecting HCC in chronic liver disease (CLD) patients.
Methods
Serum PKCδ levels in 313 CLD patients with and without HCC (n = 187 and 126, respectively) were measured using a sandwich enzyme-linked immunosorbent assay. The diagnostic performance of PKCδ for HCC was evaluated using the receiver operating characteristic (ROC) curve analysis, and was compared with that of conventional markers, α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP).
Results
Serum PKCδ levels in HCC patients were significantly higher than those in CLD patients without HCC. PKCδ distinguished HCC patients from CLD patients without HCC, with high sensitivity and specificity. Subgroup analyses revealed that the diagnostic performance of PKCδ for HCC was comparable to that of AFP and DCP, and that approximately 40% of AFP/DCP double-negative HCC patients were positive for PKCδ. PKCδ yielded better diagnostic performance for detecting solitary small-sized (i.e., very early-stage) HCC, compared to AFP and DCP. There was no significant correlation between serum PKCδ and AFP/DCP levels.
Conclusion
Serum PKCδ is a novel HCC biomarker, which is independent of and complementary to conventional markers. Specifically, PKCδ may be useful for detecting very early-stage or AFP/DCP double-negative HCC.
Background:
Increasing number of patients with advanced hepatocellular carcinoma (HCC) has recently achieved salvage interventions after introduction of new biologic agents, while there are insufficient data to determine if such additional intervention(s) after treatment with newer biologic agents are truly advantageous for patients with advanced HCC.
Methods:
The clinical records of 107 consecutive patients who underwent lenvatinib treatment for advanced HCC were extensively reviewed and the prognostic advantages of individual additional treatments after lenvatinib treatment were investigated through a regression analysis considering time-dependent covariates.
Results:
Multivariate analysis revealed that R0 resection or curative-intent radiofrequency ablation (RFA) (hazard ratio [HR], 0.07; 95% CI, 0.01-0.32), transarterial chemoembolization or transarterial infusion therapy (HR, 0.39; 95% CI, 0.19-0.81), and subsequent line of systemic therapy (HR, 0.25; 95% CI, 0.10-0.63) were associated with improved disease-specific survival (DSS), while R2 resection or palliative-intent RFA showed no correlation with DSS. The best response during lenvatinib therapy, nutritional status, plasma des-gamma-carboxyprothrombin level, a baseline CT enhancement pattern, and BCLC stage were also selected as independent predictors for DSS. Among the various treatments performed after lenvatinib therapy, R0 resection also showed clear prognostic advantage in both progression-free survival (HR, 0.30; 95% CI, 0.16-0.58) and time-to-treatment failure (HR, 0.08; 95% CI, 0.02-0.39), suggesting that successful conversion to surgery may prolong survival outcomes through prolonged cancer-free interval in advanced HCC.
Conclusions:
Additional intervention(s)/treatment(s) after lenvatinib therapy for advanced HCC may have prognostic advantage in strictly selected populations. Successful conversion to curative resection may offer survival benefit with acceptable clinical outcomes.
Background:
Repeated liver resection is an effective treatment for recurrent hepatocellular carcinoma (HCC). However, few studies have compared the outcome of laparoscopic repeat hepatectomy (LRH) and open repeat hepatectomy (ORH) for recurrent HCC, and few of those have included cirrhotic patients.
Aim:
To compare short-term and long-term outcomes of cirrhotic patients with LRH and ORH for recurrent HCC.
Methods:
We retrospectively analysed the clinical records retrieved from a prospectively collected database of all patients who underwent hepatectomy for post-hepatectomy recurrent HCC at our institute between May 2006 and June 2021. Cases of recurrent HCCs larger than 7 cm were excluded. Patient demographics, operative details, perioperative outcomes, pathologic details, disease-free survival (DFS), and overall survival (OS) data of LRH and ORH were compared.
Results:
Data from 29 patients with LRH and 22 with ORH were compared. The LRH group showed significantly better outcomes for blood loss (median 300 mL vs 750 mL, P = 0.013) and length of hospital stay (median 5 d vs 7 d, P = 0.003). The 1-, 3- and 5-year OS rates in the LRH group were 100.0%, 60.0% and 30.0%, respectively; the corresponding rates in the ORH group were 81.8%, 36.4% and 18.2% (P = 0.336). The 1-, 3- and 5-year DFS rates in the LRH group were 68.2%, 27.3% and 4.5%, respectively; the corresponding rates in the ORH group were 31.3%, 6.3% and 6.3% (P = 0.055). There were no significant differences in overall and DFS between the two groups.
Conclusion:
Laparoscopic re-resection should be considered for patients presenting with recurrent HCC less than or equal to 7 cm after previous hepatectomy.
Most hepatocellular carcinomas (HCCs) arise in a background of pre-existing chronic liver disease, the most common examples including chronic B or C viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and genetic haemochromatosis, and up to 80% of HCCs develop in cirrhotic livers. HCCs arising in backgrounds of chronic liver disease have been recognised to arise after a sequence of events (multistep hepatocarcinogenesis) in both experimental animal models and in human studies, through earlier lesions such as dysplastic foci, dysplastic nodules, and early HCCs. Hepatocarcinogenesis may also occur in non-cirrhotic livers, some cases resulting from the malignant transformation of hepatocellular adenomas. This chapter summarises and illustrates the histopathological features of the various precancerous lesions of HCC.
Hepatocellular carcinoma (HCC) has heterogeneous molecular and pathological features and biological behavior. Large-scale genetic
studies of HCC were accumulated, and a pathological-molecular classification of HCC was proposed. Approximately 35% of HCCs
can be classified into distinct histopathological subtypes according to their molecular characteristics. Among recently identified subtypes,
macrotrabecular massive HCC, neutrophil-rich HCC, vessels encapsulating tumor clusters HCC, and progenitor phenotype HCC
(HCC with CK19 expression) are associated with a poor prognosis, whereas the lymphocyte-rich HCC subtype is related to a better
prognosis. This review provides up-to-date knowledge on the pathological diagnosis of HCC according to the updated World Health
Organization Classification of Digestive System Tumors 5th ed.
With the recent advances in the field of systemic therapy, an increasing number of patients with advanced hepatocellular carcinoma (HCC) are expected to benefit from surgery. However, given the complex background of the disease and frequent presence of underlying liver injury, treatment of advanced HCC is rather complex and the treatment principle applied to colorectal liver metastases, for which conversion surgery has been actively performed, is often not applicable to patients with HCC. To maximize the survival outcomes of patients with HCC, optimization of each step of treatment through a multidisciplinary approach is inevitable. As the initial treatment, systematic removal of the tumor-bearing portal territory is associated with improved survival in patients with solitary HCC, and radiofrequency ablation is also effective for small, oligo HCCs. Although the high incidence of recurrence even after curative-intent treatment is a major issue in HCC, aggressive treatment for recurrence is also important, because a prolonged cancer-free interval is reported to be associated with improved overall survival. For patients with advanced disease, recently introduced molecular-targeted agents may potentially be effective for successful conversion to surgery in initially unresectable cases, although the overall response rate of HCC to systemic therapies remains unsatisfactory as compared to that of colorectal liver metastases. In this report, the theoretical bases for the management of HCC are revisited and the currently used strategies to maximize the survival outcomes in patients with advanced HCC is discussed.
Background
In recent years, the development of digital imaging technology has had a significant influence in liver surgery. The ability to obtain a 3-dimensional (3D) visualization of the liver anatomy has provided surgery with virtual reality of simulation 3D computer models, 3D printing models and more recently holograms and augmented reality (when virtual reality knowledge is superimposed onto reality). In addition, the utilization of real-time fluorescent imaging techniques based on indocyanine green (ICG) uptake allows clinicians to precisely delineate the liver anatomy and/or tumors within the parenchyma, applying the knowledge obtained preoperatively through digital imaging. The combination of both has transformed the abstract thinking until now based on 2D imaging into a 3D preoperative conception (virtual reality), enhanced with real-time visualization of the fluorescent liver structures, effectively facilitating intraoperative navigated liver surgery (augmented reality).
Data sources
A literature search was performed from inception until January 2021 in MEDLINE (PubMed), Embase, Cochrane library and database for systematic reviews (CDSR), Google Scholar, and National Institute for Health and Clinical Excellence (NICE) databases.
Results
Fifty-one pertinent articles were retrieved and included. The different types of digital imaging technologies and the real-time navigated liver surgery were estimated and compared.
Conclusions
ICG fluorescent imaging techniques can contribute essentially to the real-time definition of liver segments; as a result, precise hepatic resection can be guided by the presence of fluorescence. Furthermore, 3D models can help essentially to further advancing of precision in hepatic surgery by permitting estimation of liver volume and functional liver remnant, delineation of resection lines along the liver segments and evaluation of tumor margins. In liver transplantation and especially in living donor liver transplantation (LDLT), 3D printed models of the donor's liver and models of the recipient's hilar anatomy can contribute further to improving the results. In particular, pediatric LDLT abdominal cavity models can help to manage the largest challenge of this procedure, namely large-for-size syndrome.
Although microwave ablation (MWA) exhibits a high thermal efficiency, the major limitation of conventional MWA systems is the lack of predictability of the ablation zone size and shape. Therefore, a specific newer generation MWA system, The EmprintTM Ablation System with ThermosphereTM Technology, was designed to create predictable large spherical zones of ablation that are not impacted by varying tissue environments. The time required for ablation with MWA systems is short, and the shape of the necrosis is elliptical with the older systems and spherical with the new system. In addition, because MWA has no heat-sink effect, it can be used to ablate tumors adjacent to major vessels. Although these factors yield a large ablation volume and result in good local control, excessive ablation of liver tissue and unexpected ablation of surrounding organs are possible. Therefore, MWA should be carefully performed. This review highlights the efficacy and complications of MWA performed with conventional systems and the newer generation system in patients with hepatocellular carcinoma (HCC). MWA with the newer generation system seems to be a promising treatment option for large HCCs and secondary hepatic malignancies, with several advantages over other available ablation techniques, including conventional MWA. However, further randomized controlled trials are necessary to fully clarify the benefits and pitfalls of this new system.
Background
The prognostic nutritional index (PNI) is used to assess immune and nutritional status, and is a prognostic factor for several malignant tumors. However, little evidence exists regarding the predictive impact of prognostic nutritional index (PNI) after local ablation therapy for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the value of PNI to predict recurrence and survival after operative microwave ablation in patients with early-stage HCC.
Methods
This retrospective study included 341 patients who underwent operative microwave ablation for HCC in Barcelona Clinic Liver Cancer (BCLC) stage 0-A at our institute between 2007 and 2015. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis in multivariate Cox regression analyses.
Results
The OS rates at 1, 3, 5, and 10 years after microwave ablation were 100%, 92.7%, 85.1%, and 57.5% in patients with high-PNI levels, and 96.5%, 78.2%, 59.7%, and 20.7% in patients with low-PNI levels, respectively (P < 0.001). The RFS rates at 1, 3, 5, and 10 years after microwave ablation were 96.3%, 75.2%, 55.4%, and 30.4% in patients with high-PNI levels, and 94.4%, 48.8%, 36.4%, and 13.1% in patients with low-PNI levels, respectively (P < 0.001). In multivariate analyses, preoperative PNI level was an independent prognostic factor for both OS and RFS.
Conclusion
Our results revealed the preoperative PNI level was a simple and novel predictive marker of survival and recurrence after microwave ablation in patients with early-stage HCC.
Background: To assess the feasibility of radiomics based on precontrast MRI for the distinguish of s-HCC and pre-HCC.
Method: We retrospectively analyzed 146 nodules from 78 patients, with pathological confirmed. Each nodule was segment on precontrast MRI sequence(TIWI and fat-suppression T2WI), retrospectively. 1223radiomics features were extracted and the optimal 10 features were selected by LASSO to establish the logistic regression radiomics model.
Result: The AUC, sensitivity and specificity of the training group and test group were 0.757 (95% CI 0.638 -0.853), 83.02% , 66.67% and 0.789 (95% CI 0.643-0.895), 88.89% and 80.00%, respectively. The AUC, sensitivity and specificity of the training group and test group were 0.903 (95% CI 0.807-0.962), 86.79% , 86.67% and 0.778 (95% CI 0.632-0.887), 75.00%, 80.00%, respectively. Delong test has proved that, the diagnositic performances of radiomics model based on T2WI were higher than that of radiomics model based on T1WI (p = 0.0379).
Conclusion: Radiomics model can classify s-HCC and pre-HCC based on precontrast MRI. And may serve as an adjunct tool for accurate diagnosis of s-HCC.
Background
The superiority of anatomic resection (AR) over non-anatomic resection (NAR) for very early-stage hepatocellular carcinoma (HCC) has remained a topic of debate. Thus, this study aimed to compare the prognosis after AR and NAR for single HCC less than 2 cm in diameter.
Methods
Consecutive patients with single HCC of diameter less than 2 cm who underwent curative hepatectomy between 1997 and 2017 were included in this retrospective study.
Results
In total, 159 patients were included in this study. Of these, 52 patients underwent AR (AR group) and 107 patients underwent NAR (NAR group). No significant differences were noted in recurrence-free survival (RFS) and overall survival (OS) between the AR and NAR groups (P = 0.236 and P = 0.363, respectively). Multivariate analysis revealed that low preoperative platelet count and presence of satellite nodules were independent prognostic factors of RFS and OS. Wide surgical resection margin did not affect RFS (P = 0.692) in the AR group; however, in the NAR group, RFS was found to be higher with surgical resection margin widths ≥1 cm than with surgical resection margin widths <1 cm (P = 0.038).
Conclusions
Prognosis was comparable between the NAR and AR groups for very early-stage HCC with well-preserved liver function. For better oncologic outcomes, surgeons should endeavor in keeping the surgical resection margin widths during NAR ≥1 cm.
Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because β-catenin did not translocate into the nucleus due to the E-cadherin/β-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status.
Significance: In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses.
Monoqrafiya qaraciyər rezeksiyasının bir çox nəzəri və praktik məsələlərinə həsr olunmuşdur. Kitabda qaraciyərin müasir cərrahi anatomiyası, görüntüləmə və laborator müayinə üsulları, cərrahi xəstəlikləri, rezeksiya üsulları, əməliyyatdan sonrakı ağırlaşmalar haqqında müasir dünya ədəbiyyatındakı mə’lümatlar müzakirə edilmiş və ümumiləşdirilmiş şəkildə təqdim edilmişdir. Qaraciyər rezeksiyasının, qaraciyər travmalarının orijinal təsnifatından bəhs edilmişdir. Qaraciyərin rezektabelliyini tə’yin etmək üçün yeni əməliyyatdaxili müayinə üsulunun tətbiqi haqqında mə’lumat verilmişdir. Normal və fibrotik qaraciyərdə parenximanı kəsmək üçün istifadə olunan əzmə, ultrasəs bıçağı və ultrasəs bıçağı ilə arqonlu koaqulyatorun birgə tətbiqi üsulları ilə əlaqədar aparılan oriijinal klinik tədqiqatın nəticələri təqdim edilmişdir. Monoqrafiya cərrahlar, elmi işçilər üçün nəzərdə tutulmuşdur. 273 səh., 53 şəkil və qrafik, 15 cədvəl, 464 ədəbiyyat
PurposeThe surgical margin for liver resection to treat hepatocellular carcinoma (HCC) is occasionally < 1 mm. This study determined the impact of a surgical margin < 1 mm [marginal resection (MR)] on the types of recurrence and the prognosis in solitary HCC.Methods
The data of 454 patients undergoing curative liver resection for solitary HCC in our institution were analyzed. The patients were divided into the MR (n = 90) and non-MR (n = 364) groups. The clinicopathological data and outcomes after liver resection were compared. A case-matching analysis using a propensity scoring method was also performed.ResultsThe recurrence-free survival was significantly and overall survival was marginally significantly lower in the MR group than in the non-MR group (p = 0.012–0.051, respectively). According to a multivariate analysis, MR was not a significant independent factor for recurrence-free survival (p = 0.056). After propensity score matching, there were no significant differences in the recurrence-free and overall survival between the two groups (p = 0.375–0.496, respectively). Furthermore, there were no significant differences in the intrahepatic recurrence patterns between the two groups before and after matching.ConclusionMR for solitary HCC might be sufficient in patients with a limited liver functional reserve.
We attempted to establish an ultrasound (US) imaging-diagnostic system for histopathological grades of differentiation of hepatocellular carcinoma (HCC). We conducted a retrospective study of histopathologically confirmed 200 HCCs, classified as early (45 lesions), well- (31 lesions), moderately (68 lesions) or poorly differentiated (diff.) (56 lesions) HCCs. We performed grayscale US to estimate the presence/absence of halo and mosaic signs, Sonazoid contrast-enhanced US (CEUS) to determine vascularity (hypo/iso/hyper) of lesion in arterial and portal phase (PP), and echogenicity of lesion in post-vascular phase (PVP). All findings were of significance for the diagnosis of some (but not all) histological grades (p < 0.001–0.05). Combined findings with a relatively high diagnostic efficacy for early, poorly and moderately diff. HCC were a combination of absence of halo sign and isoechogenicity in PVP of CEUS (accuracy: 93.0%, AUC: 0.908), hypovascularity in PP (accuracy: 78.0%, area under the curve (AUC): 0.750), and a combination of isovascularity in PP and hypoechogenicity in PVP (accuracy: 75.0%, AUC: 0.739), respectively. On the other hand, neither any individual finding nor any combination of findings yielded an AUC of over 0.657 for the diagnosis of well-diff. HCC. Our study provides encouraging data on Sonazoid CEUS in the histological differential diagnosis of HCC, especially in early HCC, and the effectiveness of this imaging method should be further proved by prospective, large sample, multicenter studies.
Objectives
To explore the enhancement features of early hepatocellular carcinoma (HCC, including well‐differentiated HCC and high‐grade dysplastic nodules with a focus of HCC) and high‐grade dysplastic nodules (HGDNs) on contrast‐enhanced ultrasound (CEUS), correlated with the histopathologic findings.
Methods
This retrospective study enrolled 81 patients with 85 pathologically confirmed hepatic lesions (69 early HCCs and 16 HGDNs). All of the hepatic lesions were examined by CEUS with SonoVue (Bracco SpA, Milan, Italy) before surgery or biopsy. The enhancement features of early HCCs and HGDNs were evaluated and compared with histopathologic findings.
Results
Thirty‐eight (55.1%) early HCCs showed arterial‐phase hyperenhancement (APHE). The major enhancement pattern of early HCCs was APHE without portal venous/late‐phase wash‐out (20 of 69 [29.0%]). Eight (11.6%) early HCCs manifested APHE. Wash‐out was observed in 30 (43.5%) early HCCs. Sixteen (23.2%) early HCCs showed very‐late wash‐out (>120 seconds). Wash‐out was not observed in all HGDNs. Of the 16 HGDNs, arterial‐phase isoenhancement without portal venous/late‐phase wash‐out was the major enhancement pattern (n = 7 [43.8%]). The degree of CD34 expression of sinusoidal endothelial cells was more diffuse in early HCCs than in HGDNs (56.5% versus 12.5%; P = .001). Arterial‐phase enhancement patterns of early HCCs on CEUS were correlated with the degree of CD34 expression (P = .039).
Conclusions
Enhancement patterns were significantly different between early HCCs and HGDNs on CEUS. Diffuse CD34 expression of sinusoidal endothelial cells in early HCC was correlated with APHE on CEUS.
Although microwave ablation (MWA) exhibits a high thermal efficiency, the major limitation of conventional MWA systems is the lack of predictability of the ablation zone size and shape. Therefore, a specific newer generation MWA system, The Emprint™ Ablation System with Thermosphere™ Technology, was designed to create predictable large spherical zones of ablation that are not impacted by varying tissue environments. The time required for ablation with MWA systems is short, and the shape of the necrosis is elliptical with the older systems and spherical with the new system. In addition, because MWA has no heat-sink effect, it can be used to ablate tumors adjacent to major vessels. Although these factors yield a large ablation volume and result in good local control, excessive ablation of liver tissue and unexpected ablation of surrounding organs are possible. Therefore, MWA should be carefully performed. This review highlights the efficacy and complications of MWA performed with conventional systems and the newer generation system in patients with hepatocellular carcinoma (HCC). MWA with the newer generation system seems to be a promising treatment option for large HCCs and secondary hepatic malignancies, with several advantages over other available ablation techniques, including conventional MWA. However, further randomized controlled trials are necessary to fully clarify the benefits and pitfalls of this new system.
Background
Clinical guidelines recommend surveillance in high-risk population to early detect hepatocellular carcinoma (HCC), when curative treatment such as liver resection can be applied. However, it is largely unknown whether surveillance would provide long-term survival benefits to these high-risk patients who have received curative liver resection for HCC.
Methods
A prospectively maintained database on patients with chronic hepatitis B infection who underwent curative liver resection for HCC from 2003 to 2014 was reviewed. Patients’ overall survival and recurrence were compared between the groups of patients whose HCCs were diagnosed by surveillance or non-surveillance, as well as between the groups of patients operated in the first (2003–2008) and second (2009–2014) 6-year periods.
Results
Of 1075 chronic hepatitis B patients with HCC, 452 (42.0%) patients were diagnosed by preoperative surveillance. Compared with the non-surveillance group, the OS and RFS rates were significantly better in the surveillance group (both P < 0.001). Surveillance was associated with a 55% decrease in the overall survival risk and a 48% decrease in the recurrence risk (HR 0.45, 95% CI 0.38–0.53, and HR 0.52, 95% CI 0.44–0.61). Compared with the first period, a significant reduction of 12% and 19% in the overall death and recurrence risks, respectively, was observed in the second period (HR 0.88, 95% CI 0.78–0.97, and HR 0.81, 95% CI 0.70–0.95).
Conclusion
Surveillance for HCC was associated with favorable long-term overall and recurrence-free survival rates after curative liver resection of HCC in patients with chronic hepatitis B.
The albumen plays a major role in the protection of eggs against microorganisms. It contains an arsenal of natural antimicrobial molecules and antibacterial proteins, including the well-known ovotransferrin and lysozyme, which exert their activities against a range of bacteria. In the present study, the hen's albumen extract treated with the dried insect body of blister beetle M. pustulata was assessed for antibacterial, antibiofilm, anti-inflammatory and anti-proliferative activity. The zone of inhibition against Gram positive E. faecalis and S. aureus was 10.8 mm and 12.1 mm respectively at 100 μg mL-1. However, it was 13.6 mm and 15.3 mm for Gram negative P. aeruginosa and P. vulgaris respectively. The biofilm of tested bacteria was significantly inhibited at 100 μg mL-1. The hydrophobicity of bacterial biofilms was considerably condensed after treatment with the hen's albumen extracts at 100 μg mL-1. The anti-inflammatory activity of hen's albumen extracts was confirmed by the inhibition of cyclooxygenase (COX) enzyme to 84.91% at 100 μg mL-1 with the relative IC50 of 8.26 μg mL-1. The albumen extract effectively inhibited the viability (23.61%) of HepG2 hepatic cancer cells at 100 μg mL-1. The anti-proliferative activity of the albumen extracts was further revealed by the induction of HepG2 apoptotic cell morphology. This study concludes that the hen's albumen extract treated with M. pustulata is a natural therapeutic agent to treat biofilm associated clinical bacteria, inflammations and human hepatic cancer cells.
Background
Little evidence exists regarding long-term survival after microwave ablation for hepatocellular carcinoma (HCC). The aim of this study is to determine actual 10-year survival and clarify the clinicopathological features of patients surviving ≥ 10 years after surgical microwave ablation.
Patients and Methods
This retrospective study identified 459 patients who underwent surgical microwave ablation for HCC with curative intent between 2001 and 2008. We compared 100 patients who survived ≥ 10 years with 321 patients who died within 10 years.
Results
Median overall survival and recurrence-free survival rates were 5.5 and 2.4 years, respectively. The actual 10-year overall survival rate was 23.8%, and the actual 10-year recurrence-free survival rate was 8.1%. Multivariate analysis showed that age > 70 years [odds ratio 1.87, P = 0.029], hepatitis C virus positivity (OR 2.30, P = 0.004), Child–Pugh class B (OR 3.28, P = 0.003), and platelet count < 10 × 10⁴ /µL (OR 1.93, P = 0.033) were independent risk factors for actual 10-year survival. During 10-year follow-up, 66% of the ≥ 10-year survivors developed recurrence, and 91% of these patients underwent further curative treatment, including hepatic resection or local ablation, for HCC recurrence.
Conclusion
Ten-year survival after surgical microwave ablation for HCC can be expected in approximately 24% of patients, even though nearly 2/3 of our 10-year survival patients experienced recurrence. Close postoperative follow-up and further curative treatment for recurrence are important for improving long-term survival.
Background:
Little evidence exists regarding the perioperative and oncologic benefits of microwave ablation for hepatocellular carcinoma. The aim of this study was to compare the efficacy of hepatic resection and operative microwave ablation (microwave coagulo-necrotic therapy) for single hepatocellular carcinoma ≤5 cm.
Methods:
Between 1994 and 2015, a total of 551 patients with a single hepatocellular carcinoma ≤5 cm were treated in our institution (hepatic resection: n = 128; microwave coagulo-necrotic therapy: n = 423). We compared overall survival and recurrence-free survival between hepatic resection and microwave coagulo-necrotic therapy. Propensity score matching analysis identified 94 matched pairs of patients to compare outcomes.
Results:
After propensity score matching, baseline variables, including liver function and tumor size, were well-balanced between the 2 groups. The 5- and 10-year overall survival rates were 76% and 47% for hepatic resection and 77% and 48% for microwave coagulo-necrotic therapy, respectively (P = .865). The 5- and 10-year recurrence-free survival rates were 55% and 41% for hepatic resection and 47% and 32% for microwave coagulo-necrotic therapy, respectively (P = .377). In the subgroup analysis, the hepatic resection group had better recurrence-free survival than the microwave coagulo-necrotic therapy group in patients with tumor size >3 cm, with 5-year recurrence-free survival rates of 56.5% and 32.4% in the hepatic resection and microwave coagulo-necrotic therapy group, respectively (P = .029).
Conclusion:
Our propensity score matching study confirmed no statistically significant differences in both overall survival and recurrence-free survival between hepatic resection and microwave coagulo-necrotic therapy for single hepatocellular carcinoma ≤5 cm; however, hepatic resection is recommended for hepatocellular carcinoma with tumor size >3 cm when patients have good liver function.
Loss of heterozygosity on chromosome 16 is a common genetic alteration in human hepatocellular carcinoma (HCC). To clarify the pathogenetic significance of allele loss on chromosome 16, we performed restriction fragment length polymorphism analysis of 70 surgically resected tumors by using 15 polymorphic DNA markers for chromosome 16. Loss of heterozygosity on chromosome 16 was detected in 36 (52%) of 69 informative cases, and the common region of allele loss in these 36 tumors was located between the HP locus (16q22.1) and the CTRB locus (16q22.3-q23.2). These losses occurred more frequently in HCCs of poor differentiation, of larger size, and with metastasis, whereas they were not detected in HCC at the earliest stage. In addition, these losses were not associated with presence or absence of hepatitis B virus DNA integration or hepatitis C virus infection. These results show that loss of heterozygosity on chromosome 16 is a late event occurring after hepatocarcinogenesis and strongly suggest that this phenomenon is involved in enhancement of tumor aggressiveness during progression of HCC.
The purpose of this study was to determine the sensitivity of CT in detecting early hepatocellular carcinoma and to evaluate its CT appearance. An early hepatocellular carcinoma is a nodular lesion with no fibrous capsule composed of well-differentiated tumor histologically. It differs from a small hepatocellular carcinoma, which is an overt tumor that is moderately to poorly differentiated and has a fibrous capsule. Size is not a criterion for distinguishing between early and small hepatocellular carcinomas.
Thirty-one patients with 39 histopathologically proved early hepatocellular carcinomas (mean diameter, 1.7 cm) found by sonography, MR imaging, and/or intraoperative sonography were included in a retrospective study. We reviewed unenhanced CT scans of the entire liver in 30 patients (37 lesions) and early and late (35 sec and 5 min after the beginning of injection of contrast material) contrast-enhanced CT scans of the entire liver in all 31 patients (table incremental CT in 21; helical CT in 10; 39 lesions). Eighteen histologically proved small hepatocellular carcinomas (< or = 3 cm; mean diameter, 2.3 cm), present in the same patients, served for comparison. Histopathologically, nine patients had chronic hepatitis, and 22 had cirrhosis.
The overall sensitivity of CT in detecting early hepatocellular carcinoma was 56%. These tumors were usually isodense with respect to surrounding liver on unenhanced, early enhanced, and late enhanced CT scans (iso-iso-iso). This pattern was seen in 17 (46%) of 37 lesions; thus, these 17 histologically proved early hepatocellular carcinomas were not detected with CT. An iso-iso-low density pattern was recognized in eight (22%), a low-low-low pattern in seven (19%), and several different patterns in five (13%) of the 37 lesions. Only two (5%) of 39 early hepatocellular carcinomas had a high-density appearance on early enhanced CT scans. In comparison, the most common pattern of small overt hepatocellular carcinomas on CT scans was low-high-low, seen in 17 lesions (94%) detected with CT. When the density of lesions on unenhanced CT scans was compared with the histopathologic appearance of the masses, low-density lesions showed mild to moderate fatty change and isodense lesions showed no or minimal fatty change (p = .006).
The sensitivity of CT in detecting early hepatocellular carcinoma is poor (56%). However, the diagnosis of early hepatocellular carcinoma should be considered if CT scans show a small lesion with an iso-low or low-low density enhancement pattern on early and late contrast-enhanced CT scans, respectively, in patients with chronic liver disease.
In patients with hepatocellular carcinoma (hepatoma), the rate of recurrent and second primary hepatomas is high despite surgical resection and percutaneous ethanol-injection therapy. We developed an acyclic retinoid, polyprenoic acid, that inhibits hepatocarcinogenesis in the laboratory and induces differentiation and apoptosis in cell lines derived from human hepatoma. In a randomized, controlled study, we tested whether the compound reduced the incidence of recurrent and second primary hepatomas after curative treatment.
We prospectively studied 89 patients who were free of disease after surgical resection of a primary hepatoma or the percutaneous injection of ethanol. We randomly assigned the patients to receive either polyprenoic acid (600 mg daily) or placebo for 12 months. We studied the remnant liver by ultrasonography every three months after randomization. The primary end point of the study was the appearance of a histologically confirmed recurrent or new hepatoma.
Treatment with polyprenoic acid significantly reduced the incidence of recurrent or new hepatomas. After a median follow-up of 38 months, 12 patients in the polyprenoic acid group (27 percent) had recurrent or new hepatomas as compared with 22 patients in the placebo group (49 percent, P = 0.04). The most striking difference was in the groups that had second primary hepatomas--7 in the group receiving polyprenoic acid as compared with 20 in the placebo group (P = 0.04 by the log-rank test). Cox proportional-hazards analysis demonstrated that as an independent factor, polyprenoic acid reduced the occurrence of second primary hepatomas (adjusted relative risk, 0.31; 95 percent confidence interval, 0.12 to 0.78).
Oral polyprenoic acid prevents second primary hepatomas after surgical resection of the original tumor or the percutaneous injection of ethanol.
Screening for disease has become a major activity over the last few decades, and the potential for future growth is almost boundless. However, the necessity for and effectiveness of screening has often been overstated with misused survival statistics. Nevertheless, screening with certain radiologic tests may provide modest benefits at acceptable costs under certain conditions. The challenge for the future is to better identify the tests, populations, and other conditions under which screening is appropriate. Various quantitative techniques for eliciting patient preferences [76] and analyzing benefits, harms, and costs over time [77-80] may help us meet this challenge.
Background:
Great progress in the diagnosis and surgical treatment of hepatocellular carcinoma (HCC) has led to an increased number of resectable cases. Much attention has been paid to the factors affecting long term survival of patients with HCC after partial hepatectomy.
Methods:
Survival rates for approximately 5800 patients with HCC registered by the Liver Cancer Study Group of Japan who received partial hepatic resection from January 1, 1982 to December 31, 1989 were calculated relative to 14 clinicopathologic variables. Cox's multivariate analysis and the stepwise method then were performed to determine significant prognostic variables and to investigate the appropriate combination of these variables for predicting prognosis.
Results:
The use of Cox's multivariate proportional hazard model indicated that significant prognostic indicators were alpha-fetoprotein level, tumor size, number of tumors, accompanying cirrhosis, age, surgical curability, and portal involvement. The stepwise method showed that the most valuable prognostic factor was portal involvement, followed by number of tumors, alpha-fetoprotein level, tumor size, accompanying cirrhosis, age, and surgical curability. Furthermore, it was found that the best predictive combination of two factors was number of tumors and alpha-fetoprotein level and that the best predictive combination of three factors was the alpha-fetoprotein level, tumor size, and number of tumors.
Conclusion:
This extensive analysis provides information that can be used to predict the prognosis of patients with HCC after undergoing partial hepatectomy.
Review of 61 surgically resected small hepatocellular carcinomas (HCC) less than or equal to 3 cm in diameter yielded a simple gross classification system of five types based on tumor shape, which is highly correlated with microscopic and clinical features, including prognosis. Type 1 (single nodular type) tumors (n = 13) are expansile, roughly spheric, and often encapsulated. In Type 2 tumors (single nodular type with extranodular growth) (n = 21), replacing growth is often seen in the area of extranodular growth. Type 3 tumors (contiguous multinodular type) (n = 19) consist of small nodules growing in contiguity, often with replacing growth at the periphery. Type 4 (poorly demarcated nodular type) is a rare tumor showing infiltrating growth at its border. The authors define early HCC (n = 5) as the presence of tumor without destruction of the underlying liver structure. The lesions experienced are tiny (≤1.2 cm) and well differentiated. Poorly differentiated histologic characteristics and elevated alpha fetoprotein are more common in Types 2 and 3 than in Type 1. Type 1 has the highest rates of positive serum hepatitis B surface antigen and liver cirrhosis; portal vein tumor thrombus (PT) and/or intrahepatic metastasis (IM) is rare (7.7%), and the effect of transcatheter arterial embolization (TAE) is remarkable. This contrasts with Type 2, which has a high rate of PT and/or IM (71.4%) and multiple local recurrences (40%), and with Type 3, which shows a poor response to TAE.
Thirty-two benign hepatic lesions, which were resected because of a diagnosis of malignancy, were reviewed to demonstrate the characteristics of the problem and to consider the best course of management. The preoperative diagnoses included 21 hepatocellular carcinomas, six metastases and five others. As the final diagnosis, hemangioma and focal nodular hyperplasia were the two major lesions mimicking malignancy, accounting for seven and six patients, respectively. Four of seven hemangiomas were atypical, with a considerable amount of fibrosis. Focal nodular hyperplasia and adenoma were misdiagnosed as hepatocellular carcinoma among other malignancies. Two instances each of necrotic tissue and hemangioma were diagnosed as metastatic carcinoma. The lesions that were studied had main features, including a diameter of less than 4 centimeters in 23 patients, evident discrepancy among the roentgenologic diagnoses in 25 patients and no rapid increase in size in 28 patients. Four of nine needle biopsies performed gave false-positive results and did not always provide adequate information. It was concluded that 15 of the 32 patients, who satisfied the aforementioned three criteria, could have been observed more carefully. However, in the other 17 patients, surgical intervention was considered justified because of an indication of a higher likelihood of a real malignancy.
As one of the reasons for the poor prognosis of patients with hepatocellular carcinoma (HCC) and cirrhosis, the influence of cirrhosis itself has not been clarified.
We compared the postoperative long-term courses of patients with HCC and cirrhosis with the courses of patients with HCC and without cirrhosis to determine how the coexisting cirrhosis affected the prognosis after surgery. The patients with HCC who underwent curative hepatic resection consisted of 142 with associated histologically confirmed cirrhosis and 48 without cirrhosis.
The 5-, 7-, and 9-year survival rates were 44%, 32%, and 26%, respectively, in the patients with cirrhosis and 68%, 57%, and 57%, respectively, in the patients without cirrhosis. The prognosis of the group with cirrhosis was significantly worse than that of the group without cirrhosis. The main cause of death in both groups was cancer recurrence. The patients with cirrhosis had significantly lower recurrence-free survival rates at 3 years and later than had the patients without cirrhosis. A comparison of the background factors revealed no substantive disadvantages with regard to tumor-related and surgical factors in the patients with cirrhosis compared with the patients without cirrhosis. The recurrence-free survival rates after minor and major resection indicated fewer disadvantages of limited hepatectomy in the group with cirrhosis than in the group without cirrhosis. Moreover, the recurrence-free survival of the group with cirrhosis was shorter at less advanced stages than at more advanced stages when compared with that of the group without cirrhosis.
The higher carcinogenic potential in cirrhosis could be presumed to be the most likely reason for the poorer prognosis after surgery in the patients with HCC and cirrhosis.
There is growing interest in screening to detect symptomless hepatocellular carcinoma (HCC), which should be easier to treat than symptomatic tumours. Combined alpha-fetoprotein and ultrasound monitoring can detect HCCs of 1 cm, and Lipiodol retention can be detected in tumours smaller than 1 cm. A number of treatment options are available. Surgical resection may be curative in selected patients with a single small tumour, but the cirrhotic patient is left with a diseased liver and the risk of tumour recurrence or death from underlying liver dysfunction. Orthotopic liver transplantation is a rational treatment for patients with decompensating cirrhosis and a small HCC, but it is expensive and necessitates immunosuppression. A variety of targeted or local therapies, either individually or in combination, can be used to treat HCC. These include percutaneous alcohol injection into an HCC, which may be an alternative to surgical resection. Tumour necrosis can be seen after targeted Lipiodol chemotherapy or radiotherapy. Transcatheter arterial embolisation selectively embolises the feeding artery, and can be combined with Lipiodol chemotherapy. Small tumours are thus amenable to treatment, even in patients who cannot have surgery. Screening and treatment for symptomless HCC seems justified, unless controlled trials teach us differently.
Patients with cirrhosis of the liver are recognized as being at risk for hepatocellular carcinoma. The magnitude of the risk, the natural history of this disease, and the possibilities for detecting potentially curable tumors in patients in the Western world are unknown. To address these questions, we examined 447 Italian patients with well-compensated cirrhosis (which was of viral origin in 62 percent of them) from 1985 through 1990, performing serum alpha-fetoprotein assays and real-time ultrasonography every 3 to 12 months.
Hepatocellular carcinoma was found in 30 patients (7 percent) at base line and in another 29 patients (7 percent of 417 patients free of tumor at base line) during follow-up periods averaging 33 months (range, 1 to 48). The cumulative hazard of the development of hepatocellular carcinoma during follow-up was higher among patients with persistently elevated serum alpha-fetoprotein levels (12 with tumors among 42 with such levels) than among those with fluctuating levels (11 among 82) or those with consistently normal levels (6 among 255). Only 17 patients had potentially operable tumors. The proportion of potentially operable tumors among those detected during follow-up was significantly lower than the proportion at enrollment (4 of 29 vs. 13 of 30, P = 0.027). The survival at one year of the 12 patients who underwent surgery was 67 percent, and the tumor-recurrence rate was 60 percent. Outcome was not appreciably different for the five patients who refused surgery.
In the West, as in Asia, patients with cirrhosis of the liver are at substantial risk for hepatocellular carcinoma, with a yearly incidence rate of 3 percent. Our screening program did not appreciably increase the rate of detection of potentially curable tumors.
We prospectively monitored 140 cirrhotic patients for the development of hepatocellular carcinoma for 6 yr, using periodical screening by high-resolution convex-array ultrasonography and alpha-fetoprotein. Twenty-eight patients were positive for HBs antigen, 26 patients had received blood transfusions and were negative for HBs antigen and 26 patients had a history of heavy drinking. We detected hepatocellular carcinoma in 40 patients during this period. The overall cumulative incidence of hepatocellular carcinoma in the 6 yr was 39%; the cumulative incidence was 59% in patients with HBsAg, 53% in patients who had had blood transfusions and were negative for HBsAg and 22% in patients who had a history of heavy drinking and who were without HBsAg. Detection of the carcinoma in 85% of these 40 patients was based on results of ultrasonography. Twenty-six of the patients (65%) had a small hepatocellular carcinoma of 2 cm or less. alpha-Fetoprotein levels were lower than 100 ng/ml in 56% of these 40 patients. Patients with cirrhosis are at high risk of developing hepatocellular carcinoma, especially patients with HBsAg or with a history of blood transfusion who are negative for HBsAg. Periodic monitoring by use of ultrasonography in particular is recommended for early detection of hepatocellular carcinoma.
To determine whether a careful evaluation of tumor extension by preoperative computed tomography scan after intra-arterial injection of ultrafluid lipiodol and by intraoperative ultrasound examination reduced the recurrence rate of hepatocellular carcinoma after resection, a series of 47 cirrhotic patients with a single tumor operated on from 1984 was studied. Alphafetoprotein level was less than 100 ng/mL in 26 patients (55%), size of the tumor was less than 5 cm in 28 patients (59%), and capsule was present in 30 patients (63%). The resection was performed with free margin measuring 1 cm or more. The overall cumulative survival rates at 3 and 5 years were 35% and 17%, respectively. Intrahepatic recurrence was observed in 28 patients (60%), located less than 2 cm from the resection margin in only four patients. The cumulative intrahepatic recurrence rate at 3 years was 81% and was significantly higher in patients with tumor greater than or equal to 5 cm and in patients with preoperative alphafetoprotein level of greater than or equal to 100 ng/mL. In this series the cumulative intrahepatic recurrence rate at 5 years was 100%. This high recurrence rate after resection, even with careful evaluation of tumor extension, indicates that liver transplantation might be envisaged for the treatment of cirrhotic patients with resectable hepatocellular carcinoma.
From a series of 320 heptocellular carcinoma (HCC) cases treated surgically, we selected small nodular lesions that had not destroyed the preexisting liver structure grossly. After excluding metastases and large regenerative nodules, 58 lesions from 41 cases were chosen. All the lesions were hypercellular. Among them, 33 lesions showing histologic features of very well-differentiated HCC (Edmondson grade I), that is, small hepatocytes with little cellular atypia but with structural atypia, such as a thin trabecular structure of acinar formation in some areas, were classified as early HCC (eHCC). In seven eHCCs, areas of overt carcinoma, classified as Edmondson grade II, were found in the background of Edmondson grade I carcinoma. The remaining 25 lesions lacked structural atypia and were classified as adenomatous hyperplasia (AH). Among the AHs, 10 nodules with a very focal abnormal structure were subclassified as atypical adenomatous hyperplasia (AAH). There was a tendency for the size and cellularity of the atypical lesions to increase in order from AH to AAH to eHCC. All nodules larger than 1.5 cm were eHCC. A degree of cellularity more than twice that of a regenerative nodular was suggested to be an indicator of HCC. All small nodular lesions were associated with chronic liver disease. These histologic observations appear to explain the stepwise development of overt HCC from very well-differentiated eHCC, and of eHCC from AH probably through AAH, at least in cases of HCC associated with chronic liver disease.
To clarify the course of adenomatous hyperplasia (AH) of the liver, 17 patients with 20 biopsy-proven AH nodules were followed clinically for 1-5 years. At the initial biopsy the mean nodular diameter was 10 (SD 4) mm and the relative cellularity [( mean cellularity of AH divided by mean parenchymal cellularity] x 100) 141 (27). The criteria for diagnosis of malignant transformation of AH were both a doubling of nodular volume and changes on imaging. Between 6 and 50 months after biopsy, 9 of the 18 nodules which could still be accurately identified met the criteria for transformation; histological proof of hepatocellular carcinoma (HCC) was obtained later for 7 of these 9 nodules. The product of diameter and cellularity (transformation index) was the strongest predictor of the time to transformation. 9 AH nodules did not undergo transformation--7 did not meet one or both criteria and 2 became undetectable by imaging. Because of the high risk of malignant transformation, it can be concluded that AH is an absolute precursor of HCC. It should therefore be treated as a potential malignant disorder.
Primary liver cancer (PLC) is a malignant disease which is difficult to detect in its early stages and has very poor prognosis. Although relatively uncommon among Caucasians it is one of the major malignancies in many countries throughout the world, particularly in sub-Saharan Africa and the Far East. It accounts for 65.5% of all malignant disease in men and 31% of malignant tumors in women among Shangaan blacks in South Africa. It is the third cause of cancer death in males and the fourth among females in China; it raned third and fifth in these groups, respectively, in Japan in 1983. Of PLC, hepatocellular carcinoma (HCC) is the major histological type followed in frequency by cholangiocellular carcinoma - the ratio of HCC to cholangiocellular carcinoma varies from 5:1 to nearly 40:1. In other words, the major malignant killer in the high PLC incidence areas in HCC. A close association of HCC with cirrhosis, particularly the posthepatitic or macronodular variety, has long been known. This interrelationship, an enigma in the past, now seems explainable in part by the hepatocarcinogenic properties of hepatitis B virus infection. However, some epidemiological data speak against the theory that this virus is the sole etiologic factor in HCC. Besides food contamination by aflatoxins in the tropical and subtropical regions, chronic non-A, non-B hepatitis is one recent etiologic candidate in Japan where HCC incidence has more than doubled in the past 15 years despite a concomitant increase in hepatitis B virus seronegative cases. A recent study in Tokyo shows that 40% of patients with HCC now have a history of past blood transfusion. Because of frustrations due to late diagnosis and bad therapeutic results, Japanese gastroenterologists have pioneered clinical programs for the early detection of HCC.
Fifty-four patients underwent total hepatectomy and liver replacement in the presence of a primary liver malignancy. In 13 recipients in whom the hepatic tumors were incidental to some other endstage liver disease, recurrence was not seen and 12 of the 13 patients are alive after 4 months to 15 1/2 years. In contrast, tumors recurred in 3 of every 4 patients who received liver replacement primarily because of hepatic malignancies that could not be resected by conventional techniques of subtotal hepatectomy and who lived for at least 2 months after transplantation. The most encouraging results were in patients with the fibrolamellar hepatocellular carcinomas that grow slowly and metastasize late, but even with this lesion, the recurrence rate was 57%. In future trials, additional effective anticancer therapy will be needed to improve the results of liver transplantation for primary liver malignancy, but what an improved strategy should be has not yet been defined.
We studied the features of 18 cases of hepatocellular carcinoma (HCC) with prominent intra-atrial tumor growth that were seen among 439 autopsy cases of HCC. Diuretic-resistant, marked edema in the lower extremities and marked venous dilatation in the abdominal wall were observed in 14 cases (77.7%) and five cases (27.7%), respectively. Consistent tachycardia was seen in three cases. Macroscopically, most of the cases showed an infiltrative or mixed (infiltrative and nodular) growth pattern. A continuous tumor thrombus involving the right atrium, the IVC, and the hepatic vein was seen in 15 cases; a tumor that involved the right atrium alone was present in three cases. In five cases, the tumor bolus crossed the tricuspid valve and entered the ventricle.
To use computed tomography (CT) during arterial portography (CTAP) and CT arteriography to compare the hemodynamic properties of early hepatocellular carcinoma (HCC) with those of small HCC.
Forty-four early HCCs (mean diameter, 1.5 cm) in 37 patients (26 men and 11 women aged 52-74 years; mean age, 59.2 years) were studied. CTAP was performed on 35 early HCCs, CT arteriography on 20, and both studies on 11. CTAP, CT arteriography, or both were performed on 90 small HCCs (mean diameter, 2.0 cm) in 57 patients (44 men and 13 women aged 48-71 years; mean age, 61 years). The findings for small HCC were compared with those for early HCC.
CTAP depicted 23 early HCCs as hypoattenuating masses and 12 as isoattenuating. CT arteriography depicted 11 early HCCs as hypoattenuating masses, six as isoattenuating, and three as hyperattenuating. CTAP depicted 85 of 88 small HCCs as hypoattenuating masses and three as isoattenuating. CT arteriography depicted 13 of 14 small HCCs as hyperattenuating masses.
CTAP, the standard of reference for the detection of small HCC, is not sensitive enough for the detection of early HCC.
During the last 16 years, we have resected small hepatocellular carcinomas (HCCs) measuring 5 cm or less from 362 patients, 266 of whom also had liver cirrhosis. The operative and hospital mortality rate were 1.7% and 1.9%, respectively. These showed a gradual decrease year by year in parallel with reduction of intraoperative blood loss achieved by the selective vascular occlusion technique and Pringle method. In 1989, 87% of hepatectomy patients were discharged without the need for whole blood transfusion, and 5-year survival was 43.7%. Tumor size, number of tumors, intrahepatic metastasis, vascular invasion, and capsular invasion were significant prognostic factors. Edmondson grade and the operative procedure employed were significantly related to outcome. Our standard policy for selection of operative procedures and perioperative care is described, and the selection of treatment modalities is discussed.
This study was intended to compare the survival rates of two contemporary cohorts of patients with solitary hepatocellular carcinomas < or = 4 cm subjected to surgical resection (n = 33) or percutaneous ethanol injection (n = 30). Outcomes in a third cohort, 21 patients with hepatocellular carcinoma who underwent orthotopic liver transplantation, were also assessed. Surgical and ethanol-treated patients were similar with regard to age and tumor stage, differing only in liver function; 30 of the 33 surgical patients were of Child-Pugh class A, whereas only 7 of the 30 ethanol-treated patients were of class A (p < 0.05). Surgical resection was successful in 30 cases; ethanol injection achieved initial success in 23 patients. Tumor recurrence rate at 2 yr was 45% in the surgical group and 66% in the ethanol group. The difference was significant only for cases with tumors between 3 and 4 cm. Despite poorer liver function, the 1-, 2-, 3- and 4-yr survival rates of ethanol-treated patients (83%, 66%, 55% and 34%, respectively) were not different from those of surgically treated patients (81%, 73%, 44% and 44%, respectively). The 1- and 2-yr survival rates of patients given liver transplants were 81% and 66%, without tumor recurrence, after 16-mo follow-up. These data confirm that ethanol injection is a useful treatment for patients with solitary small hepatocellular carcinomas and suggest that surgical resection and liver transplantation may achieve better results only after strict candidate selection to reduce mortality and tumor recurrence during follow-up.
This study analyzed the results in 229 patients with primary hepatocellular carcinoma (HCC) who were treated by radical hepatic resection in the past 11 years.
Due to marked advances in diagnostic and therapeutic methods, the therapeutic strategy for HCC has changed significantly. However, there are still many problems to be solved when hepatic resection is to be performed for HCC associated with chronic liver disease. A satisfactory result may be possible only when all of accurate operative indication, skillful surgical technique, and sophisticated postoperative management are met.
There were 188 men and 41 women. Age ranged from 32 to 79 years averaging 60.8. Underlying cirrhosis of the liver was found in 177 patients, and chronic hepatitis was found in 47 instances. Before surgery, 114 patients had 157 associated conditions; diabetes mellitus in 66, esophageal varices in 42, cholelithiasis in 22, peptic ulcer in 12, and miscellaneous in 15 cases. In addition to various types of hepatic resection, 69 patients underwent concomitant operations such as cholecystectomy, the Warren shunt, splenectomy, partial gastrectomy, and so forth.
The 30-day (operative) mortality rate was 7.0%, and there were eight additional late deaths (3.5%). Child's class, bromosulphalein (BSP) test, and the estimated blood loss during surgery were good predictors for operative death. The cumulative 5- and 10-year survival rates for all patients were 26.4% and 19.4%, respectively. At present, 110 patients are alive; 2 more than 10 years and 21 more than 5 years. Younger age, absence of cirrhosis, smaller tumor, and postoperative chemotherapy were associated with increased survival.
The results of hepatic resection in 229 patients with HCC were analyzed. Child's class, BSP test, and blood loss during surgery were good predictors for operative death. The 5- and 10-year survival rates were 26.4% and 19.4%, respectively. Age, liver cirrhosis, tumor size, and postoperative chemotherapy were prognostic factors. Multidisciplinary approach with liver resection, postoperative chemotherapy, and liver transplantation will be a realistic direction for the surgical treatment of HCC in future.
Currently, there is considerable controversy about the place of transplantation in the treatment of hepatocellular carcinoma (HCC). This study compared resection to transplantation in cirrhotic patients with HCC in order to determine reasonable indications of each treatment.
The usual procedure is to resect when feasible and to transplant in other cases.
Three-year survival with and without recurrence was analyzed in 60 patients who underwent resection and 60 who underwent transplantation. Several prognostic factors, such as size, number of nodules, portal thrombus, and histologic form, were studied.
In terms of overall survival rates, resection and transplantation yield the same results (50% vs. 47%, respectively, at 3 years). For transplantation, however, the rate for survival without recurrence is better than that for resection (46% vs. 27%, respectively; p < 0.05). In the case of small uninodular or binodular tumors (< 3 cm), transplantation has much better results than resection (survival without recurrence, 83% vs. 18%, respectively; p < 0.001). However, it seems that a group of patients with high risk of recurrence after transplantation can be determined (diffuse form, more than two nodules > 3 cm, or presence of portal thrombus).
The best indication for transplantation seems to be patients with small and uninodular or binodular tumors; until now, these patients were considered to be the best candidates for resection. Patients undergoing transplantation for unresectable, large, multinodular or diffuse tumors seem to represent bad indications for transplantation. These results could help define reasonable indications for transplantation in an era with a shortage of liver grafts.
The long-term outcome in 480 patients with primary hepatocellular carcinoma (HCC) who underwent hepatic resection between 1980 and 1990 was investigated. Overall 5- and 10-year survival rates were 44.1% and 17.8%, respectively, with a hospital mortality rate of 3.1%. The survival of patients who underwent curative resection was better than that of patients treated with noncurative resection. Tumor invasiveness, defined by the presence of vascular invasion and/or intrahepatic metastases, was a major prognostic factor for early recurrence in the patients treated with curative resection. The effect of tumor size and number on prognosis was attributable to a strong correlation with tumor invasiveness. One-third of patients with multiple lesions were considered to have multicentric disease, and their prognosis was better than that of patients with invasive lesions. The width of the resection margin did not affect the prognosis. An unfavorable effect of associated liver disease, especially cirrhosis, was prominent in the later period. A beneficial effect of anatomically systematic resection was apparent in non-cirrhotic patients with non-invasive HCC.
Surgical resection for hepatocellular carcinoma (HCC) can be curative in selected patients, particularly in those with a solitary small HCC (s-sHCC; 2 cm or less in diameter). However, even these patients often have a risk of tumor recurrence or death from underlying liver dysfunction. Therefore it is important to determine which clinicopathologic features are related to the long-term prognosis after resection of s-sHCC.
Fifty patients with s-sHCC underwent partial hepatectomy at our department between 1977 and 1992. Six (12%) died of liver failure in hospital after operation. Eight clinicopathologic features were examined in the remaining 44 patients with regard to their long-term prognosis by use of univariate and multivariate analyses.
The 1-, 3-, and 5-year survival rates were 90%, 75%, and 53%, respectively. The corresponding disease-free survival rates were 80%, 53%, and 30%, respectively. None of the following parameters was significantly related to survival rate or disease-free survival rate: presence of vascular invasion or capsular formation, the distance of free surgical margin (1 cm or more or not), serum alpha-fetoprotein level, positive hepatitis B surface antigen, and preoperative transarterial embolization. Complicated liver function was the only significant factor related to survival rate and disease-free survival rate.
A good hepatic reserve is an important factor in treating patients with s-sHCC by surgical resection, even for a long-term prognosis. Liver transplantation should be considered for patients with severe cirrhosis and s-sHCC, even though a curative resection might be possible.
Unlabelled:
Macroregenerative nodules are commonly thought to be hyperplastic lesions, deriving both their large size and premalignant potential from an increased proliferative rate. We have previously suggested an alternate model of macroregenerative nodule development in which neither size nor premalignant potential of macroregenerative nodules would depend on increased proliferation. We tested this hypothesis by examining the proliferative activity in macroregenerative and surrounding cirrhotic nodules.
Methods:
Eighteen macroregenerative nodules, including five type I and 13 type II, were immunostained for proliferating cell nuclear antigen (PCNA). Type II macroregenerative nodules included ten with diffuse large (7) or small (3) liver cell dysplasia only and eight containing nodule-in-nodule lesions. Five nodule-in-nodule lesions met the histologic criteria for hepatocellular carcinoma. PCNA labeling indices (PCNA-LIs; percentage positive hepatocyte nuclei/500 randomly counted cells) were determined in macroregenerative nodules and the four largest adjacent cirrhotic nodules. Nodule-in-nodule lesions were assessed separately from the background macroregenerative nodule.
Results:
4/5 type I and 12/13 type II macroregenerative nodules (exclusive of NIN lesions) had PCNA-LIs lower than the mean of surrounding cirrhotic nodules. All nodule-in-nodule lesions, whether atypical or overtly malignant, had PCNA-LIs greater than any surrounding nodules. In conclusion, macroregenerative nodules have PCNA-LIs indistinguishable from, and often lower than, surrounding cirrhotic nodules. Increased proliferative activity only occurs with the development of atypia and transition to hepatocellular carcinoma.
Conclusion:
Macroregenerative nodules derive neither their size nor their premalignant potential from on-going rapid proliferation, a finding consistent with our alternate hypothesis of macroregenerative nodule development.
A total of 386 patients who underwent complete resection of hepatocellular carcinoma over an 8-year period were assessed retrospectively for tumour recurrence. Some 219 (56.7 per cent) of the patients developed recurrence. Patients with a greater degree of cirrhosis showed a longer interval to recurrence; the median (range) interval until recurrence was 7.9 (1.8-84.2) months in patients with a normal liver, 13.4 (2.0-79.5) months in those with chronic hepatitis and 16.7 (1.5-73.1) months in those with cirrhosis. Intrahepatic recurrence was observed more frequently in either the same (26.4 per cent) or the adjacent (24.8 per cent) Healey segment than in the lobe contralateral to the primary tumour (17.8 per cent). The presence of portal venous invasion and/or intrahepatic metastasis, underlying liver cirrhosis and perioperative blood transfusion were determined to be independent predictors of recurrence by multivariate analysis. Because intrahepatic spread of hepatocellular carcinoma occurs in a segment-by-segment manner, surgeons should use an anatomically wide resection within the hepatic functional reserve.
To assess intrahepatic metastasis (IM) and multicentric occurrence (MO) after initial treatment of small hepatocellular carcinomas (HCC) < or = 2 cm in diameter, we performed clinical and pathological studies in 112 patients who underwent percutaneous ethanol injection therapy (PEIT) or hepatic resection for HCC from January 1985 to December 1994. Patients with intrahepatic recurrences were classified into two groups based on the type of recurrence: the IM group (n = 29, 50.9%) and the MO group (n = 28, 49.1%). Overall recurrence rates after initial treatment were 23.7% at 1 year, 64.5% at 3 years, and 76.1% at 5 years. In patients with IM, the majority of intrahepatic recurrences were observed within 3 years of initial treatment and the primary HCC lesions were closely related to the degree of tumor cell differentiation. Alternatively, intrahepatic recurrences occurred throughout the follow-up period in patients with MO, and the evidence of underlying liver disease (anti-HCV [antibody to hepatitis C virus] positive) and elevated serum alfa-fetoprotein (AFP) concentrations were closely associated with intrahepatic recurrence. Prognoses following additional treatment in MO group patients were superior to those in IM group patients. These results suggest that differentiation between IM and MO in patients with HCC is important for understanding the development and biological behavior of the tumor. That is, the early detection of intrahepatic recurrence and the institution of appropriate additional therapy (PEIT or hepatic resection) may prolong survival in patients with MO.
KiwamuOkita, NamikiIzumi, KenjiIkeda, YukioOsaki, KazushiNumata, MasafumiIkeda, NorihiroKokudo, KazuhoImanaka, ShuheiNishiguchi, ShunsukeKondo, YoichiNishigaki, SusumuShiomi, KazuomiUeshima, NorioIsoda, YoshiyasuKarino, MasatoshiKudo, KatsuakiTanaka, ShuichiKaneko, HisatakaMoriwaki, MasatoshiMakuuchi, TakujiOkusaka, NorioHayashi, YasuoOhashi, HiromitsuKumada. (2015) Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial. Journal of Gastroenterology 50, 667-674
CrossRef
This article reviews methodological issues around screening for hepatocellular carcinoma, and discusses selection of the at-risk group, which screening test to use, and how frequently it should be applied. Screening of patients at risk for hepatocellular carcinoma should be undertaken using ultrasonography applied at six-month intervals. Patients at risk include all those with cirrhosis, and certain non-cirrhotic patients withchronic hepatitis B. In this population, screening has been shown to reduce disease-specific mortality. Although data do not exist for other populations, screening is nonetheless advised because small cancers can be cured with appreciable frequency.
Management of Gastrointestinal Cancer
- Takayama T
- Makuuchi M
- James ND
- Kerr D
- Takayama Et
HEPATOLOGY Vol. 28, No. 5, 1998
TAKAYAMA ET AL. 1245
Screening for disease
- W C Black
- H G Welch
Black WC, Welch HG. Screening for disease. Am J Roentgenol 1997;168:
3-11.
International Working Party. Terminology of nodular hepatocellular lesions
International Working Party. Terminology of nodular hepatocellular
lesions. HEPATOLOGY 1995;22:983-993.
The Liver Cancer Study Group of Japan. Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan
The Liver Cancer Study Group of Japan. Predictive factors for long term
prognosis after partial hepatectomy for patients with hepatocellular
carcinoma in Japan. Cancer 1994;74:2772-2780.
- Yamamoto
- Black
- Kumada