Stress response, complications, and postoperative recovery in patients with hepatocellular carcinoma and comorbid anxiety/depression undergoing ultrasound-guided intervention

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is a common and frequently encountered malignancy in clinical practice. Patients who lack understanding of the disease and surgical treatment are prone to fear, depression, and other negative emotions, which further aggravate psychological stress. As such, less stimulating and minimally invasive surgical modalities, such as ultrasound-guided interventions, should be adopted to alleviate or eliminate negative perioperative psychological states, which can be evaluated using validated tools such as the Hamilton Anxiety Scale (HAM-A) and Hamilton Depression Scale (HAM-D).

AIM

To investigate the impact of ultrasound-guided surgery on stress, complications, and recovery in patients with HCC and comorbid anxiety/depression.

METHODS

Ninety patients with primary small HCC and comorbid anxiety/depression were randomly divided into 2 groups according to treatment (n = 45 each): Experimental (ultrasound-guided intervention); and control (conventional laparoscopic hepatectomy). The HAM-A and HAM-D were used to assess psychological states before and 1 week after surgery. C-reactive protein (CRP), vascular endothelial growth factor (VEGF), and superoxide dismutase (SOD) levels, in addition to specific liver-function indicators, complication rates, and postoperative metrics were measured. Recurrence rates were monitored for 6 months.

RESULTS

There were no significant differences in preoperative HAM-A and HAM-D scores between the 2 groups (P > 0.05); however, scores in the study group were significantly lower postoperatively (P < 0.05). On postoperative day 1, there were no significant differences in serum levels of CRP, VEGF, or SOD between the groups (P > 0.05), whereas the levels in the intervention group were significantly lower than those in the control group on days 3 and 7 (P < 0.05). The incidence of postoperative complications in the study group (6.66%) was significantly lower than that in the control group [17.78% (P < 0.05)]. The study group also had a significantly shorter time to first flatus, oral intake, and postoperative hospital stay (P < 0.05). Postoperative serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels decreased in both groups compared with preoperative levels, although with significantly lower values in the study group (P < 0.05) but no differences preoperatively (P > 0.05). There was no statistical difference in tumor recurrence rates between the 2 groups during the six-month follow-up (P > 0.05).

CONCLUSION

Ultrasound-guided intervention for patients with primary small HCC and anxiety/depression effectively improves negative emotional states, reduce stress responses, decreases postoperative complications, promotes recovery, and enhances quality of life.

Key Words: Ultrasound-guided interventional surgery; Primary small hepatocellular carcinoma; Anxiety; Depression; Stress response; Postoperative recovery

Core Tip: Compared with conventional laparoscopic hepatectomy, ultrasound-guided interventional surgery for small hepatocellular carcinoma effectively improved negative emotions (according to the Hamilton Depression and Anxiety Scales), reduced stress-response markers (e.g., C-reactive protein and vascular endothelial growth factor), decreased complication rates, promoted postoperative recovery, and enhanced quality of life.

INTRODUCTION

Hepatocellular carcinoma (HCC) is a common and frequently encountered malignant tumor in clinical practice. It ranks third among the causes of cancer-related death in China and poses a serious threat to patient health and life safety[1]. Currently, radical surgery is the primary clinical treatment method that plays a positive role in improving prognosis and prolonging survival. However, surgery often induces varying degrees of anxiety, which is a major source of traumatic stress. Additionally, due to a lack of correct understanding of the disease and surgical procedure, patients are prone to fear, depression, and other negative emotions, which further aggravate psychological stress. The more severe the negative emotions, the less favorable the clinical treatment and postoperative recovery[2,3]. As such, for patients diagnosed with HCC and preoperative anxiety/depression, less stimulating and minimally invasive surgical methods should be adopted to alleviate or eliminate negative perioperative psychological states. In recent years, ultrasound-guided interventional surgery has been widely used in the treatment of primary small HCC due to its minimally invasive nature, low pain, high safety, repeatability, and favorable efficacy. Common surgical techniques include ultrasound-guided radiofrequency ablation (RFA), microwave ablation, and high-intensity focused ultrasound, all of which can accurately deliver energy to the tumor region to destroy the tumor tissues[4]. Accordingly, this controlled clinical trial aimed to analyze and evaluate the impact of ultrasound-guided interventional surgery on stress response, complications, and postoperative recovery in patients diagnosed with primary small HCC and comorbid anxiety and depression.

MATERIALS AND METHODS

General data

Data from 90 patients diagnosed with primary small HCC and comorbid anxiety/depression, who were admitted to the authors’ hospital between August 2021 and August 2024, were included in this study. The present study was approved by the ethics committee of the authors’ hospital.

Inclusion/exclusion criteria

The inclusion criteria were as follows: (1) Diagnosed with primary HCC through imaging and pathological examination, fulfilling the diagnostic criteria for primary HCC[5]; (2) Preoperative examination and assessment confirmed the presence of mild anxiety and depression; (3) Age > 18 years; maximum tumor diameter < 5 cm and number of tumors < 3, attaining the indications for curative surgery or ultrasound-guided interventional therapy; (4) Child-Turcotte liver function classification A or B, American Society of Anaesthesiologists grade I-II; and (5) Patients and their families were informed and consented to participate in the study. The exclusion criteria were as follows: (1) Recent use of antipsychotic drugs; severe organic diseases of the heart, brain, or immune system; and (2) Distant metastases already present.

Patients were randomly divided into 2 groups using a random numbers table: Study group [n = 45; 24 male, 21 female; 26-64 years of age (mean 56.27 ± 4.15 years); tumor diameter 3-5 cm (mean 3.74 ± 0.35 cm)] and control [n = 45; 26 male, 19 female; 28-65 years of age (mean 56.84 ± 4.23 years); tumor diameter 3-5 cm (mean 3.69 ± 0.37 cm)]. There were no significant differences in baseline clinical data between the 2 groups (P > 0.05), indicating good comparability.

Protocol

Patients in the control group underwent laparoscopic liver resection using standard laparoscopic hepatectomy. The patients were positioned supine under general anesthesia. An incision was made below the umbilicus to establish a pneumoperitoneum, and a laparoscope was inserted to explore the abdominal cavity. Three to four operative channels were established in the upper abdomen. Based on the intraoperative real-time evaluation, the decision to perform Pringle’s maneuver was made. Depending on the tumor location and degree of hepatic cirrhosis, anatomical or local liver resection was performed, ensuring a surgical margin of 2-5 cm from the tumor edge.

Patients in study group underwent ultrasound-guided RFA. Patients were required to fast for 4-6 hours before surgery, and an intravenous line was established before local anesthesia. The surgical area was disinfected and covered with a sterile drape. A systematic ultrasound scan was performed to plan the puncture path, preferably penetrating the tumor through part of the normal liver tissue to minimize interference and injury, thereby reducing the risk for tumor seeding. Under ultrasound guidance, a radiofrequency electrode needle was inserted percutaneously into the liver and positioned inside the tumor. Based on the tumor size and shape, appropriate ablation parameters were selected, usually with a power of 60-80 W and an ablation time of 10-20 minutes, ensuring that the ablation area extended 0.5-1.0 cm beyond the tumor margin to achieve complete coverage and reduce residual tumor. For tumors adjacent to vital organs or major blood vessels, absolute ethanol was injected into the adjacent side before ablation to prevent thermal injury. During withdrawal of the ablation needle, the puncture tract was ablated to prevent postoperative bleeding and tumor cell dissemination along the needle path. Postoperatively, another ultrasound scan was performed to verify that the ablation zone completely covered the lesion and to exclude complications, such as tumor rupture or bleeding.

Observation indicators

Negative psychological status: The psychological status of the patients was assessed using the Hamilton Anxiety Scale (HAM-A) and the Hamilton Depression Scale (HAM-D) 1 week before and after surgery. The HAM-A consists of 14 items, each rated on a scale of 0 to 4. A total score < 7 indicates no or minimal anxiety; 7-16 indicates mild anxiety; 17-24, moderate anxiety; and ≥ 25, severe anxiety. The HAM-D includes 17 items: Items 4-6, 12-14, and 16 are scored from 0 to 2, and the remaining items are scored from 0 to 4. A total score < 7 was considered to be normal, 7-17 indicated possible depression, 17-24 indicated definite depression, and > 24 indicated severe depression. Cronbach’s alpha coefficients for the HAM-A and HAM-D were 0.833 and 0.821, respectively, indicating good internal consistency and reliability[6,7].

Stress response indicators: Peripheral venous blood (5 mL) was collected on postoperative days 1, 3, and 5. The samples were then centrifuged at 3000 rpm for 15 minutes. C-reactive protein (CRP) and superoxide dismutase (SOD) levels were measured using the turbidimetric method and vascular endothelial growth factor (VEGF) was measured using a commercially available chemiluminescence kit, in strict accordance with the manufacturer’s instructions.

Postoperative complications: The incidences of incision infection, hepatic pain, abdominal infection, and pleural effusion were observed and recorded, and complication rates were calculated.

Postoperative recovery: Time to first flatus, ambulation, and oral intake were recorded.

Liver function: Peripheral venous blood samples (5.0 mL) were collected from the patients on the morning after fasting, both preoperatively and on postoperative day 7. Total bilirubin (TBIL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were measured using an automated biochemical analyzer and a commercially available enzymatic colorimetric method in strict accordance with manufacturer’s instructions.

Postoperative recurrence rate: All patients were followed-up for 6 months after surgery. Recurrence was determined based on the presence of new hepatic lesions or renewed elevation in alpha-fetoprotein levels as confirmed by imaging and laboratory investigations.

Statistical analysis

Statistical analysis was performed using SPSS version 25.0 (IBM Corporation, Armonk, NY, United States). Count data are expressed as number and percentage, and were compared between the groups using the χ² test. Normally distributed data are expressed as mean ± SD, and were compared between the groups using the t-test. Differences with P < 0.05 were considered to be statistically significant.

RESULTS

Comparison of negative psychological state scores before and after surgery between the groups

There were no statistical differences in preoperative HAM-A and HAM-D scores between the groups (P > 0.05). Postoperatively, however, these scores in the study group were significantly lower than those in the control group (P < 0.05; Table 1).

Table 1 Comparison of negative psychological state scores before and after surgery between the groups.

Group	Cases, n	HAM-D		HAM-A
		Before	After	Before	After
Research	45	14.09 ± 1.33	6.25 ± 1.12a	17.10 ± 1.41	7.02 ± 1.21
Control	45	14.01 ± 1.25	8.78 ± 1.25a	17.06 ± 1.39	9.13 ± 1.26a
t value		0.415	4.116	0.187	6.032
P value		0.071	0.001	0.066	0.010

^aP < 0.05 vs preoperative and postoperative values in the same group.

HAM-A: Hamilton Anxiety Scale; HAM-D: Hamilton Depression Scale.

Comparison of stress response at different nodes between the groups after surgery

There were no significant differences in serum CRP, VEGF, and SOD levels between the 2 groups on postoperative day 1 (P > 0.05). However, CRP, VEGF, and SOD levels were significantly lower in the study group on postoperative days 3 and 7 than those in the control group (P < 0.05; Table 2).

Table 2 Comparison of serum levels of inflammatory factors between the 2 groups.

Group	CRP (mg/L)			VEGF (pg/mL)			SOD (U/mL)
	Postoperative day 1	Postoperative day 3	Postoperative day 7	Postoperative day 1	Postoperative day 3	Postoperative day 7	Postoperative day 1	Postoperative day 3	Postoperative day 7
Research (n = 45)	17.81 ± 2.32	7.24 ± 1.28a	4.73 ± 1.04a,b	140.29 ± 23.08	83.72 ± 10.33a	50.33 ± 6.71a,b	112.07 ± 10.38	89.22 ± 7.23a	62.10 ± 5.37a,b
Control (n = 45)	17.54 ± 2.77	9.35 ± 1.36a	6.07 ± 1.22a,b	139.78 ± 24.11	101.62 ± 11.07a	83.72 ± 9.26a,b	112.56 ± 11.07	97.28 ± 8.14a	79.27 ± 7.19a,b
t value	0.512	6.332	5.903	0.377	12.093	8.271	0.775	11.102	9.284
P value	0.103	0.001	0.001	0.115	0.010	0.001	0.137	0.001	0.000

^aP < 0.05 vs the same group 1 day after surgery.

^bP < 0.05 vs the same group 3 days after surgery.

Data presented as mean ± SD unless otherwise indicated. CRP: C-reactive protein; VEGF: Vascular endothelial growth factor; SOD: Superoxide dismutase.

Comparison of postoperative complications between the groups

The incidence of postoperative complications in the study group was 6.66%, which was significantly lower than that in the control group (17.78%; P < 0.05; Table 3).

Table 3 Comparison of postoperative complications between the groups.

Group	Infection of incisional wound	Hepatalgia	Abdominal infection	Pleural effusion	Incidence
Research (n = 45)	1 (2.22)	2 (4.44)	0 (0)	0 (0)	3 (6.66)
Control (n = 45)	2 (4.44)	3 (6.66)	1 (2.22)	2 (4.44)	8 (17.78)
χ2					12.322
P value					0.001

Data presented as n (%) unless otherwise indicated.

Comparison of postoperative recovery between the groups

Time to first flatulence, time to oral feeding, and length of hospital stay after the operation were significantly lower than those in the control group (P < 0.05; Table 4).

Table 4 Comparison of postoperative recovery between the groups.

Group	Time to first flatulence after surgery (hour)	Time to oral intake (hour)	Postoperative hospital stays (day)
Research (n = 45)	23.17 ± 2.08	7.72 ± 1.05	4.71 ± 1.04
Control (n = 45)	26.73 ± 3.14	9.03 ± 2.16	7.25 ± 1.13
t value	7.192	5.206	4.287
P value	0.001	0.000	0.001

Data presented as n (%) unless otherwise indicated.

Comparison of liver function indicators between the groups before and after surgery

Postoperative measurements revealed that serum levels of ALT, AST, and TBIL decreased in both groups compared with preoperative levels. The levels in the intervention group were significantly lower than those in the control group (P < 0.05), whereas there were no significant differences between the 2 groups before surgery (P > 0.05; Table 5).

Table 5 Comparison of liver function parameters between the two groups before and after surgery.

Group	ALT (U/L)		AST (U/L)		TBIL (μmol/L)
	Before	After	Before	After	Before	After
Research (n = 45)	97.23 ± 7.31	54.15 ± 4.67a	102.43 ± 11.83	56.11 ± 6.14a	81.43 ± 7.52	40.15 ± 4.23a
Control (n = 45)	97.16 ± 7.28	67.23 ± 6.14a	101.96 ± 10.47	70.73 ± 7.27a	81.45 ± 7.61	59.27 ± 4.36a
t value	0.706	15.122	0.214	17.312	0.416	11.504
P value	0.114	0.001	0.286	0.000	0.108	0.015

^aP < 0.05 vs preoperative and postoperative comparisons in the same group.

Data presented as n (%) unless otherwise indicated. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; TBIL: Total bilirubin.

Comparison of postoperative recurrence rates between the groups

During the six-month postoperative follow-up, no recurrence was observed in the study group (i.e., recurrence rate, 0%), while 1 case of recurrence occurred in the control group (recurrence rate, 2.22%). The difference between the 2 groups, however, was not statistically significant (P > 0.05).

DISCUSSION

Liver cancer is often asymptomatic in its early stages; however, a small number of patients may experience abdominal distension, significant weight loss, or fever. Without timely intervention, liver cancer can pose a severe threat to life[8,9]. Surgery is the standard clinical treatment that effectively removes lesions and prolongs patient survival. However, its inherent invasiveness may trigger negative emotions, such as anxiety and fear, particularly in patients with a limited understanding of their disease, ultimately affecting treatment efficacy and postoperative recovery[10]. While surgery plays a therapeutic role, it inevitably causes physical trauma, the extent of which is positively correlated with the inflammatory response and can elevate ghrelin levels, leading to post-traumatic stress disorder in severe cases[11]. Surgical trauma, coupled with postoperative pain and concerns regarding complications and outcomes, often induces anxiety and depression directly. Therefore, selecting an appropriate surgical method for patients with primary small HCC and comorbid anxiety/depression is crucial to ensure favorable therapeutic outcomes.

Liver resection is the preferred treatment for HCC. However, due to its invasiveness and the high risk for postoperative complications, it may not be suitable for all patients. Some patients have insufficient liver function, which makes them unable to tolerate laparoscopic resection. As a result, < 30% of patients with liver cancer ultimately undergo surgical resection[12,13]. In recent years, advances in clinical medicine have led to diverse approaches for the treatment of liver cancer. With growing emphasis on minimally invasive surgery and precision medicine, RFA for small HCC has become a research focus. Ultrasound-guided RFA, a minimally invasive interventional technique that uses thermal energy to inactivate tumor cells, has been increasingly applied in clinical settings for primary liver cancer[14,15].

This study investigated the feasibility and efficacy of ultrasound (US)-guided interventional surgery in patients with small primary HCC and comorbid anxiety and depression. Results revealed that postoperative HAM-A and HAM-D scores in the study group were significantly lower than those in the control group, who underwent conventional laparoscopic resection. This suggests that US-guided interventional therapy has a clear advantage over traditional surgical methods for alleviating anxiety and depression. Further analysis indicated that individuals experiencing physical and psychological discomfort often develop stress disorders, especially when facing life-threatening conditions such as cancer, which tend to trigger negative psychological responses[16]. Studies have confirmed that patients with malignant tumors are more likely to have emotional disorders than those with general internal medical diseases. Taking primary liver cancer as an example, patients must endure not only the uncertainty of diagnosis, treatment, and prognosis but also physical symptoms such as pain, insomnia, anorexia, and palpitations throughout the clinical course[17]. Due to insufficient psychological resilience and coping capacity in some patients, emotional disorders are relatively common. However, as treatment progresses and the prognosis improves, physical function gradually recovers, which in turn helps alleviate anxiety and depression.

In addition, postoperative functional recovery and the occurrence of complications vary depending on treatment methods and individual differences, which further influence patients' psychological expectations and emotional disorders. Anxiety and depression have profound effects on mental and physical health. These emotional states impair psychological well-being and negatively affect physiological function. Stress response is the body's defensive reaction to mental pressure, trauma, or infection. In this study, the serum levels of CRP, VEGF, and SOD were significantly lower in the intervention group than in the control group on postoperative days 3 and 7 (P < 0.05), indicating that the intervention group exhibited better performance in stress control and emotional regulation. Surgical trauma activates the stress response and immune system, resulting in elevated levels of inflammatory markers such as CRP, which typically peak within 24 hours to 48 hours postoperatively and then gradually decline[18,19].

Surgical stress regulates VEGF expression through various mechanisms. First, surgical trauma, associated inflammation, and tissue hypoxia can activate VEGF transcription, increasing VEGF levels to promote angiogenesis and support tissue repair. Second, the stress hormones induced by surgical trauma may negatively regulate VEGF expression. Furthermore, surgical stress may lead to the excessive reactive oxygen species (ROS) production, causing oxidative stress[20,21]. SOD, a key antioxidant enzyme, catalyzes the dismutation of superoxide anions into oxygen and hydrogen peroxide, thereby mitigating ROS-induced cytotoxic damage. In the early stages of surgical stress, SOD activity may compensatorily increase as the body attempts to enhance its antioxidant defenses. However, excessive trauma or prolonged stress may impair SOD activity, leading to weakened antioxidant capacity[22,23].

This study also showed that the incidence of postoperative complications was significantly lower in the intervention group than in the control group at all postoperative time points. The time to first flatus and oral intake, and length of hospital stay were also significantly shorter in the study group, suggesting that US-guided interventional surgery promotes faster recovery and shorter hospitalization. Although both ultrasound-guided interventional surgery and laparoscopic resection are effective treatments for primary small HCC, they differ significantly in terms of postoperative recovery and patient experience[24]. Laparoscopic surgery, which requires general anesthesia and open abdominal access, results in greater trauma, longer operative duration, and higher risks. In contrast, US-guided interventional therapy involves less trauma, milder stress responses, and faster recovery. Many patients experience fear or aversion to laparoscopic surgery, which increases their susceptibility to negative perioperative emotions. For patients with anxiety and depression, psychological stress is often heightened before surgery due to fear and uncertainty[25]. With less postoperative trauma and pain, US-guided interventional surgery is likely to reduce psychological stress and enhance patient cooperation during treatment and recovery.

In terms of surgical outcomes, both groups exhibited postoperative improvements in liver function, with serum ALT, AST, and TBIL levels lower than the preoperative values. The study group exhibited significantly lower levels than the control group, suggesting that ultrasound-guided interventional surgery causes less parenchymal liver injury and a lower bile duct burden. Laparoscopic surgery often requires occlusion of total hepatic blood flow and vascular clamping, potentially resulting in ischemia-reperfusion injury and mechanical compression. In contrast, ultrasound-guided percutaneous ablation precisely targets the tumor tissue, preserves the normal liver parenchyma, and minimizes microvascular damage, which benefits postoperative recovery and treatment outcomes. During the six-month follow-up, no significant difference in recurrence rates was observed between the 2 groups, suggesting that both procedures have comparable clinical efficacy, although this may be influenced by the small sample size and short follow-up period. The present study had several limitations that warrant consideration. First, subgroup analyses based on tumor anatomical location (e.g., proximity to major blood vessels or the gallbladder), which may influence the technical difficulty and therapeutic response to ultrasound-guided interventions, were not performed. Therefore, the applicability of this treatment modality in patients with tumors located in complex anatomical regions remains unclear. Second, the psychological assessment relied solely on standardized rating scales (i.e., HAM-A and HAM-D) without incorporating qualitative interviews or physiological markers, such as cortisol levels. Therefore, the evaluation of emotional changes may not fully capture patients’ subjective experiences or neuroendocrine stress responses. Third, this was a single-center study with a relatively small sample size (n = 45 per group), potentially limiting the external validity of the findings owing to regional treatment patterns and population characteristics. Additionally, most enrolled patients had well-compensated liver function (Child-Pugh A/B) and limited tumor burden (≤ 3 nodules, maximum diameter ≤ 5 cm). Thus, our conclusions may not be generalizable to patients with advanced disease, multifocal lesions, or compromised liver function. Future multicenter studies with larger and more diverse cohorts, incorporating stratified analyses, and multidimensional psychological assessments to validate and expand upon these findings are warranted.

CONCLUSION

In conclusion, US-guided interventional surgery for patients with primary small HCC, particularly those with comorbid anxiety and depression, can effectively alleviate negative emotional states, reduce stress responses, and lower the risk for postoperative complications, thereby promoting recovery. Moreover, this surgical method has a positive impact on patient quality of life.