Pathophysiological Mechanisms of Lymph Node Metastasis Differences Between HCC and ICC: Anatomical, Molecular Biology, and Microenvironment Factors

1. Introduction: Differences in Metastasis of Malignant Liver Tumors

Primary liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (Hepatocellular Carcinoma, HCC) and intrahepatic cholangiocarcinoma (Intrahepatic Cholangiocarcinoma, ICC) being the two main histological types, accounting for approximately 75%-85% and 10%-15% of primary liver cancer cases, respectively 1. Although both malignancies originate in the liver and share similar pathogenic risk factors in some cases (such as chronic viral hepatitis and liver cirrhosis), their biological behaviors, particularly the choice of metastatic pathways, exhibit distinctly different pathophysiological characteristics.

This article aims to explore a phenomenon observed clinically: Why does hepatocellular carcinoma (HCC) tend to disseminate or metastasize distantly through hematogenous routes while rarely invading lymph nodes early; conversely, why does intrahepatic cholangiocarcinoma (ICC) tend to metastasize to the hilar lymph nodes early?

The incidence of lymph node metastasis in ICC patients can be as high as 28%-40%, while in HCC patients without specific high-risk features, the lymph node metastasis rate is usually below 8% 1. This difference is not coincidental but is determined by the physical barriers of the liver’s microanatomy, the origin of tumor cells, the differential activation of molecular signaling pathways (especially the expression profiles of the vascular endothelial growth factor family), and the heterogeneity of the stromal response in the tumor microenvironment (TME). This biological behavior difference affects surgical strategies: radical surgery for ICC generally includes routine hilar lymphadenectomy, while surgery for HCC typically does not recommend routine lymphadenectomy, which profoundly impacts patient prognosis 3.

This article will elaborate on this phenomenon from multiple dimensions, including anatomical basis, cellular molecular mechanisms, microenvironment characteristics, and clinical significance.

2. Epidemiological and Clinical Prognosis Differences

Before delving into the microscopic mechanisms, it is essential to clarify the epidemiological differences in lymph node metastasis patterns between HCC and ICC, which provide a clinical empirical basis for subsequent pathological mechanism discussions.

2.1 Differences in Lymph Node Metastasis Incidence

Large-scale clinical cohort studies have revealed differences in the frequency of lymph node involvement between HCC and ICC. According to multicenter data from the United States and Asia, approximately 28% to 40% of ICC patients have been confirmed to have lymph node metastasis (Lymph Node Metastasis, LNM) at initial diagnosis or surgery 3. Even in early ICC cases with smaller tumor volumes (<5cm), the risk of occult lymph node metastasis remains significant, leading to an underestimation of disease severity when relying solely on imaging assessments.

In contrast, lymph node metastasis in HCC is relatively rare. In resectable HCC cases, the pathologically confirmed lymph node metastasis rate typically hovers between 1.7% and 8% 1. Only when the disease progresses to advanced stages or specific aggressive subtypes (such as HCC expressing stem cell markers) does the incidence of lymph node metastasis increase. A post-mortem study indicated that the lymph node metastasis rate in ICC patients can be as high as 69%, while in HCC, it is 30% (more common in end-stage widely metastatic cases) 7. This difference suggests that lymph node metastasis is an inherent biological characteristic of ICC, while in HCC, it is more indicative of end-stage disease.

2.2 Asymmetry in Prognostic Impact

The weight of lymph node status on prognosis differs between the two tumors. For ICC, positive lymph nodes (N1) are a poor prognostic indicator. Studies show that the 3-year survival rate for ICC patients without lymph node involvement is approximately 55.7%, while once lymph node metastasis occurs, the 3-year survival rate plummets to 0.2% 8. This drastic drop in survival rate makes lymph node status one of the most critical parameters in the ICC staging system.

In HCC, although lymph node metastasis also indicates poor prognosis, its clinical dominance is often overshadowed by intrahepatic tumor burden, vascular invasion (especially portal vein tumor thrombus PVTT), and the severity of underlying liver disease (cirrhosis, liver function reserve) 9. The primary causes of death in HCC patients are often intrahepatic recurrence or liver failure, rather than complications directly caused by lymph node metastasis.

2.3 Association of Gender and Incidence Trends

Epidemiological data also reveal a potential link between gender and incidence rates as well as metastatic risks. The incidence of HCC is significantly higher in males than in females (with a male-to-female ratio of approximately 3:1 to 5:1), and the incidence in male patients shows a more pronounced trend with increasing age 1. In contrast, the gender difference in ICC is smaller (with a male-to-female ratio of approximately 1.6:1) 1. Although males are generally a high-risk group for liver cancer, some studies suggest that estrogen may play a role in inhibiting IL-6 mediated inflammatory responses, which could partially explain the lower incidence of HCC in females, but whether this is directly related to the specific mechanisms of lymph node metastasis requires further exploration.

3. Anatomical Barriers and Microcirculatory Dynamics: The Roots of Physical Barriers

To understand “why HCC cannot enter lymphatic vessels while ICC can,” one must delve into the microanatomical structure of the liver lobule. The liver possesses a unique dual blood supply system and a finely tuned lymphatic drainage network, which sets natural physical barriers or pathways for different types of tumor cells.

3.1 Microenvironment of Liver Lobules: Absence of Lymphatics in the Space of Disse

Hepatocytes are the origin cells of HCC, arranged in cords between liver sinusoids. Liver sinusoids are a special type of capillary with fenestrated endothelial cells and lack a continuous basement membrane. This structure allows plasma components to filter directly into the narrow space between hepatocytes and endothelial cells—the Space of Disse 12.

The key anatomical fact is: There are no lymphatic vessels in the Space of Disse.

The amount of lymph fluid produced by the liver is enormous, accounting for 25%-50% of the lymph flow in the thoracic duct 15, but this lymph fluid is not absorbed directly by lymphatic vessels; instead, it is formed by interstitial fluid flowing in the Space of Disse from plasma filtrate. This fluid flows towards the portal tracts surrounding the liver lobules due to pressure gradients. Fluid dynamics studies indicate that after filtering out of the blood sinusoids, the fluid passes through the Space of Disse and ultimately converges into a potential space located between the stroma of the portal tracts and the outermost layer of hepatocytes—the Space of Mall 12.

3.2 The Limiting Plate as a Physical Barrier

HCC cells face a natural physical barrier—the Limiting Plate—to enter the lymphatic circulation. The Limiting Plate is a layer composed of tightly packed hepatocytes that physically separates the parenchyma of the liver lobule from the connective tissue of the portal tracts (Glisson’s sheath) 18.

The initial lymphatics do not extend into the liver lobules but originate in the connective tissue of the portal tracts. This means that HCC cells located within the liver lobules must complete a series of invasive actions to enter the lymphatic vessels:

1. Detachment: Shedding from the hepatocyte cords.
2. Migration: Crossing the Space of Disse.
3. Breakthrough: Destroying and penetrating the Limiting Plate.
4. Invasion: Entering the connective tissue of the portal tracts and ultimately penetrating the lymphatic endothelial cells to enter the lumen 18.

In contrast, HCC cells are directly exposed to the fenestrations of the blood sinusoids, separated from the blood circulation by only a highly permeable layer of endothelial cells. Therefore, the biophysical principle of “least resistance path” dictates that HCC cells are more likely to enter the bloodstream, leading to a much higher incidence of portal vein tumor thrombus (PVTT) compared to lymph node metastasis 20.

3.3 Cholangiocytes as “Close to Water’s Edge”: The Portal Tract and Peribiliary Plexus (PBP)

ICC originates from cholangiocytes. The bile duct system formed by these cells is directly embedded in the connective tissue of the portal tracts. Moreover, the intrahepatic bile ducts are closely surrounded by a unique network of blood and lymphatic vessels known as the Peribiliary Plexus (PBP) 21.

The PBP is a 3D network microcirculation system that provides nutrition to the bile ducts. More importantly, this vascular plexus is rich in lymphatic networks. When cholangiocyte epithelial cells undergo malignant transformation to form ICC, the tumor cells are already surrounded by the lymphatic network from the moment of their birth. They do not need to “search for” lymphatic vessels or break through the Limiting Plate as HCC does, because they reside within the lymphatic-rich stroma of the portal tracts.

Additionally, in pathological conditions commonly associated with ICC (such as chronic cholangitis, gallstones, and primary sclerosing cholangitis), the PBP undergoes significant hyperplasia and expansion, further increasing the density and surface area of lymphatic vessels, providing more opportunities for tumor cell invasion 23. This anatomical “close to water’s edge” effect is the anatomical root of the high incidence of lymph node metastasis in ICC.

3.4 Partitioning of the Lymphatic Drainage System: Deep and Superficial

The lymphatic drainage of the liver is divided into deep and superficial systems, which also explains the subtle differences in metastatic pathways of the two tumors.

• Deep System: Responsible for draining 80% of the liver’s lymphatic fluid. It retrogresses along the portal triad and converges into the lymph nodes at the hepatic hilum. Since ICC originates from the bile ducts within the portal triad, it naturally spreads along this main channel to the hilar lymph nodes (Group 12 lymph nodes) 17.
• Superficial/Capsular System: Distributed in the connective tissue beneath the liver capsule. This portion of lymphatic fluid primarily drains to the subdiaphragmatic, supradiaphragmatic, and mediastinal lymph nodes, with some directly entering the thoracic duct. If HCC is located on the liver surface and invades the capsule, it may utilize this system to undergo skip metastasis to thoracic lymph nodes, which is one reason why some HCC patients exhibit mediastinal metastasis without hilar metastasis 2.

4. Cellular Origins and Molecular Drivers: The Competition Between Angiogenesis and Lymphangiogenesis

The anatomical structure provides the stage, while molecular signals determine the plot’s direction. HCC and ICC originate from hepatocytes and cholangiocytes, respectively, and these two cell lines express distinctly different growth factor profiles after malignant transformation, driving angiogenesis and lymphangiogenesis.

4.1 Hepatocellular Carcinoma: VEGF-A Driven Hematogenous Metastasis Pattern

HCC is one of the most vascularized solid tumors in the human body. Its core driving force is the high expression of Vascular Endothelial Growth Factor A (VEGF-A).

• Angiogenesis Advantage: HCC cells secrete large amounts of VEGF-A under the stimulation of a hypoxic microenvironment (HIF-1α pathway activation). VEGF-A acts on the VEGFR-2 receptor on vascular endothelial cells, strongly promoting the formation of new blood vessels 26. This also leads to the characteristic “fast in, fast out” imaging features of HCC, where the contrast agent rapidly fills during the arterial phase.
• Biological Outcome: The dominance of VEGF-A leads to the formation of an extremely rich capillary network around the tumor, while relatively neglecting the construction of lymphatic vessels. Additionally, HCC cells express various factors that are endothelial cell-affine, making them highly prone to invade newly formed, structurally immature blood vessels, subsequently entering the portal vein system with the blood flow, forming portal vein tumor thrombus (PVTT). Studies have shown that excessive expression of VEGF-A is positively correlated with vascular invasion and poor prognosis in HCC, while its correlation with lymph node metastasis is weak 29.

4.2 Intrahepatic Cholangiocarcinoma: VEGF-C/D Driven Lymphangiogenesis Pattern

In contrast to HCC, ICC often exhibits hypovascular characteristics but possesses a strong ability for lymphangiogenesis. This is primarily attributed to the high expression of VEGF-C and VEGF-D.

• Lymphangiogenesis Axis: VEGF-C and VEGF-D are specific ligands for lymphangiogenesis, binding to the VEGFR-3 (Flt-4) receptor on lymphatic endothelial cells (LEC) 31. ICC tumor cells and surrounding stromal cells secrete large amounts of VEGF-C, activating the VEGFR-3 signaling pathway, inducing lymphatic vessel dilation, proliferation, and sprouting around and within the tumor.
• Increased Lymphatic Vessel Density (LVD): Using specific lymphatic endothelial markers D2-40 (Podoplanin) for immunohistochemical staining, studies consistently find that the lymphatic vessel density (LVD) in ICC tissues is significantly higher than in HCC 33. High LVD means that the probability of tumor cells contacting lymphatic vessels increases geometrically.
• Active Recruitment: ICC not only passively utilizes existing lymphatic vessels but also actively recruits immune cells and tumor cells expressing CCR7 to migrate towards lymphatic vessels by secreting chemokines (such as CCL21), forming a chemokine axis (CCL21-CCR7 axis), further promoting lymph node metastasis 35.

4.3 Imbalance of Molecular Switches: The Ratio of VEGF-A to VEGF-C

Comparative studies have found significant differences in the expression ratios of the VEGF family between HCC and ICC. In well-differentiated HCC, VEGF-A expression predominates, while VEGF-C expression is very low; in ICC or poorly differentiated HCC, the expression level of VEGF-C is significantly elevated 30. This difference in molecular expression profiles effectively acts as a “switch” for tumor metastasis pathway selection: VEGF-A opens the door to hematogenous metastasis, while VEGF-C paves the way for lymphatic metastasis.

5. Tumor Microenvironment (TME): The Opposition of Stromal Response and Physical Barriers

A tumor is not merely a mass of cancer cells; it is a complex ecosystem composed of cells, stroma, and signaling molecules. HCC and ICC adopt distinctly different strategies in constructing their microenvironments: one tends to “self-wrap,” while the other tends to “stromal remodeling.”

5.1 Encapsulation in HCC: A Shield Against Dissemination

Typical HCC exhibits expansile growth; as the tumor volume increases, it compresses the surrounding normal liver parenchyma. In response, the surrounding liver tissue undergoes atrophy and fibrosis, forming a dense fibrous capsule.

• Physical Isolation Effect: This capsule acts as a physical barrier in the early and mid-stages of HCC, confining tumor cells within the nodule and blocking direct contact with the lymphatic vessels of the portal tracts 29.
• Microenvironment Closure: The presence of the capsule creates a relatively closed high-pressure environment within the tumor, forcing tumor cells to seek exit routes through internal neovascularization (hematogenous). Only when the tumor breaches the capsule (Capsular Invasion) does the risk of lymph node metastasis significantly increase 29.

5.2 Desmoplastic Reaction in ICC: A Pump Towards Lymphatics

ICC is a typical scirrhous tumor, with its most notable pathological feature being a strong desmoplastic reaction.

• Activation of Cancer-Associated Fibroblasts (CAFs): ICC tissues are rich in cancer-associated fibroblasts (CAFs). These CAFs not only secrete collagen to form dense stroma but also highly express Podoplanin (D2-40) 36.
• Functional Stroma: Studies have found that Podoplanin-expressing CAFs can remodel the extracellular matrix (ECM), opening physical pathways for tumor cell migration. More importantly, these CAFs can also secrete VEGF-C, further stimulating lymphangiogenesis 37.
• Interstitial Fluid Pressure (IFP): The dense fibrous stroma leads to extremely high interstitial fluid pressure within the tumor. The principles of physics dictate that fluids flow from high-pressure areas to low-pressure areas. The lymphatic vessels located at the tumor margins become “flood outlets” to reduce pressure, and this pressure difference effectively creates a physical pump, driving interstitial fluid containing tumor cells into the lymphatic vessels 39.

Table 1: Comparison of Microenvironment and Metastatic Features Between HCC and ICC

Feature Dimension	Hepatocellular Carcinoma (HCC)	Intrahepatic Cholangiocarcinoma (ICC)
Main Metastatic Pathway	Hematogenous Metastasis (Portal Vein, Hepatic Vein)	Lymphatic Metastasis (Hilar Lymph Nodes)
Anatomical Barriers	Presence of Limiting Plate Isolation	No Isolation, Originating from Portal Tract Stroma
Dominant Growth Factor	VEGF-A (Angiogenesis)	VEGF-C / VEGF-D (Lymphangiogenesis)
Gross Pathological Morphology	Expansile Growth, Often Encapsulated	Infiltrative Growth, No Capsule
Stromal Response	Sparse Stroma, Rich in Sinusoids	Significant Desmoplastic Reaction
Lymphatic Vessel Density (LVD)	Low (Commonly Outside Capsule)	Extremely High (Within and Around Tumor)
Fibroblast Characteristics	Mainly Quiescent or Capsule Forming	Activated CAFs, Expressing Podoplanin
Perineural Invasion (PNI)	Rare	Common, Often Concurrent with Lymphatic Metastasis

6. Cell Adhesion Molecules and Epithelial-Mesenchymal Transition (EMT): Differences in Escape Mechanisms

For tumor cells to metastasize, they must first loosen their connections to each other, a process involving changes in cell adhesion molecules.

6.1 E-Cadherin and N-Cadherin

In normal liver tissue, both hepatocytes and cholangiocytes express E-cadherin to maintain epithelial polarity. However, the regulatory mechanisms of their expression differ.

• Adhesion Complex in Hepatocytes: Hepatocytes express both E-cadherin and N-cadherin, which together maintain the polarity of hepatocytes and the structure of bile canaliculi. Studies have shown that the localization of E-cadherin at the lateral membrane of hepatocytes is crucial for maintaining tight junctions between cells 40. In HCC, downregulation of E-cadherin is often associated with tumor dedifferentiation and increased invasiveness, but this more often leads to vascular invasion rather than lymphatic invasion.
• EMT Tendency in Cholangiocytes: ICC cells exhibit more active epithelial-mesenchymal transition (EMT) characteristics. Under the stimulation of factors such as TGF-β, ICC cells rapidly downregulate E-cadherin and upregulate N-cadherin (Cadherin Switch). This phenotypic conversion endows ICC cells with strong motility, enabling them to traverse the basement membrane and utilize pathways opened by CAFs to enter lymphatic vessels 42.

6.2 Integrins and Selectins

Integrins are key receptors for cell-extracellular matrix (ECM) interactions. ICC cells highly express specific integrins (such as αvβ6), which facilitate their interaction with the collagen-rich and laminin-rich stroma of the portal tracts, promoting migration. In contrast, the integrin profile on HCC cells tends to bind to receptors on vascular endothelial cells (such as ICAM-1, VCAM-1), which explains at the molecular level why HCC cells are more likely to “adhere” to the vessel walls to form tumor thrombi 44.

7. Perineural Invasion (PNI): “Parallel Highway”

When discussing lymphatic metastasis, one cannot overlook another hallmark feature of ICC—perineural invasion (PNI). This feature is extremely rare in HCC but is one of the core biological behaviors of ICC.

7.1 Neurotropism of ICC

The nerve fibers in the liver run parallel to the portal vein, hepatic artery, and bile ducts within Glisson’s sheath. ICC cells can secrete Nerve Growth Factor (NGF), which specifically binds to the TrkA receptor on nerve fibers. This ligand-receptor interaction produces a bidirectional effect: on one hand, it stimulates nerve fibers to grow towards the tumor (axonogenesis), and on the other hand, it guides tumor cells to migrate along the perineural spaces of the nerve fibers 46.

7.2 Synergy of PNI and Lymphatic Metastasis

Since nerve bundles and lymphatic vessels anatomically accompany each other closely in the hepatoduodenal ligament, PNI effectively provides a “parallel highway” for tumor cells to reach the hepatic hilum. Studies have found a strong positive correlation between the incidence of PNI in ICC and the rate of lymph node metastasis. In some cases, tumor cells may first invade the nerve spaces and then undergo secondary dissemination through the lymphatic network surrounding the nerves. In contrast, HCC lacks activation of the NGF/TrkA signaling axis and rarely exhibits PNI, which is one reason why it struggles to reach the hilar region 48.

8. Gray Area: CK19 Positive HCC and Mixed Hepatocellular Carcinoma

Although the overall lymph node metastasis rate of HCC is low, exceptions exist. Analyzing these “exceptions” can provide clearer insights into the aforementioned mechanisms.

8.1 CK19 Positive HCC: Cholangiocarcinoma in Disguise?

Approximately 4%-10% of HCC expresses the cholangiocyte marker CK19 (Keratin 19) 43. This type of CK19+ HCC is believed to originate from hepatic progenitor cells or undergo dedifferentiation.

• Phenotypic Mimicry: CK19+ HCC behaves biologically similarly to ICC. They exhibit more aggressive infiltrative growth, denser fibrous stroma, higher VEGF-C expression levels, and significantly elevated lymph node metastasis rates 51.
• Mechanistic Insights: This indicates that once HCC cells acquire cholangiocyte characteristics (Biliary Differentiation), they simultaneously gain the ability to break through anatomical barriers and activate lymphangiogenesis. The expression of CK19 is not merely a marker; it may participate in cytoskeletal remodeling and enhanced invasiveness.

8.2 Combined Hepatocellular-Cholangiocarcinoma (cHCC-ICC)

This is a rare tumor that contains both HCC and ICC components. Its lymph node metastasis rate falls between that of pure HCC and pure ICC but tends to lean towards the behavior pattern of ICC. Clinical data indicate that the lymph node metastasis rate of cHCC-ICC can reach around 30%-40%, necessitating a more aggressive lymph node dissection strategy when managing such tumors 5.

9. Clinical and Surgical Implications

The complex pathophysiological differences discussed above ultimately converge into a core clinical decision-making question: Is lymphadenectomy necessary?

9.1 ICC: Basis for Lymphadenectomy

Given the high rate of lymph node metastasis in ICC (even in early stages) and the decisive impact of lymph node status on prognosis, major international guidelines (such as AJCC, NCCN) recommend routine regional lymphadenectomy (LND) during radical resection of ICC.

• Staging Requirement: At least 6 lymph nodes must be dissected to accurately perform N staging 3.
• Prognostic Stratification: Accurately identifying N1 patients helps screen high-risk populations that may require adjuvant chemotherapy postoperatively.

9.2 HCC: Controversies and Consensus on Routine Dissection

For HCC, the current consensus is not to recommend routine prophylactic lymphadenectomy for the following reasons:

• Low Yield: The incidence of lymph node metastasis is low (<8%), and routine dissection offers no survival benefit for the vast majority of patients 4.
• High Risk: Most HCC patients have underlying cirrhosis. Lymphadenectomy may disrupt the lymphatic drainage pathways at the hepatic hilum. In cases of portal hypertension, this could lead to postoperative intractable ascites or even liver failure 56.
• Specific Indications: Lymphadenectomy should be reserved for patients with highly suspicious lymph nodes on preoperative imaging or those found to have enlarged lymph nodes during intraoperative exploration. Additionally, for high-risk subtypes such as CK19 positive or mixed hepatocellular carcinoma, more aggressive lymph node management strategies may need to be considered, but this still requires prospective research support.

10. Conclusion

The significant differences in lymph node metastasis patterns between HCC and ICC are not due to a single factor but are the result of multidimensional biological determinism:

1. Anatomical Structure: HCC is physically isolated from lymphatic vessels by the Limiting Plate and the Space of Disse; whereas ICC originates in the portal tracts, naturally surrounded by the lymphatic vessel network.
2. Molecular Pathways: HCC relies on VEGF-A to construct vascular networks, leading to hematogenous metastasis; ICC relies on VEGF-C to construct lymphatic networks, leading to lymphatic metastasis.
3. Tumor Microenvironment: The encapsulation in HCC serves a restraining function; the desmoplastic stromal response and perineural invasion in ICC act as accelerators of metastasis.
4. Cellular Origins: Hepatocytes are vascular-affine, while cholangiocytes are lymphatic and neural-affine.

This not only explains the pathological phenomena but also directly guides surgical intervention strategies, reminding us that when facing liver tumors, we must look beyond the surface and discern the essential differences at the cellular and molecular levels.

Table 2: Comparison of Risk Factors and Predictive Model Indicators Related to Lymph Node Metastasis in HCC and ICC

Predictive Indicators	Risk of Lymph Node Metastasis in Hepatocellular Carcinoma (HCC)	Risk of Lymph Node Metastasis in Intrahepatic Cholangiocarcinoma (ICC)
Serum Tumor Markers	AFP levels (usually require very high values to be relevant)	High expression of CA19-9 (strong correlation)
Immunohistochemical Markers	CK19+, EpCAM+, High expression of MMP-2	D2-40 (Podoplanin)+, High expression of VEGF-C
Tumor Size	Large tumors (>5-10cm) increase risk	Considerable risk even with small tumors (<3cm)
Background Liver Disease	Cirrhosis may limit early metastasis due to structural damage	Cholangitis, intrahepatic cholangitis increases risk
Microvascular Invasion (MVI)	Strong correlation (but more indicative of intrahepatic recurrence)	Strong correlation (often accompanied by lymphatic invasion)
Perineural Invasion (PNI)	Extremely rare	Common, and an independent predictor of LNM

———————-

This article was generated and edited by Gemini Deep Research

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