Analysis of Risk Factors for Lymph Node Metastasis in Hepatic Alveolar Echinococcosis

  


    
Sports event

    
B

    
SE

    
Wald

    
df

    
P value

    
OR

    
95% CI

  

  


    
Lower limit

    
Limit

  

  


    
Sex

    
1.105

    
0.435

    
6.459

    
1

    
0.011

    
3.019

    
1.288

    
7.8

  

  


    
Year

    
-0.017

    
0.016

    
1.093

    
1

    
0.296

    
0.983

    
0.953

    
1.015

  

  


    
Ehni group

    


    


    
14.682

    
7

    
0.04

    


    


    


  

  


    
Han etnic group

    
18.346

    
22796.285

    
0

    
1

    
0.999

    
92771756.81

    


    


  

  


    
Tibetan ethnic group

    
20.25

    
22796.285

    
0

    
1

    
0.999

    
623187710.6

    


    


  

  


    
Kazakh ethnic group

    
18.887

    
22796.285

    
0

    
1

    
0.999

    
159338481.1

    


    


  

  


    
Hui Islamic ethnic group

    
19.574

    
22796.285

    
0

    
1

    
0.999

    
316826595.7

    


    


  

  


    
Kyrghiz ethnic group

    
19.367

    
22796.285

    
0

    
1

    
0.999

    
257693667.8

    


    


  

  


    
Mongol ethnic group

    
18.302

    
22796.285

    
0

    
1

    
0.999

    
88793703.78

    


    


  

  


    
Uyghur etnic group

    
9.277

    
22796.285

    
0

    
1

    
0.999

    
235545782.5

    


    


  

  


    
lesion location

    


    


    
9.418

    
2

    
0.999

    


    


    


  

  


    
right lobe of the liver

    
-1.416

    
0.469

    
9.112

    
1

    
0.003

    
0.243

    
0.097

    
0.609

  

  


    
left lobe of the liver

    
-1.218

    
0.601

    
4.115

    
1

    
0.043

    
0.296

    
0.091

    
0.96

  

  


    
Whether distant metastasis

    


    
0.491

    
11.578

    
1

    
0.001

    
5.325

    
2.032

    
13.953

  

  


    
Percentage of neutrophils

    
-0.028

    
0.015

    
3.364

    
1

    
0.067

    
0.972

    
0.943

    
1.002

  

  


    
direct bilirubin

    
-0.001

    
0.004

    
0.018

    
1

    
0.894

    
0.999

    
0.991

    
1.007

  

Table 4: Multifactorial Logistic Regression Analysis of Factors Influencing Liver AE Lymph Node Metastasis.

Discussion

AE is a zoonotic parasitic disease that poses a serious threat to global public health [7]. After humans ingest eggs of the Echinococcus Multilocularis (EM) tapeworm, they are digested into eggshells and oncospheres (25-30μm) in the small intestine, which then invade the hepatic through the portal vein system [8]. Hepatic AE can spread to distant organs such as the lungs, brain, bones, and kidneys, with lymph node metastasis being relatively rare. Eckert J and Mehlhorn et al [9]. first reported in animal experiments that AE might lead to "lymph node metastasis" by damaging the interlobular lymphatics after detachment from the hepatic and subsequently draining into the local lymph nodes. The lymph nodes adjacent to the hepatoduodenal ligament are the most common site of metastasis, and depending on the location of metastasis, it can cause more serious complications such as jaundice and portal hypertension [10]. Radical hepatic resection is the preferred treatment for hepatic AE, but there is no standardized approach for managing hepatic AE with lymph node metastasis. Intraoperative regional lymph node dissection is considered a key step in reducing the risk of persistent infection and preventing recurrence [11]. The purpose of this study is to explore the risk factors for lymph node metastasis in hepatic AE, providing a scientific reference for clinical diagnosis, assessment, and intervention.

A global epidemiological study has shown that parts of Western, Northern, and Eastern Europe, as well as some pastoral areas in Central Asia, are high-risk regions for hepatic Alveolar Echinococcosis (AE). Rodents and dogs are the main transmission vectors [12]. In regions of China such as Tibet, Qinghai, Gansu, and Xinjiang, where animal husbandry is a major occupation and there is a high number of domestic dogs, the population's exposure to AE eggs is increased. Additionally, in some areas with lower levels of medical and educational resources, the likelihood of contracting alveolar echinococcosis is increased. In this study, univariate analysis of two groups of hepatic AE patients showed significant statistical differences in gender, age, and ethnicity (P<0.05), which is consistent with the results of past epidemiological investigations. Wang et al.'s epidemiological meta-analysis suggested that female gender, age =30 years, and engagement in animal husbandry are high-risk factors for hepatic AE [13]. In this study, compared to males, females with hepatic AE had a higher probability of lymph node metastasis, with multivariable logistic regression indicating that the probability of metastasis in females was 3.019 times higher than in males. These higher probabilities may be due to the fact that in pastoral areas, women are responsible for feeding dogs, leading to direct and frequent contact with the definitive hosts [14]. Additionally, as the primary participants in household chores, women are more exposed to contamination from animal feces or Echinococcus multilocularis eggs. Studies have also indicated that estrogen can enhance cell proliferation and metastasis [15]. Echinococcus cells may be more prone to cause lymph node metastasis under the influence of estrogen. As a result, specific lifestyle habits and elevated estrogen levels may be the reasons why women are a high-risk population for hepatic AE, leading to a higher incidence of lymph node metastasis in female patients with hepatic AE. The long incubation period of hepatic AE (5-15 years) leads to a delayed onset of clinical symptoms[16], making the disease more easily detectable in individuals aged 30 and over. In this study, 69.1% of patients with hepatic AE and lymph node metastasis were aged 30 and above, with no significant difference in age observed in the multivariable analysis between the two groups. The likelihood of hepatic AE patients in pastoral regions of Northwest China developing lymph node metastasis is relatively high.

In hepatic Alveolar Echinococcosis (AE), the primary lesion is most commonly located in the right lobe of the hepatic (80%), followed by involvement of both the left and right lobes [17]. In this study, there was a statistically significant difference in the location of the primary lesion between the two groups of hepatic AE patients. Multivariable analysis revealed that patients with lesions involving both the left and right lobes had a higher probability of lymph node metastasis compared to patients with lesions confined to one side of the hepatic. The main reasons for this, as supported by the pathological and anatomical characteristics of AE, seem to be more convincing. AE colonizes the hepatic through the portal vein and then damages the intrahepatic blood vessels, bile ducts, and lymphatic vessels through external budding, compression, infiltration, and other means [18]. Dislodged AE can be transported to regional lymph nodes through the deep and superficial lymphatic drainage systems of the hepatic along with the lymphatic fluid, leading to lymph node metastasis. Approximately 80% or more of the lymphatic fluid enters the first hepatic hilum lymph node through the deep lymphatic drainage system distributed around the portal vein [19]. Therefore, in patients with hepatic AE with larger diameters, lesions spanning the left and right lobes, or diffuse growth, the invasion of the hepatic portal vein and microlymphatic vessels is more severe, providing a better opportunity for lymph node metastasis.

Hepatic Alveolar Echinococcosis (AE) is the only parasitic disease with malignant biological characteristics and can cause both intrahepatic and extrahepatic metastasis through infiltration and hematogenous spread. Literature reports suggest that the incidence of hepatic AE with distant organ metastasis is approximately 20%-40% [20]. Currently, there are no articles specifically addressing the correlation between lymph node metastasis and distant organ metastasis in hepatic AE. However, the results of this study, through univariate and multivariable analysis, indicate that the presence of distant organ metastasis is an independent risk factor for lymph node metastasis in hepatic AE (P=0.001, OR=5.37). There are two possible reasons for this. First, distant organ metastasis is a manifestation of advanced stages of hepatic AE. Studies by Long Dan et al. [21] have shown that when distant organ metastasis occurs, the intrahepatic lesions have larger diameters, multiple lesions, and more severe invasion of intrahepatic blood vessels and bile ducts. When the portal vein and hepatic veins are significantly affected, the deep lymphatic drainage system of the hepatic can also be compromised, making it easier for AE to spread to various regional or distant lymph nodes through lymphatic fluid. Second, lesions from distant organ metastases can cause lymph node metastasis through local lymphatic flow. For example, pulmonary AE can spread to the hilar and mediastinal lymph nodes [10], pancreatic AE can cause metastasis to peripancreatic lymph nodes, and when the adrenal glands and kidneys are involved, AE can flow out along the hepatorenal ligament through lymphatic fluid, leading to metastasis in the para-aortic lymph nodes. Therefore, when hepatic AE is accompanied by distant organ metastasis, lymph node metastasis should be given special attention.

Inflammation is a key characteristic of AE infection, and hematological inflammatory markers such as neutrophils, lymphocytes, and platelets are involved in the chronic inflammatory response to the parasite, indirectly reflecting the body’s immune status [22]. In the present study, univariate analysis revealed a statistical difference in the Neutrophil Percentage (NE) in the blood routine tests of the two groups of hepatic AE patients (P=0.048<0.05). In patients with Echinococcus infection, neutrophils, through the activation of pro-inflammatory cytokines (IL-6, IL-8, a-tumor necrosis factor), promote the inflammatory response and tissue damage [23]. They can also secrete Vascular Endothelial Growth Factor (VEGF) to facilitate angiogenesis, thus promoting the metastasis and invasion of AE [24]. However, multivariable analysis did not show a significant positive correlation between NE and lymph node metastasis in hepatic AE. In advanced stages of hepatic AE, obstruction jaundice can result from lesion invasion or compression of the intrahepatic and extrahepatic bile ducts, leading to direct bilirubin level elevation. Additionally, extensive hepatic cell damage can cause abnormal hepatic function and indirect bilirubin elevation. Furthermore, lymph node metastasis in hepatic AE most commonly occurs adjacent to the hepatoduodenal ligament [10], where these lymph nodes can compress or erode the common bile duct and portal vein, leading to obstructive jaundice, portal vein cavernous transformation, and consequent direct bilirubin level elevation. Univariate analysis in this study showed a statistical difference in the direct bilirubin levels between the groups, while multivariable analysis did not reveal a significant correlation with lymph node metastasis.

In conclusion gender is female, combined with extrahepatic distant organ metastasis, and lesions invading both right and left lobes of the hepatic are independent risk factors that may cause lymph node metastasis of hepatic AE. Clinical physicians should pay attention to and take preventive measures against the identified risk factors. Our center recommends routine prophylactic clearance of regional lymph nodes in patients with hepatic AE who have these risk factors during surgery to improve patient quality of life and reduce recurrence rates. This study is retrospective in nature and not a randomized controlled trial, thus there is a certain degree of selection bias. Additionally, this is a single-center clinical trial with a relatively small sample size, and larger multi-center clinical trials are still needed.

Author Statements

Acknowledgements

The authors thank Ainiwaer·Aikebai for help collecting the follow-up data.

Funding

This work was supported by Natural Science Foundation of Xinjiang Province Project: Xinjiang Province Natural Science Foundation Projects (22022D01D17).

Author Contributions

Tuerganaili·Aji and Tieminjiang designed the research and approved the submitted manuscript. Ainiwaer·Aikebai and Yierfan·Yilihaer drafted the manuscript. Ainiwaer·Aikebai and Yilizhati·Aimaitijiang collected the data and analyzed the data. All authors read and approved the final manuscript.

Institutional Review Board Statement

This study was approved by the Ethics Committee of The First Affiliated Hospital of Xinjiang Medical University (No. 20211015-53) and was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all subjects and/or their legal guardians. All methods used in this study were performed in accordance with the approved guidelines.

Conflict of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

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