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World J Gastrointest Surg. Apr 27, 2026; 18(4): 116412
Published online Apr 27, 2026. doi: 10.4240/wjgs.v18.i4.116412
Navigation value of intraoperative ultrasound combined with indocyanine green fluorescence in complex hepatocellular carcinoma resection
Sheng Zhang, Shao-Ying Li, Bing Zhou, Department of Hepatobiliary, Pancreatic and Splenic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
ORCID number: Bing Zhou (0009-0000-9033-0887).
Author contributions: Zhang S contributed to methodology, original draft preparation; Zhang S and Li SY contributed to data collection, and statistical analysis; Zhang S, Li SY, and Zhou B contributed to manuscript revision; Zhang S and Zhou B contributed to conceptualization; Li SY contributed to data curation; Zhou B contributed to supervision, data interpretation, and study oversight. All authors have read and approved the final version of the manuscript.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of Xinxiang Medical University (Approval No. EC-025-668).
Informed consent statement: This was a retrospective study. The requirement for written informed consent was waived by the Medical Ethics Committee of the First Affiliated Hospital of Xinxiang Medical University due to the retrospective nature of the study and the use of anonymized clinical data.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.
Corresponding author: Bing Zhou, Associate Chief Physician, Department of Hepatobiliary, Pancreatic and Splenic Surgery, The First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui 453100, Henan Province, China. zhoubing202511@163.com
Received: November 25, 2025
Revised: January 14, 2026
Accepted: February 12, 2026
Published online: April 27, 2026
Processing time: 149 Days and 18.9 Hours

Abstract
BACKGROUND

Primary hepatocellular carcinoma (HCC) is a common malignancy worldwide, with surgical resection being the most effective treatment for long-term survival. For complex HCC (large diameter, central location, multiple lesions, or proximity to major vessels), traditional surgery relying on surgeon experience and palpation has limitations including difficulty identifying deep lesions and high positive margin rates. Intraoperative ultrasound (IOUS) provides real-time hepatic structural visualization but has limited capability for isoechoic lesions, while indocyanine green (ICG) fluorescence imaging enables real-time tumor visualization but lacks deep anatomical information. Combined application may offer complementary advantages, yet systematic evaluation studies in complex HCC resection remain scarce.

AIM

To evaluate the clinical application value of IOUS combined with ICG fluorescence imaging technology in radical resection of complex HCC.

METHODS

Clinical data of 200 patients with complex HCC who underwent radical hepatectomy from January 2019 to August 2024 were retrospectively analyzed. Patients were divided into a combined navigation group (n = 103) and a conventional surgery group (n = 97) based on whether IOUS and ICG fluorescence imaging technology were used in combination. Intraoperative indicators, oncological indicators, postoperative recovery indicators, and long-term prognosis were compared between the two groups. Logistic regression analysis was used to analyze factors influencing postoperative complications, and Cox regression analysis was used to analyze factors influencing survival prognosis.

RESULTS

Baseline characteristics were balanced between the two groups. The combined navigation group had shorter tumor localization time (P < 0.001), less intraoperative blood loss (P = 0.004), lower intraoperative transfusion rate (P = 0.021), higher detection rate of occult lesions (23.3% vs 6.2%, P < 0.001), and higher anatomical resection rate (P = 0.040). The combined navigation group had lower positive margin rate (2.9% vs 13.4%, P = 0.006), higher R0 resection rate (97.1% vs 86.6%, P = 0.006), and greater margin distance (P < 0.001). The combined navigation group had lower overall postoperative complication rate (18.4% vs 28.9%, P = 0.042) and severe complication rate (5.8% vs 12.4%, P = 0.042), and shorter postoperative hospital stay (P = 0.003). With a median follow-up of 28.6 months, the combined navigation group had higher 2-year overall survival rate (76.8% vs 65.2%, P = 0.033) and 2-year disease-free survival rate (58.4% vs 45.7%, P = 0.022), and lower postoperative recurrence rate (36.9% vs 50.5%, P = 0.048). Multivariate analysis showed that application of combined navigation technology was an independent protective factor for postoperative complications (odds ratio = 0.498, P = 0.027), and was also an independent protective factor for overall survival (hazard ratio = 0.584, P = 0.028) and disease-free survival (hazard ratio = 0.631, P = 0.025).

CONCLUSION

IOUS combined with ICG fluorescence imaging technology can improve tumor localization accuracy in complex HCC surgery, improve margin control, reduce intraoperative blood loss, decrease the incidence of postoperative complications, and improve long-term survival prognosis in patients, demonstrating important clinical application value.

Key Words: Hepatocellular carcinoma; Complex hepatocellular carcinoma; Intraoperative ultrasound; Indocyanine green fluorescence imaging; Surgical navigation; Precision hepatectomy

Core Tip: This retrospective study evaluated 200 patients with complex hepatocellular carcinoma undergoing radical hepatectomy. Intraoperative ultrasound combined with indocyanine green fluorescence imaging significantly improved tumor localization, increased R0 resection and anatomical hepatectomy rates, reduced intraoperative blood loss and postoperative complications, and enhanced long-term survival compared with conventional surgery. The combined navigation approach provides real-time visualization and precise resection guidance, offering a safe, effective, and clinically valuable strategy for precision hepatectomy in complex hepatocellular carcinoma.



INTRODUCTION

Primary hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and surgical resection remains the most effective treatment for achieving long-term survival[1]. However, for complex HCC, including cases with large tumor diameter, central location, multiple lesions, or close proximity to important vascular structures, surgical difficulty is significantly increased, and accurate intraoperative localization of tumor boundaries, determination of resection range, and protection of important vascular structures become key to surgical success[2]. Traditional surgery mainly relies on the surgeon’s experience, intraoperative palpation, and hepatic surface anatomical landmarks for tumor localization, but there are obvious limitations in judging deep lesions, small lesions not shown on preoperative imaging, and the precise spatial relationship between tumors and vessels, which may lead to increased positive margin rates, missed occult lesions, and elevated postoperative recurrence rates[3]. Intraoperative ultrasound (IOUS) technology can display liver internal structures and vessel courses in real-time, significantly improving tumor localization accuracy, but its ability to identify isoechoic or small lesions is limited[4]. Indocyanine green (ICG) fluorescence imaging technology utilizes the selective uptake of ICG by hepatocytes and its retention characteristics in tumor tissue, and through near-infrared fluorescence imaging systems can display fluorescence signal differences between tumors and normal liver tissue in real-time, helping to identify tumor boundaries and occult lesions intraoperatively, and can mark the anatomical resection plane[5,6]. Recent studies suggest that IOUS and ICG fluorescence imaging technology have complementary advantages, with the former providing deep anatomical information and vascular relationships, and the latter achieving real-time fluorescence visualization of tumors, and combined application may further improve the precision and safety of complex HCC surgery[7]. However, there are still few systematic evaluation studies on the combined application of the two technologies in complex HCC resection, and their effects on surgical outcomes, oncological outcomes, and long-term prognosis need further verification[8]. Therefore, this study retrospectively analyzed clinical data of 200 patients with complex HCC to compare the therapeutic differences between IOUS combined with ICG fluorescence imaging technology and conventional surgical methods, aiming to evaluate the clinical application value of combined navigation technology in radical resection of complex HCC.

MATERIALS AND METHODS
General information

Clinical data of patients who underwent radical hepatectomy for HCC at our hospital from January 2019 to August 2024 were retrospectively analyzed. Patient allocation was based on patient/surgeon preference and equipment availability rather than temporal criteria. The conventional surgery group had cases distributed across the entire period (mean: 17.3 cases/year), and the combined navigation group also had cases throughout the period (mean: 18.4 cases/year), with a temporal overlap coefficient of 0.87, indicating substantial concurrency. All surgeries were performed by the same surgical team (three senior surgeons with > 15 years of hepatobiliary experience), and standardized perioperative care protocols were maintained throughout the study period to minimize temporal confounding. All patients underwent surgery by the same surgical team, with identical surgical indications and technical standards.

Inclusion criteria: (1) Preoperative imaging examination [enhanced computed tomography (CT) or magnetic resonance imaging (MRI)] confirmed diagnosis of primary HCC; (2) Met the definition of complex HCC: Tumor diameter ≥ 5 cm, or central location (according to Makuuchi classification, tumor located in Couinaud segments I, IV, V, VIII, or involving the first or second hepatic hilum region), or multiple lesions (≥ 3), or close to important vascular structures (main hepatic vein, main portal vein or first-order branches, inferior vena cava); (3) Liver function Child-Pugh grade A or B (7-9 points); (4) No surgical contraindications, with indications for hepatectomy; (5) For Child-Pugh A patients, preoperative ICG 15-minute retention rate (ICG-R15) < 30%; for Child-Pugh B patients, ICG-R15 < 20%; (6) Complete clinical data; and (7) Complete follow-up data, follow-up time ≥ 6 months or death during observation period (based on International Consensus Guidelines for HCC and Japanese Clinical Practice Guidelines).

Exclusion criteria: (1) Combined with extrahepatic metastasis; (2) History of previous liver surgery; (3) Received anti-tumor treatment such as transarterial chemoembolization, ablation therapy, or radiotherapy within 6 months before surgery; (4) Severe coagulation dysfunction [prothrombin time-international normalized ratio (PT-INR) > 1.5 or platelets < 50 × 109/L] or dysfunction of other important organs (cardiac function New York Heart Association class ≥ III, renal function serum creatinine > 177 μmol/L, severe pulmonary dysfunction); (5) Allergy to ICG or iodinated contrast agents; (6) Pregnant or lactating women; (7) Combined with other malignant tumors; and (8) Intraoperative exploration found unresectable.

Surgical methods

Equipment and standardization: All IOUS examinations used the Aloka ProSound Alpha 7 system (7.5 MHz probe), and ICG fluorescence imaging used the Stryker SPY Elite system. Equipment remained unchanged from January 2019 to August 2024, ensuring standardization. Combined navigation group protocol: All cases received comprehensive IOUS scanning of all 8 liver segments with tumor-vessel relationship mapping and occult lesion search (mean duration: 8.7 ± 2.3 minutes), plus ICG fluorescence imaging with preoperative ICG injection (0.5 mg/kg, 12-24 hours before surgery) and real-time fluorescence visualization during hepatic transection. Conventional surgery group protocol: This group relied on manual palpation, preoperative CT/MRI imaging, and visual inspection. IOUS was used selectively in only 23 of 97 cases (23.7%) for problem-solving scans (mean duration: 3.2 ± 1.1 minutes) when tumors were non-palpable, deep-seated, or location was uncertain. No ICG fluorescence imaging was used.

Detailed surgical protocols preoperative evaluation: Enhanced CT/MRI with three-dimensional reconstruction (Iqqa-Liver or MI-3DVS) to plan resection; liver function assessment including ICG-R15 and CT volumetry ensuring remnant liver volume > 40% (> 50% for cirrhosis). Combined navigation group received peripheral intravenous ICG (0.5 mg/kg, maximum 25 mg) 24 hours preoperatively. Surgical procedure: All surgeries performed by the same senior team (> 10 years’ experience). After laparotomy and exploration, the conventional group used palpation and preoperative imaging with selective IOUS assistance, determining resection range through anatomical landmarks and ischemic boundaries. The combined navigation group systematically: (1) Performed IOUS scanning of entire liver (right/Left lobes, hepatic hilum, IVC and hepatic veins) to confirm tumor characteristics and vessel relationships; (2) Used near-infrared fluorescence imaging (excitation 760 nm, emission 800-830 nm) to observe tumor development, record fluorescence differences (target-to-normal ratio), identify anatomical resection planes after vascular occlusion, and search for occult lesions (< 1 cm not on preoperative imaging); (3) Precisely planned resection with ≥ 1 cm margins, performed parenchymal dissection under fluorescence guidance with real-time adjustments, rechecking resection plane every 2-3 cm; and (4) Examined resection surface post-dissection to confirm no residual tumor, with frozen section for suspicious margins. Both groups used individualized Pringle maneuver (15-minute block, 5-minute release, cumulative < 120 minutes), ultrasonic scalpel/cavitron ultrasonic surgical aspirator for dissection, regional lymphadenectomy, and drainage placement.

Data collection

Baseline characteristics: Age, gender, body mass index (BMI); hepatitis B virus/hepatitis C virus infection, cirrhosis grade; Child-Pugh class, total bilirubin (TBIL), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), PT-INR, ICG-R15; tumor diameter/number/Location/vascular involvement, alpha-fetoprotein (AFP) level; CT/MRI volumetry; Eastern Cooperative Oncology Group score; comorbidities.

Intraoperative indicators: Operation time, blood loss, transfusion volume, hepatic hilar blocking time, tumor localization time; occult lesion detection (confirmed by pathology); surgical procedure adjustments; actual procedures performed.

Oncological indicators: Margin status (positive rate, distance: < 0.5 cm/0.5-1.0 cm/> 1.0 cm); R0 resection rate; anatomical resection rate; pathological features (diameter, number, type, differentiation); microvascular invasion (MVI) status (M0/M1/M2); capsule invasion, satellite nodules, peritumoral cirrhosis.

Postoperative recovery: Complications within 90 days (Clavien-Dindo classification): Bile leakage (International Study Group of Liver Surgery criteria), abdominal infection/hemorrhage, liver failure (“50-50” criteria), pleural effusion, pulmonary/wound infection, renal insufficiency, other events; liver function (TBIL, ALT, AST, albumin, PT-INR on day 1, day 3, day 5, and day 7); reoperation rate; 30-day/90-day mortality; hospital stay; time to ambulation/diet/drain removal.

Follow-up: Reexaminations every 2 months (year 1), 3 months (year 2), 6 months (thereafter) including liver function, AFP, enhanced CT/MRI. Follow-up until September 30, 2025 or death.

Recorded: Overall survival (OS), disease-free survival (DFS), recurrence (intrahepatic/extrahepatic sites and timing), 1-year and 2-year OS/DFS rates. Recurrence defined as new lesions with characteristic enhancement patterns confirmed by multi-disciplinary team/pathology.

Subgroup analyses: Subgroup comparison of conventional cases with IOUS (n = 23) vs without (n = 74); temporal analysis comparing early (2019-2021) vs late (2022-2024) periods.

Statistical analysis

SPSS version 26.0 and R version 4.2.0 used for analysis. Normality tested by Shapiro-Wilk, variance by Levene test. Continuous data: mean ± SD or median (interquartile range); t-test or Mann-Whitney U test for comparison. Categorical data: n (%); χ2 or Fisher’s exact test for comparison. Multivariate logistic regression for complication risk factors (backward elimination, P < 0.10 entry). Kaplan-Meier curves and log-rank test for survival; Cox regression for prognostic factors; receiver operating characteristic curve for predictive value. Two-sided tests, P < 0.05 significant.

RESULTS
Comparison of baseline characteristics

This study enrolled a total of 200 patients with complex HCC, including 103 cases in the combined navigation group and 97 cases in the conventional surgery group. There were no statistically significant differences between the two groups in age, gender, BMI, hepatitis B virus infection rate, hepatitis C virus infection rate, degree of cirrhosis, Child-Pugh grade, preoperative liver function indicators, tumor characteristics (tumor size, number, location, vascular involvement, AFP level), imaging evaluation indicators, Eastern Cooperative Oncology Group score, and comorbidities (P > 0.05; Table 1).

Table 1 Comparison of baseline characteristics between two groups, mean ± SD/n (%)/median (interquartile rage).
Indicator
Combined navigation group (n = 103)
Conventional surgery group (n = 97)
Statistic
P value
General demographic characteristics
    Age (years)54.3 ± 10.755.8 ± 11.2t = 0.9780.329
    Gender (male)86 (83.5)79 (81.4)χ2 = 0.1680.682
    BMI (kg/m2)23.8 ± 3.224.1 ± 3.4t = 0.6540.514
Underlying liver disease
    HBV infection89 (86.4)82 (84.5)χ2 = 0.1560.693
    HCV infection8 (7.8)9 (9.3)χ2 = 0.1560.693
Cirrhosisχ2 = 0.8240.662
    No cirrhosis28 (27.2)24 (24.7)
    Mild cirrhosis51 (49.5)51 (52.6)
    Moderate to severe cirrhosis24 (23.3)22 (22.7)
Preoperative liver function indicators
    Child-Pugh A91 (88.3)87 (89.7)χ2 = 0.0920.762
    TBIL (μmol/L)16.8 ± 6.317.2 ± 6.8t = 0.4310.667
    ALB (g/L)41.2 ± 4.640.8 ± 4.9t = 0.6010.548
    ALT (U/L)42 (28-68)45 (30-71)Z = 0.7210.471
    AST (U/L)38 (26-59)40 (28-62)Z = 0.6830.495
    PT-INR1.08 ± 0.121.09 ± 0.13t = 0.5670.571
    ICG-R15 (%)12.4 ± 5.812.9 ± 6.1t = 0.6030.547
Tumor characteristics
    Maximum tumor diameter (cm)7.8 ± 3.27.6 ± 3.4t = 0.4310.667
Tumor numberχ2 = 0.4120.814
    Single67 (65.0)66 (68.0)
    2 lesions24 (23.3)21 (21.6)
    ≥ 3 lesions12 (11.7)10 (10.3)
Central tumor58 (56.3)52 (53.6)χ2 = 0.1470.701
Large vessel involvement47 (45.6)42 (43.3)χ2 = 0.1090.741
AFP > 400 ng/mL52 (50.5)46 (47.4)χ2 = 0.1910.662
Imaging evaluation
Tumor volume (cm3)286 (145-512)273 (138-498)Z = 0.5120.609
Estimated resection liver volume (cm3)618 (425-856)602 (410-841)Z = 0.6210.535
Residual liver volume percentage (%)58.3 ± 12.457.6 ± 13.1t = 0.3940.694
ECOG scoreχ2 = 0.2860.867
    0 points64 (62.1)62 (63.9)
    1 point32 (31.1)28 (28.9)
    2 points7 (6.8)7 (7.2)
Comorbidities
    Hypertension31 (30.1)27 (27.8)χ2 = 0.1270.722
    Diabetes18 (17.5)15 (15.5)χ2 = 0.1470.701
    Cardiovascular and cerebrovascular disease12 (11.7)10 (10.3)χ2 = 0.0930.761
Comparison of intraoperative indicators

The combined navigation group had significantly shorter tumor localization time (P < 0.001) but longer operation time (P = 0.012) than the conventional surgery group. The navigation group demonstrated less intraoperative blood loss (P = 0.004) and lower transfusion rate (P = 0.021). Hepatic hilar blocking time showed no significant difference between groups (P = 0.156). The navigation group achieved higher rates of occult lesion detection (P < 0.001, referring to additional lesions detected immediately intraoperatively and confirmed by pathology, excluding lesions < 5 mm found only on postoperative pathology), surgical procedure adjustment (P = 0.007), and anatomical resection (P = 0.040; Table 2).

Table 2 Comparison of intraoperative indicators between two groups, mean ± SD/n (%)/median (interquartile rage).
Indicator
Combined navigation group (n = 103)
Conventional surgery group (n = 97)
Statistic
P value
Operation time (minutes)298.5 ± 68.3276.2 ± 71.6t = 2.2550.012
Intraoperative blood loss (mL) 420 (280-680)550 (350-850)Z = 2.8910.004
Intraoperative transfusion28 (27.2)41 (42.3)χ2 = 5.3430.021
Red blood cell units (U)14 (2-6)4 (2-8)Z = 1.2340.217
Plasma volume (mL)1200 (100-400)300 (150-450)Z = 1.1560.248
Hepatic hilar blocking time (minutes)48 (28-72)54 (32-78)Z = 1.4210.156
Tumor localization time (minutes)12.6 ± 4.318.9 ± 6.7t = 7.831< 0.001
Intraoperative detection of occult lesions224 (23.3)6 (6.2)χ2 = 12.358< 0.001
Number of lesions detected31 (1-2)1 (1-1.5)Z = 1.1560.248
Surgical procedure adjustment31 (30.1)14 (14.4)χ2 = 7.2960.007
Surgical procedureχ2 = 7.891/Fisher0.048
    Hemi-hepatectomy42 (40.8)35 (36.1)
    Extended hemi-hepatectomy18 (17.5)22 (22.7)
    Segmentectomy38 (36.9)28 (28.9)
    Local resection5 (4.9)12 (12.4)
    Anatomical resection98 (95.1)85 (87.6)χ2 = 4.2180.04

The increased operative time (median 15 minutes) is attributed to comprehensive IOUS scanning (approximately 8-10 minutes) and ICG fluorescence imaging (approximately 5-7 minutes). This represents a justified trade-off given significant benefit: 3.6-fold higher occult lesion detection, 10.5% increase in R0 resection rate, and 10.5% reduction in complications. Learning curve analysis showed operative time decreased from 245 ± 48 minutes to 225 ± 42 minutes (P = 0.021) between early (2019-2021) and late (2022-2024) phases while maintaining outcomes, indicating the time overhead diminishes with experience.

Comparison of oncological indicators

The combined navigation group demonstrated lower positive margin rate (P = 0.006), higher R0 resection rate (P = 0.006), and greater margin distance (P < 0.001) compared to the conventional surgery group. No significant differences were observed in postoperative pathological features including maximum tumor diameter, final tumor number, pathological type, differentiation degree, MVI grade, liver capsule invasion, or satellite nodules (all P > 0.05).

Postoperative final tumor number was defined as: Preoperative imaging lesions + intraoperative occult lesions (≥ 5 mm) + small lesions found only on pathology (< 5 mm). In the navigation group, 24 cases (23.3%) had occult lesions detected intraoperatively with 0 additional small lesions on pathology. In the conventional group, 6 cases (6.2%) had intraoperative occult lesion detection while 12 cases had small lesions found only on pathology, totaling 18 cases (18.6%) exceeding preoperative imaging. Although the navigation group had higher intraoperative occult lesion detection (23.3% vs 6.2%, P < 0.001), the proportion with final tumor numbers exceeding preoperative imaging showed no significant difference (P = 0.365), indicating the main advantage lies in immediate intraoperative detection of larger occult lesions (≥ 5 mm; Table 3).

Table 3 Comparison of oncological indicators between two groups, mean ± SD/n (%)/median (interquartile rage).
Indicator
Combined navigation group (n = 103)
Conventional surgery group (n = 97)
Statistic
P value
Positive margin3 (2.9)13 (13.4)χ2 = 7.6210.006
Margin distance (cm)1.2 (0.8-1.8)0.8 (0.5-1.3)Z = 3.912< 0.001
Margin distance grouping1χ2 = 14.3280.001
    < 0.5 cm8 (7.8)22 (22.7)
    0.5-1.0 cm32 (31.1)35 (36.1)
    > 1.0 cm63 (61.2)40 (41.2)
R0 resection100 (97.1)84 (86.6)χ2 = 7.6210.006
Pathological features
Maximum tumor diameter (cm)7.9 ± 3.37.7 ± 3.5t = 0.4210.674
Postoperative final confirmed total tumor number2χ2 = 0.8210.365
Consistent with preoperative imaging79 (76.7)79 (81.4)
More than preoperative imaging24 (23.3)18 (18.6)
Among which: Detected immediately intraoperatively (≥ 5 mm)24 (23.3)6 (6.2)
Found on postoperative pathology (< 5 mm)0 (0)12 (12.4)
Pathological typeFisher0.782
    Hepatocellular carcinoma98 (95.1)93 (95.9)
    Cholangiocarcinoma3 (2.9)2 (2.1)
    Mixed type2 (1.9)2 (2.1)
Differentiation degreeχ2 = 1.2340.745
    Well-differentiated21 (20.4)18 (18.6)
    Moderately differentiated56 (54.4)54 (55.7)
    Poorly differentiated23 (22.3)22 (22.7)
    Undifferentiated3 (2.9)3 (3.1)
MVI gradeχ2 = 0.6210.733
    M048 (46.6)42 (43.3)
    M138 (36.9)38 (39.2)
    M217 (16.5)17 (17.5)
Liver capsule invasion42 (40.8)37 (38.1)χ2 = 0.1490.7
Satellite nodules28 (27.2)24 (24.7)χ2 = 0.1560.693
Intact tumor capsule67 (65.0)61 (62.9)χ2 = 0.1010.751
Comparison of postoperative recovery indicators

The combined navigation group had lower overall complication rate than the conventional surgery group (18.4% vs 28.9%, P = 0.042). The incidence of Clavien-Dindo grade III-V complications was also lower (P = 0.042), though overall grade distribution showed no significant difference (P = 0.078). Multiple complications occurred in some patients: 19 patients with 26 episodes in the navigation group vs 28 patients with 46 episodes in the conventional group.

Bile leakage incidence was significantly lower in the navigation group (P = 0.041), while other specific complications showed no differences (P > 0.05). Postoperative liver function recovered faster in the navigation group, with lower TBIL, ALT, and AST levels on day 3 and day 5 (P < 0.05). The navigation group had shorter hospital stays (P = 0.003). Reoperation rates (1.9% vs 6.2%, P = 0.104) and 30-day/90-day mortality rates showed no significant differences between groups (P > 0.05; Tables 4 and 5).

Table 4 Comparison of postoperative complications between two groups, n (%).
Indicator
Combined navigation group (n = 103)
Conventional surgery group (n = 97)
Statistic
P value
Overall complications19 (18.4)28 (28.9)χ2 = 4.1230.042
Clavien-Dindo grade1χ2 = 6.8210.078
    Grade I-II13 (12.6)16 (16.5)
    Grade III4 (3.9)9 (9.3)
    Grade IV2 (1.9)2 (2.1)
    Grade V0 (0)1 (1.0)
Grade III-V complications 6 (5.8)12 (12.4)χ2 = 4.1280.042
Total complication episodes2646
Specific complication types (counted by episodes)
Bile leakage5 (4.9)10 (10.3)χ2 = 4.1780.041
    Grade A3 (2.9)5 (5.2)
    Grade B1 (1.0)4 (4.1)
    Grade C1 (1.0)1 (1.0)
Abdominal infection4 (3.9)6 (6.2)χ2 = 0.6280.428
Abdominal hemorrhage2 (1.9)5 (5.2)Fisher0.133
Liver failure1 (1.0)3 (3.1)Fisher0.354
Pleural effusion6 (5.8)8 (8.2)χ2 = 0.5210.47
Pulmonary infection4 (3.9)6 (6.2)χ2 = 0.6280.428
Wound infection2 (1.9)4 (4.1)Fisher0.428
Renal insufficiency1 (1.0)2 (2.1)Fisher0.607
Other complications1 (1.0)2 (2.1)Fisher0.607
Postoperative reoperation 2 (1.9)6 (6.2)Fisher0.104
30-day postoperative mortality0 (0)1 (1.0)Fisher0.485
90-day postoperative mortality1 (1.0)3 (3.1)Fisher0.354
Table 5 Comparison of postoperative liver function indicators and recovery indicators between two groups, mean ± SD/n (%)/median (interquartile rage).
Indicator
Combined navigation group (n = 103)
Conventional surgery group (n = 97)
Statistic
P value
Postoperative day 1
    TBIL (μmol/L)28.6 ± 12.431.2 ± 14.8t = 1.3420.181
    ALT (U/L)286 (198-412)312 (218-445)Z = 1.5230.128
    AST (U/L)268 (182-385)295 (201-421)Z = 1.6120.107
    ALB (g/L)35.8 ± 4.235.2 ± 4.6t = 0.9620.337
    PT-INR1.28 ± 0.181.32 ± 0.21t = 1.4560.147
Postoperative day 3
    TBIL (μmol/L)32.4 ± 14.638.7 ± 17.2t = 2.7810.006
    ALT (U/L)156 (98-238)198 (128-285)Z = 2.6340.008
    AST (U/L)142 (88-215)178 (112-256)Z = 2.5120.012
    ALB (g/L)34.6 ± 4.133.8 ± 4.5t = 1.3210.188
    PT-INR1.24 ± 0.161.29 ± 0.19t = 2.0120.045
Postoperative day 5
    TBIL (μmol/L)28.3 ± 12.834.6 ± 15.4t = 3.1120.002
    ALT (U/L)98 (62-148)128 (82-186)Z = 2.8910.004
    AST (U/L)86 (54-132)112 (72-165)Z = 2.7340.006
    ALB (g/L)35.2 ± 4.334.6 ± 4.6t = 0.9620.337
    PT-INR1.18 ± 0.141.23 ± 0.17t = 2.2340.027
Postoperative day 7
    TBIL (μmol/L)22.4 ± 9.626.8 ± 12.3t = 2.8120.005
    ALT (U/L)68 (45-102)82 (56-125)Z = 2.1230.034
    AST (U/L)58 (38-88)72 (48-108)Z = 2.2340.026
    ALB (g/L)36.4 ± 4.235.8 ± 4.5t = 0.9810.328
    PT-INR1.12 ± 0.121.16 ± 0.14t = 2.1560.032
Postoperative recovery indicators
    Postoperative hospital stays (days)12 (9-16)15 (11-20)Z = 3.0120.003
    Time to first ambulation (days)2 (1-3)2 (2-3)Z = 1.8230.068
    Time to first liquid diet (days)2 (2-3)3 (2-4)Z = 2.2340.026
    Time to drainage tube removal (days)5 (4-7)6 (5-9)Z = 2.5670.01
Analysis of factors influencing postoperative complications

To identify independent factors influencing postoperative complications, univariate analysis was first performed, and variables with P < 0.10 were included in multivariate Logistic regression model. Variables included were age, BMI, Child-Pugh grade, degree of cirrhosis, tumor diameter, tumor number, central tumor, intraoperative blood loss, operation time, application of combined navigation technology, etc. Backward method was used for variable screening, with P < 0.05 as the variable retention standard. Multivariate Logistic regression analysis showed that intraoperative blood loss ≥ 600 mL [odds ratio (OR) = 2.856, 95% confidence interval (CI): 1.423-5.732, P = 0.003], operation time ≥ 300 minutes (OR = 2.134, 95%CI: 1.087-4.189, P = 0.028), and moderate to severe cirrhosis (OR = 2.687, 95%CI: 1.298-5.563, P = 0.008) were independent risk factors for postoperative complications, and application of combined navigation technology (OR = 0.498, 95%CI: 0.268-0.925, P = 0.027) was an independent protective factor for postoperative complications (Table 6).

Table 6 Multivariate logistic regression analysis of factors influencing postoperative complications.
Factor
β
SE
Wald χ2
OR
95%CI
P value
Combined navigation technology-0.6970.3184.8120.4980.268-0.9250.027
Intraoperative blood loss ≥ 600 mL1.0490.3568.6892.8561.423-5.7320.003
Operation time ≥ 300 minutes0.7580.3454.8262.1341.087-4.1890.028
Moderate to severe cirrhosis0.9880.3717.0982.6871.298-5.5630.008
Follow-up results

Median follow-up time was 28.6 months (range 6-68 months). Kaplan-Meier survival analysis included all 200 patients, with log-rank test comparing entire survival curves between groups. For OS, the combined navigation group achieved 1-year and 2-year rates of 89.3% and 76.8% respectively, compared to 81.4% and 65.2% in the conventional surgery group, with significantly different survival curves (log-rank χ2 = 4.521, P = 0.033). For DFS, the navigation group achieved 1-year and 2-year rates of 72.8% and 58.4% vs 61.9% and 45.7% in the conventional group, also showing significantly different curves (log-rank χ2 = 5.234, P = 0.022). The navigation group demonstrated lower postoperative recurrence rate (P = 0.048) and marginally lower intrahepatic recurrence rate (P = 0.050), while extrahepatic metastasis rates showed no significant difference (P = 0.431; Table 7).

Table 7 Comparison of follow-up results between two groups, n (%)/median (interquartile rage).
Indicator
Combined navigation group (n = 103)
Conventional surgery group (n = 97)
Statistic
P value
Median follow-up time (months)29.5 (18-42)27.8 (16-40)Z = 0.8230.411
1-year overall survival rate (%)89.381.4
2-year overall survival rate (%)76.865.2
Overall survival curve comparison1Log-rank χ2 = 4.5210.033
1-year disease-free survival rate (%)72.861.9
2-year disease-free survival rate (%)58.445.7
Disease-free survival curve comparison1Log-rank χ2 = 5.2340.022
Postoperative recurrence38 (36.9)49 (50.5)χ2 = 3.9210.048
Recurrence time (months)16.8 (10.2-24.5)13.5 (8.6-20.3)Z = 2.0120.044
Recurrence site classification
    Intrahepatic recurrence only26 (25.2)34 (35.1)χ2 = 2.5120.113
    Single18 (17.5)19 (19.6)
    Multiple8 (7.8)15 (15.5)
Extrahepatic metastasis only6 (5.8)6 (6.2)χ2 = 0.0120.913
Lung metastasis4 (3.9)4 (4.1)
Bone metastasis1 (1.0)1 (1.0)
Peritoneal metastasis1 (1.0)1 (1.0)
Intrahepatic + extrahepatic metastasis6 (5.8)9 (9.3)χ2 = 0.9210.337
Total intrahepatic recurrence232 (31.1)43 (44.3)χ2 = 3.8470.05
Total extrahepatic metastasis212 (11.7)15 (15.5)χ2 = 0.6210.431
Survival analysis

Univariate and multivariate Cox regression analyses identified independent prognostic factors for OS and DFS. Variables with P < 0.10 in univariate analysis were included in multivariate models using backward elimination (P < 0.05 retention).

For OS, independent protective factors were combined navigation technology [hazard ratio (HR) = 0.584, 95%CI: 0.362-0.942, P = 0.028] and R0 resection (HR = 0.412, 95%CI: 0.248-0.684, P < 0.001); independent risk factors were tumor diameter ≥ 8 cm (HR = 1.876, 95%CI: 1.165-3.022, P = 0.010), MVI M2 grade (HR = 2.234, 95%CI: 1.324-3.769, P = 0.003), and AFP > 400 ng/mL (HR = 1.698, 95%CI: 1.056-2.731, P = 0.029; Figure 1A; Table 8).

Figure 1
Figure 1 Kaplan-Meier curves. The blue curve represents the combined navigation group (n = 103), and the purple curve represents the conventional surgery group (n = 97). The X-axis represents follow-up time (months), and the Y-axis represents disease-free survival (%). A: Comparing overall survival between the two groups. Shaded areas indicate 95% confidence intervals. Log-rank test demonstrated a statistically significant difference in overall survival curves between groups (χ2 = 4.521, P = 0.033). The 1-year and 2-year overall survival rates were 893% and 76.8% in the combined navigation group vs 81.4% and 65.2% in the conventional surgery group, respectively; B: Comparing disease-free survival between the two groups. Shaded areas indicate 95% confidence intervals. Log-rank test demonstrated a statistically significant difference in disease-free survival curves between groups (χ2 = 5.234, P = 0.022). The 1-year and 2-year disease-free survival rates were 728% and 58.4% in the combined navigation group vs 61.9% and 45.7% in the conventional surgery group, respectively.
Table 8 Cox multivariate regression analysis of factors influencing overall survival.
Factor
β
SE
Wald χ2
HR
95%CI
P value
Combined navigation technology-0.5380.2454.8210.5840.362-0.9420.028
R0 resection-0.8860.26111.5230.4120.248-0.684< 0.001
Tumor diameter ≥ 8 cm0.6290.2436.6981.8761.165-3.0220.01
MVI M2 grade0.8040.2688.9892.2341.324-3.7690.003
AFP > 400 ng/mL0.5290.2424.7811.6981.056-2.7310.029

For DFS, independent protective factors were combined navigation technology (HR = 0.631, 95%CI: 0.421-0.945, P = 0.025), R0 resection (HR = 0.468, 95%CI: 0.306-0.715, P < 0.001), and margin distance > 1.0 cm (HR = 0.598, 95%CI: 0.389-0.919, P = 0.019); independent risk factors were tumor number ≥ 3 (HR = 2.156, 95%CI: 1.234-3.767, P = 0.007), MVI M2 grade (HR = 2.487, 95%CI: 1.568-3.945, P < 0.001), and central tumor (HR = 1.623, 95%CI: 1.078-2.443, P = 0.020; Figure 1B; Table 9).

Table 9 Cox multivariate regression analysis of factors influencing disease-free survival.
Factor
β
SE
Wald χ2
HR
95%CI
P value
Combined navigation technology-0.4610.2074.9610.6310.421-0.9450.025
R0 resection-0.7590.21812.1230.4680.306-0.715< 0.001
Margin distance > 1.0 cm-0.5140.225.4610.5980.389-0.9190.019
Tumor number ≥ 30.7680.2857.2672.1561.234-3.7670.007
MVI M2 grade0.9110.23515.0212.4871.568-3.945< 0.001
Central tumor0.4850.2085.4361.6231.078-2.4430.02
DISCUSSION

This study systematically evaluated the navigation value of IOUS combined with ICG fluorescence imaging technology in complex HCC resection through retrospective analysis of clinical data from 200 patients with complex HCC. The results showed that combined navigation technology demonstrated significant advantages in tumor localization, margin control, intraoperative blood loss, postoperative complications, and long-term prognosis, providing important technical support for precision surgical treatment of complex HCC.

This study found that the tumor localization time in the combined navigation group was significantly shorter than the conventional surgery group (12.6 minutes vs 18.9 minutes, P < 0.001), which is consistent with previous research results[9]. IOUS can display liver deep structures and vessel courses in real-time, while ICG fluorescence imaging can intuitively display tumor boundaries through fluorescence signal differences, and the combined application of the two technologies achieves complementary advantages, significantly improving the efficiency and accuracy of tumor localization[10]. However, the operation time in the combined navigation group was slightly longer than the conventional surgery group (298.5 minutes vs 276.2 minutes, P = 0.012), which may be related to the need for IOUS scanning and fluorescence imaging examination, but the increased time is within clinically acceptable range, and this time investment resulted in more precise tumor resection[11].

The intraoperative detection of occult lesions is one of the important findings of this study. The rate of immediate intraoperative detection of occult lesions in the combined navigation group was significantly higher than the conventional surgery group (23.3% vs 6.2%, P < 0.001). Studies have shown that approximately 15%-25% of HCC patients have small lesions not shown on preoperative imaging, and these occult lesions are an important cause of early postoperative recurrence[12]. ICG fluorescence imaging technology utilizes the retention characteristics of tumor tissue for ICG and can identify lesions with diameter greater than 5 mm, significantly improving intraoperative detection rate[13]. It is worth noting that in this study, 12 cases of small lesions (diameter < 5 mm) were found on postoperative pathological examination in the conventional surgery group, while no such lesions were found in the combined navigation group, which may be related to the combined navigation group expanding resection range due to finding occult lesions intraoperatively, but it also suggests that current technology still has limitations in detecting extremely small lesions[14].

In terms of oncological outcomes, the positive margin rate in the combined navigation group was significantly lower than the conventional surgery group (2.9% vs 13.4%, P = 0.006), R0 resection rate was higher (97.1% vs 86.6%, P = 0.006), and margin distance was greater (median 1.2 cm vs 0.8 cm, P < 0.001). Adequate margin distance is a key factor affecting postoperative recurrence and long-term survival of HCC, and multiple studies have shown that margin distance > 1.0 cm can significantly reduce recurrence risk[15,16]. In this study, 61.2% of patients in the combined navigation group had margin distance > 1.0 cm, while only 41.2% in the conventional surgery group, and this difference partly stems from the ability of combined navigation technology to display tumor boundaries in real-time, guiding surgeons to expand margin distance as much as possible while ensuring complete tumor resection[17]. In addition, the anatomical resection rate in the combined navigation group was higher than the conventional surgery group (95.1% vs 87.6%, P = 0.040), which is closely related to the characteristic of ICG fluorescence imaging being able to precisely mark the anatomical resection plane by observing fluorescence disappearance interface after blocking target hepatic segment blood flow[18].

Control of intraoperative blood loss is an important challenge in complex HCC surgery. This study showed that intraoperative blood loss in the combined navigation group was significantly less than the conventional surgery group (median 420 mL vs 550 mL, P = 0.004), and transfusion rate was also significantly lower (27.2% vs 42.3%, P = 0.021). This result can be attributed to multiple factors: First, IOUS can clearly display vessel courses, avoiding injury to important vessels; second, ICG fluorescence imaging can monitor resection plane in real-time, reducing bleeding caused by blind dissection; third, precise anatomical resection reduces the risk of unplanned vascular injury[19,20]. Reducing intraoperative blood loss not only decreases transfusion requirements but may also improve patient prognosis by reducing immunosuppression and inflammatory response[21].

In terms of postoperative complications, the overall complication rate in the combined navigation group (18.4% vs 28.9%, P = 0.042) and severe complication rate (Clavien-Dindo grade III-V: 5.8% vs 12.4%, P = 0.042) were significantly lower than the conventional surgery group. Multivariate logistic regression analysis confirmed that application of combined navigation technology is an independent protective factor for postoperative complications (OR = 0.498, P = 0.027). Specifically, the incidence of bile leakage in the combined navigation group was lower (4.9% vs 10.3%, P = 0.041), which may be related to precise anatomical resection reducing bile duct injury[22]. In addition, postoperative liver function indicators in the combined navigation group recovered faster, with TBIL, ALT, and AST levels on postoperative day 3, day 5, and day 7 significantly lower than the conventional surgery group, suggesting that combined navigation technology promoted early recovery of liver function by reducing unnecessary liver tissue damage[23]. Postoperative hospital stay in the combined navigation group was also significantly shortened (median 12 days vs 15 days, P = 0.003), which not only reflects improvement in patient recovery quality but also has important health economics significance[24].

Long-term prognosis analysis showed that the combined navigation group was superior to the conventional surgery group in both OS and DFS. The 2-year OS rate in the combined navigation group was 76.8%, significantly higher than 65.2% in the conventional surgery group (log-rank P = 0.033); the 2-year DFS rate was 58.4%, also higher than 45.7% in the conventional surgery group (log-rank P = 0.022). Cox multivariate regression analysis confirmed that application of combined navigation technology is an independent protective factor for OS (HR = 0.584, P = 0.028) and DFS (HR = 0.631, P = 0.025). This result is consistent with domestic and international multicenter research reports[25,26]. The mechanism by which combined navigation technology improves prognosis may be multifaceted: First, higher R0 resection rate and greater margin distance directly reduce local recurrence risk; second, finding and treating occult lesions intraoperatively reduces the possibility of residual tumor; third, reducing intraoperative blood loss and postoperative complications may indirectly improve prognosis by reducing immunosuppression and inflammatory response[27]. This study also found that the intrahepatic recurrence rate in the combined navigation group showed a marginally significant trend lower than the conventional surgery group (31.1% vs 44.3%, P = 0.050), while there was no significant difference in extrahepatic metastasis rate between the two groups, suggesting that combined navigation technology mainly reduces recurrence risk by improving local control.

This study has certain clinical significance. For patients with complex HCC, especially cases with tumors located in central regions, multiple lesions, or close to important vascular structures, IOUS combined with ICG fluorescence imaging technology provides a safe and effective surgical navigation method that can significantly improve tumor localization accuracy, improve margin quality, reduce intraoperative blood loss and postoperative complication incidence, and ultimately improve patients’ long-term prognosis. The combined application of these technologies embodies the concept of precision hepatobiliary surgery and is worthy of promotion in clinical practice.

This study has several important limitations that warrant critical consideration. First, the retrospective design introduces potential selection bias, as technology adoption was gradual and early cases in the navigation group may have been selected for greater complexity. However, our comprehensive baseline matching and multivariate adjustments help mitigate these concerns. Second, as a single-center study from a specialized hepatobiliary center, our results may not be directly generalizable to community hospitals with different resources and experience levels; external validation through multicenter prospective trials is needed. Third, regarding economic considerations, while navigation equipment requires substantial initial investment and per-care costs, potential reductions in complications, reoperations, and recurrence may justify these expenses, though formal cost-effectiveness analysis is needed, particularly for resource-limited settings[28].

CONCLUSION

In conclusion, IOUS combined with ICG fluorescence imaging technology has important navigation value in complex HCC resection, can improve tumor localization accuracy, improve margin control, reduce intraoperative blood loss, decrease postoperative complication incidence, and significantly improve patients’ long-term survival. This combined navigation strategy provides effective technical support for precision surgical treatment of complex HCC and has good clinical application prospects. In the future, multicenter prospective randomized controlled trials need to be conducted to further verify the clinical value of combined navigation technology and explore its optimal application strategies in different HCC subtypes.

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Footnotes

Peer review: Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country of origin: China

Peer-review report’s classification

Scientific quality: Grade B, Grade C

Novelty: Grade C, Grade C

Creativity or innovation: Grade B, Grade C

Scientific significance: Grade C, Grade C

P-Reviewer: Granieri S, MD, Italy; Lo Tesoriere R, PhD, Italy S-Editor: Zuo Q L-Editor: A P-Editor: Wang CH