Primary Solitary Hepatocellular Carcinoma Research Articles

Durable Stable Disease by Atezolizumab/Bevacizumab Can Provide Long-term Survival of Patients With Hepatocellular Carcinoma Lung Metastases.

Multiple bilateral lung metastases secondary to hepatocellular carcinoma (HCC) are mainly treated with molecular therapy. Atezolizumab plus bevacizumab can provide excellent long-term survival for patients with a good response. A 67-year-old woman underwent right hepatectomy for a primary solitary HCC, 11 cm in diameter, after portal embolization. After 2 years, she developed bilateral lung metastases with >100 nodules, <1 cm in size. She had no viral hepatitis or liver cirrhosis, and the Child-Pugh Grade was A (5 points). Lenvatinib (12 mg daily) was administered as a first-line treatment and continued for 18 months. The best response was stable disease (SD). Subsequently, intravenous atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) was administered once every three weeks. The best response was SD, which continued for 26 months. After that, cabozantinib treatment was initiated and discontinued after one cycle. Subsequently, dual immune checkpoint inhibitor treatment (durvalumab + tremelimumab) was administered. She has had multiple, but lung-only, metastases over four years. She has been well as an outpatient with the Child-Pugh Grade of A and a performance status of 0. Even if atezolizumab plus bevacizumab does not induce a good response, a durable SD could prolong survival in patients with metastatic HCC while maintaining liver function and a good quality-of-life.

Novel Nomogram Based on Inflammatory Markers for the Preoperative Prediction of Microvascular Invasion in Solitary Primary Hepatocellular Carcinoma.

PurposeWe aimed to develop and to validate a novel nomogram based on inflammatory markers to preoperatively predict microvascular invasion (MVI) in patients with solitary primary hepatocellular carcinoma (HCC).Patients and MethodsData from 658 patients with solitary primary HCC who underwent hepatectomy at the First Affiliated Hospital of Zhengzhou University from June 2018 to October 2021 were retrospectively analyzed. Patients were divided into training (n=441) and validation (n=217) cohorts according to surgical data. Independent risk factors for MVI were identified via univariate and multivariate logistic regression analyses in the training cohort. A novel nomogram was developed based on the independent risk factors identified. Its accuracy was evaluated using a calibration curve and concordance index (C-index). The predictive value was evaluated using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA).ResultsPreoperative alpha-fetoprotein >969 µg/L (P<0.001), tumor size (P=0.002), neutrophil >1.8×109/L (P=0.002), gamma-glutamyl transpeptidase-to-platelet ratio (GPR) >0.32 (P=0.001), aspartate aminotransferase-to-platelet ratio (APR) >0.18 (P<0.001), gamma-glutamyl transpeptidase-to-albumin ratio (GAR) >2.30 (P=0.001), and gamma-glutamyl transpeptidase-to-lymphocyte ratio >29.58 (P<0.001) were identified as preoperative independent risk factors for MVI and were used to establish the nomogram. The C-index of the training and validation cohorts were 0.788 (95% confidence interval [CI]: 0.744–0.831) and 0.735 (95% CI: 0.668–0.802), respectively. The calibration curve analysis revealed that the standard curve fit well with the predicted curve. ROC curve analysis demonstrated high efficiency of the nomogram. DCA verified that the nomogram had notable clinical value.ConclusionPreoperative GPR >0.32, APR >0.18, and GAR >2.30 were independent risk factors for MVI in patients with solitary primary HCC, suggesting their utility as preoperative predictors of MVI. The novel nomogram developed and validated in this study may aid in determining optimal therapeutic approaches for patients with solitary HCC at risk for MVI.

Multicenter prospective study of stereotactic body radiotherapy for previously untreated solitary primary hepatocellular carcinoma: The STRSPH study.

To prospectively evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) for patients with previously untreated solitary primary hepatocellular carcinoma (HCC). The main eligibility criteria included the following: (1) primary solitary HCC; (2) no prior treatment for HCC; (3) Child-Turcotte-Pugh score of seven or less; and (4) unsuitability for or refusal of surgery and radiofrequency ablation (RFA). The prescribed dose of SBRT was 40Gy in five fractions. The primary endpoint was 3-year overall survival (OS); the secondary endpoints included local progression-free survival (LPFS), local control (LC), and adverse events. The accrual target was 60 patients, expecting a 3-year OS of 70% with a 50% threshold. Between 2014 and 2018, 36 patients were enrolled; enrollment was closed early because of slow accrual. The median tumor size was 2.3cm. The median follow-up at the time of evaluation was 20.8months. The 3-year OS was 78% (95% confidence interval [CI]: 53%-90%). The 3-year LPFS and LC proportion were 73% (95% CI: 48%-87%) and 90% (95% CI: 65%-97%), respectively. Grade 3 or higher SBRT-related toxicities were observed in four patients (11%), and grade five toxicities were not observed. This study showed acceptably low incidence of SBRT-related toxicities. LC and OS after SBRT were comparable for previously untreated solitary HCC for patients unfit for resection and RFA. Although a definitive conclusion cannot be drawn by this study, the promising results indicate that SBRT may be an alternative option in the management of early HCC.

Successful Anatomic Resection of Tumor-Bearing Portal Territory Delays Long-Term Stage Progression of Hepatocellular Carcinoma.

Optimal choice of surgical procedure for hepatocellular carcinoma (HCC) remains inconclusive. This study seeks to investigate the oncological superiority of anatomic resection (AR) of the tumor-bearing portal territory and potential mechanism of survival benefit for patients undergoing AR. In 203 patients who underwent curative resection for primary solitary HCC measuring ≤ 5cm in diameter, which was resectable either by AR or limited resection (non-AR), long-term outcomes were compared with propensity score adjustment. Advantages of AR in local tumor control and postprogression survival were then evaluated by a multivariate analysis and a Markov model. The AR group showed better recurrence-free survival [hazard ratio (HR), 0.51; 95% CI, 0.28-0.91; P = 0.023), time-to-interventional failure (TIF) (HR, 0.08; 95% CI, 0.01-0.60; P = 0.014), and overall survival (HR, 0.11; 95% CI, 0.01-0.79, P = 0.029) than the non-AR group. Competing-risks regression revealed that AR significantly decreases local recurrence (HR, 0.13; 95% CI, 0.02-0.97; P = 0.047) and is correlated with smaller number and size of recurrent lesions, both of which were predictors for better TIF and postprogression survival. A Markov model demonstrated that annual transition rate from the early recurrence stage (i.e., curative-intent treatment indicated) to the intermediate stage (i.e., only palliative-intent treatment indicated) was significantly lower (9.0% versus 35.6%, P = 0.027) when AR was completed at the initial hepatectomy. AR is oncologically advantageous for patients with primary solitary HCC. Initial choice of surgical procedure may have significant influence on the pattern of recurrence and postprogression clinical course that may affect overall survival of patients with HCC.

Beneficial body mass index to enhance survival outcomes in patients with early-stage hepatocellular carcinoma following microwave ablation treatment

Purpose To identify the beneficial body mass index (BMI) for patients with hepatocellular carcinoma (HCC) to achieve longer survival time following curative microwave ablation (MWA). Methods This retrospective study evaluated 474 patients with solitary primary HCC who underwent MWA. BMI at initial admission and other characteristics were collected. The associations of the BMI with the overall survival (OS) and disease-free survival (DFS) were analyzed by Cox proportional hazards regression analysis in multiple models. A two-piecewise linear regression model was applied to examine the threshold effect of the BMI on OS and DFS by maximized log likelihood method. The threshold level was determined by using trial and error. Results Patients with a normal BMI range achieved improved survival outcomes but similar DFS in multiple models. In the model with adjustments of the age, size, and Charlson score, patients with BMI ≤ 22.9 and ≤24.9 kg/m2 exhibited a lower death rate than patients with BMI ≤18.5 kg/m2 (p < 0.05). U-shaped relationships between the BMI and OS were illustrated when the BMI was set as a continuous variable. The death prevalence decreased with an increasing BMI up to the first turning point of 21.5 and increased with an increasing BMI up to the second turning point of 23.1 (p = 0.00). The threshold effect analysis indicated that no turning point was selected in the DFS results (p = 0.10). Conclusions The beneficial BMI level for HCC patients following MWA, with a more likely favorable survival outcome, is 21.5 to 23.1 kg/m2.

Clinical predictors of small solitary hepatitis B virus-related hepatocellular carcinoma microinvasion.

Microinvasion serves as a reliable indicator of poor prognosis after hepatectomy or transplantation for hepatocellular carcinoma (HCC). However, microinvasion is difficult to detect with current imaging modalities and is usually diagnosed histopathologically. The aim of this study is to identify the preoperative clinical predictors of microinvasion of small solitary hepatitis B virus (HBV)-related HCC. From January 2000 to December 2009, 110 patients with HBV-related small primary solitary HCC (tumour diameter ≤3.0 cm) who underwent hepatectomy at Chinese PLA General Hospital were enrolled. The independent predictors of microinvasion, such as microvascular invasion and microscopic satellite nodules, were analysed. The prognosis of patients with microinvasion was compared with that of patients without microinvasion. Of the 110 patients, 31 (28.2%) exhibited microinvasion. Among them, 16 (51.6%) had microvascular invasion with microscopic satellite nodules, five (16.1%) had microscopic satellite nodules without microvascular invasion and 10 (32.3%) had microvascular invasion without microscopic satellite nodules. Two independent predictors of microinvasion were identified: serum alpha-fetoprotein >20 ng/mL and a viral load of >104 copies/mL. Patients without microinvasion exhibited a significantly better prognostic outcome compared with those with microinvasion. Regarding HBV-related small HCC, patients presenting with alpha-fetoprotein levels >20 ng/mL and a high viral load (HBV-DNA >104 copies/mL) are at substantial risk for microinvasion.

Phase II Study of Image-Guided Proton Therapy for Solitary Primary Hepatocellular Carcinoma with Indication for Standard Treatment

The aim of this study was to evaluate the efficacy and safety of image-guided proton therapy (IGPT) for solitary primary hepatocellular carcinoma (HCC) that was amenable to standard treatment (resection or ablation). Eligibility criteria were as follows: (1) histologically-confirmed or image-diagnosed solitary primary HCC staged as T1N0M0 (UICC TNM 7th ed.); (2) no history of previous HCC; (3) patient refusal of surgery or radiofrequency ablation; (4) no previous radiation therapy around the lesion; (5) age > 20 and ≤ 80 years; (6) ECOG-PS ≤ 1; (7) Child-Pugh classification A5, 6 or B7; (8) dose constraints of the organs at risk achievable; (9) tumor diameter ≤ 12 cm; and (10) written informed consent. Primary endpoint was the 2-year overall survival (OS). Secondary endpoint was the local control rate (LCR), incidence of Grade 3 or higher adverse events, and change of quality of life (QOL). Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. QOL score were evaluated with the EORTC QLQ-C30 version 3.0 and QLQ-HCC18. We hypothesized that the 2-year OS would be increased from a baseline of 68% to 84% and calculated that 45 patients would need to be enrolled to have a 90% chance of demonstrating improvement using a 2-sided test with a significance level of .05 and 5% of drop-out patients. Survival was analyzed by using the Kaplan-Meier method. Prior to treatment planning, a fiducial marker was placed near the tumor. Proton therapy was performed using respiratory-gated and image-guided techniques. From June 2013 to February 2016, 45 patients were enrolled. The major underlying liver diseases were hepatitis B infection (n=16), hepatitis C infection (n=13), alcoholic hepatitis (n=3), and nonalcoholic fatty liver disease (NAFLD) (n=13). Thirty-three patients had a Child-Pugh score of A5, 8 had a score of A6, and 4 had a score of B7. Twelve patients had Barcelona Clinic Liver Cancer stage 0 disease, 30 had stage A disease, and 3 had stage C disease. Thirty-seven patients with a peripherally located tumor were given 66 GyE in 10 fractions and 8 patients with a centrally located tumor received 72.6 GyE in 22 fractions. Maximum tumor diameter ranged from 10 to 100 mm (median, 25). The median follow-up period of surviving patients was 37.0 months (range: 24.0-50.5). The 2-year OS and LCR were 87% (95% confidence interval: 77-97%) and 95% (86-100%), respectively. There were significant differences in 2-year OS between the NAFLD group and others (P = 0.033). Only 1 grade 3 radiation-induced liver disease was observed. There were no significant differences in the QOL score before treatment and after 1 year except for body image (QLQ-HCC-18). IGPT is safe and effective for treating solitary primary HCC. As a new treatment modality, IGPT may become one of standard treatments for solitary primary HCC.

The Clinicopathological and Prognostic Significance of the Gross Classification of Hepatocellular Carcinoma.

BackgroundWe aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines.MethodsA retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of “stemness”-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)–related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers.ResultsSignificant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p<.05, all). CK19, EpCAM, uPAR, and ezrin expression was more frequently seen in type 2 HCCs (p<.05, all). Gross classification was an independent predictor of both overall and disease-free survival by multivariate analysis (overall survival: p=.030; hazard ratio, 4.118; 95% confidence interval, 1.142 to 14.844; disease-free survival: p=.016; hazard ratio, 1.617; 95% confidence interval, 1.092 to 2.394).ConclusionsThe gross classification of HCC had significant prognostic value and type 2 HCCs were associated with clinicopathological features of aggressive behavior, increased expression of “stemness”- and EMT-related markers, and decreased survival.

Evaluation of hepatocellular carcinoma spread via the portal system by 3-dimensional mapping

Background/PurposeThe pattern of tumor cell spread via the portal system has not been fully clarified in patients with hepatocellular carcinoma (HCC). This study aimed to evaluate the intrahepatic distribution of cancer cells derived from the main tumor by assessing histological portal invasion and/or intrahepatic metastasis (vp/im). MethodsIn 14 patients who underwent anatomical resection of primary solitary HCC ≤ 50 mm in diameter, vp/im were examined pathologically, and the sites of the lesions were reproduced on preoperative 3D-CT images. The number of vp/im and the distance of each lesion from the tumor margin were also determined. ResultsThe tumor diameter was <30 mm in seven patients (smaller HCCs) and 30–50 mm in seven patients (larger HCCs). 3D mapping revealed that almost all vp/im were localized to the peritumoral area within one cm of the tumor margin in smaller HCCs, whereas vp/im seemed to spread extensively to the feeding 3rd level portal branches in larger HCCs. The number of vp/im was greater in patients with larger HCCs than in those with smaller HCCs. Conclusions3D mapping suggested tumor cells of HCC spread via the portal vein extensively in several cases.

Hepatocellular carcinoma biology predicts survival outcome after liver transplantation in the USA.

The aim of this study is to evaluate the clinicopathologic prognostic factors of cancer-specific survival (CSS) in hepatocellular carcinoma (HCC) patients who underwent liver transplantation (LT) stratified by tumor size. From the Surveillance, Epidemiology, and End Results (SEER) 18 registries (2004-2012), we retrieved data of 570 patients who underwent LT for a solitary primary HCC lesion ≤5cm. A two multivariable Cox models were constructed to identify prognostic factors of CSS in a two different tumor sizes (2cm cutoff). Out of 570 HCC patients (median age 57years), 16% had microvascular invasion (MVI) and 12% had a poorly differentiated tumor. Male sex (odds ratio [OR] 2.6), tumor size >2cm (OR 1.78), elevated AFP (OR 2.31), and poor tumor differentiation (OR 2.59) are significant predictors of MVI. With a median follow up of 41.5months (range 1-107months), the 5-year CSS rate was 90% in the absence of MVI compared to 75% in the presence of MVI (p<0.001). Multivariate models revealed that age ≥60years (hazard ratio [HR] 2.08), MVI (HR 2.26), and poor tumor differentiation (HR 2.42), were significant risk factors of a dismal CSS with HCC size >2cm, but not with HCC ≤2cm. Primary HCC tumor size ≤2cm had an excellent prognosis after LT and was not affect by the presence of MVI or poor tumor differentiation.

Importance of tumor size as a prognostic factor after partial liver resection for solitary hepatocellular carcinoma: Implications on the current AJCC staging system.

Presently, the impact of tumors size as a prognostic factor after curative liver resection (LR) for solitary hepatocellular carcinoma (HCC) remains controversial. This study was performed to determine the prognostic factors of patients undergoing LR for solitary HCC with special emphasis on the importance of tumor size. Between 2000 and 2013, 560 patients underwent curative LR for solitary primary HCC which met the study criteria. One-hundred and seventy-eight patients underwent major hepatectomies and the overall in-hospital mortality was 2.0%. There were 282 patients (50.4%) with liver cirrhosis. The 5-year overall survival (OS) was 64% and recurrence free survival (RFS) was 50%, respectively. Multivariate analyses demonstrated that cirrhosis, microvascular invasion and size were independent predictors of RFS and cirrhosis, microvascular invasion and age were independent prognostic factors of OS. Subset analysis demonstrated that tumor size was a prognostic factor for solitary HCC with microvascular invasion (AJCC T2) but not solitary HCC without microvascular invasion (AJCC T1). Size, microvascular invasion, and cirrhosis are independent prognostic factors of RFS for solitary HCC after LR. Tumor size is an important prognostic factor in T2 but not T1 solitary tumors. These findings suggest that the current AJCC TNM staging system may need to be revised.

Outcomes and predictors of microvascular invasion of solitary hepatocellular carcinoma

Microvascular invasion (MVI) is an important risk factor for early recurrence of hepatocellular carcinoma (HCC), but preoperative prediction of MVI is difficult. A retrospective review was undertaken on 167 patients with primary solitary HCC who underwent initial hepatectomy. Independent predictors of MVI were identified, and factors affecting disease-free survival in patients with MVI were clarified. Of the 167 patients, 20 patients (12%) had MVI. Recurrence rates of HCC after hepatectomy in MVI patients were significantly worse than in patients without MVI (P < 0.0361). Univariate analysis revealed that positive L3-AFP, PIVKA-II ≥ 150 mAU/mL and tumor size ≥3 cm preoperatively were associated with positive MVI. On multivariate analysis, independent predictors of MVI were PIVKA-II ≥ 150 mAU/mL (odds ratio [OR], 5.19; 95% confidence interval [95% CI], 1.44-24.87; P = 0.0109) and positive L3-AFP (OR, 3.47; 95% CI, 1.19-10.75; P = 0.0229). Among the MVI-positive group, the 1-, 2- and 3-year disease-free survival rates were 78%, 58%, and 58% in patients with surgical margin (SM) ≥ 10 mm and 38%, 29%, and 29% in those with SM < 10 mm, respectively (P = 0.0263). Patients with PIVKA-II ≥ 150 mAU/mL and positive L3-AFP on preoperative examination are at high risk for MVI.

Risk factors of post‐operative recurrence and adequate surgical approach to improve long‐term outcomes of hepatocellular carcinoma

IntroductionA high recurrence rate of hepatocellular carcinoma (HCC) remains a significant concern. The risk factors for recurrence were analysed and the optimal surgical approaches were investigated. MethodsThe subjects comprised 280 consecutive patients with primary solitary HCC measuring ≤5 cm in diameter, who underwent curative resections. Multivariate analysis was conducted to identify the risk factors for post‐operative recurrence, and the clinical significance of an anatomic resection was evaluated. ResultsMultivariate analysis identified HCV infection, a des‐gamma‐carboxyprothrombin level >100 mAU/ml, underlying cirrhosis, the presence of microvascular invasion, the presence of micrometastases and non‐anatomic resection as being significant risk factors for post‐operative recurrence. The 5‐year recurrence rate was 56.7% in the anatomic resection (AR) group and 74.7% in the non‐AR group. The 5‐year survival rate was 82.2% in the AR group and 71.9% in the non‐AR group. Local recurrence within the same segment was observed in 25% of the patients of the non‐AR group. The prognostic superiority of AR was confirmed only in patients with histopathological evidence of microvascular invasion and/or micrometastases, and in patients having a solitary HCC measuring 2 to 5 cm in diameter. ConclusionsAnatomic resection may decrease local recurrence and improve the surgical outcomes in solitary HCC measuring 2 to 5 cm in diameter.

Predictors for Microinvasion of Small Hepatocellular Carcinoma ≤2 cm

Hepatocellular carcinoma (HCC) ≤ 2 cm in diameter is considered to have a low potential for malignancy. A retrospective review was undertaken of 149 patients with primary solitary HCC ≤ 2 cm who underwent initial hepatic resection between 1994 and 2010. The independent predictors of the microinvasion (MI) such as portal venous, hepatic vein, or bile duct infiltration and/or intrahepatic metastasis were identified by multivariate analysis. Prognosis of patients with HCC ≤ 2 cm accompanied by MI was compared to that of patients with HCC ≤ 2 cm without MI. Forty-three patients with HCC ≤ 2 cm had MI in patients (28.9%). Three independent predictors of the MI were revealed: invasive gross type (simple nodular type with extranodular growth or confluent multinodular type), des-γ-carboxy prothrombin (DCP) >100 mAU/ml, and poorly differentiated. Disease-free survival rates of patients with HCC ≤ 2 cm with MI (3 year 44%) were significantly worse than those for HCC ≤ 2 cm without MI (3 year 72%). This disadvantage of disease-free survival rate of patients with HCC ≤ 2 cm with MI could be dissolved by hepatic resection with a wide tumor margin of ≥ 5 mm (P = 0.04). Even in cases of HCC ≤ 2 cm, patients who are suspected of having invasive gross type tumors in preoperative imaging diagnosis or who have a high DCP level (>100 mAU/ml) are at risk for MI. Therefore, in such patients, hepatic resection with a wide tumor margin should be recommended.