Clinicopathological insights and management of liver metastases: Current advances and future perspectives

Table 1 Key ligands and their receptors in primary liver neoplasms and hepatic metastases

Ligand	Receptor(s)	Functional role	Tumor association
HGF	c-MET (HGF receptor)	Facilitates cellular proliferation, migration, and invasive behavior	Highly expressed in HCC and iCCA; generally low in metastatic lesions
VEGF	VEGFR-1, VEGFR-2, VEGFR-3	Mediates angiogenesis and increases vascular permeability	Elevated in poorly differentiated HCC, iCCA, and certain metastases such as colorectal carcinoma
TGF-β	TGF-β receptors 1 and 2	Regulates EMT, fibrotic processes, and immune suppression	Upregulated in HCC and iCCA, contributing to fibrosis and EMT induction
PDGF	PDGFR-α, PDGFR-β	Activates stromal components and induces desmoplastic reactions	Predominantly expressed in iCCA and select metastatic adenocarcinomas (e.g., pancreatic, breast origin)
EGF	EGFR (human epidermal growth factor receptor 1)	Promotes cell growth, survival, and motility	EGFR signaling is active in iCCA, some HCC cases, and also in colorectal and pulmonary metastases
FGF	FGFR1 to FGFR4	Involved in angiogenesis and cellular proliferation	FGFR2 gene fusions are characteristic of iCCA (especially small-duct subtype); less frequent in HCC
Wnt ligands (e.g., Wnt3a, Wnt5a)	Frizzled receptors and lipoprotein receptor-related protein 5/6 co-receptors	Regulates Wnt/β-catenin pathway affecting cell differentiation and proliferation	Aberrant Wnt/β-catenin activation is common in HCC; expression in metastases is variable
Notch ligands (Jagged1, DLL1)	Notch receptors 1 to 4	Controls cellular differentiation and angiogenic processes	Notch signaling is upregulated in iCCA but less prominent in HCC or metastatic tumors
CXCL12 (stromal cell-derived factor 1)	CXCR4	Directs chemotaxis, promotes metastasis and angiogenesis	High CXCR4/CXCL12 axis activity is observed in metastases from colorectal, breast, and pancreatic cancers
IL-6	IL-6 receptor (via gp130/Janus kinase/signal transducer and activator of the transcription pathway)	Mediates inflammatory responses, proliferation, and survival	Elevated levels noted in HCC and metastatic colorectal carcinoma
Mucin-1	Cell surface protein without classic receptor (functions as ligand)	Involved in tumor progression and immune evasion	Overexpressed in iCCA and certain metastatic adenocarcinomas, especially of breast and pancreatic origin

CXCL: C-X-C motif ligand; CXCR: C-X-C chemokine receptor; EGF: Epidermal growth factor; EMT: Epithelial-mesenchymal transition; FGF: Fibroblast growth factor; iCCA: Intrahepatic cholangiocarcinoma; IL-6: Interleukin-6; HCC: Hepatocellular carcinoma; HGF: Hepatocyte growth factor; PDGF: Platelet-derived growth factor; TGF-β: Transforming growth factor beta; VEGF: Vascular endothelial growth factor.

Table 2 Differential diagnosis of liver metastases and primary liver tumors: Histology, immunohistochemistry, and imaging perspectives

Feature	Liver metastases	Primary liver tumors (HCC/iCCA)	Key insights
Lesion number and distribution	Frequently multiple, scattered nodules of varying sizes; often in a non-cirrhotic liver	HCC: Typically, a solitary mass, occasionally with satellite nodules; iCCA: Usually, a single mass, often subcapsular	Multiple lesions in a non-cirrhotic liver strongly suggest metastases; a solitary lesion in cirrhosis favors HCC
Liver background	Generally, arises in a normal liver without underlying chronic disease	HCC: Commonly associated with cirrhosis or chronic hepatitis; iCCA: May arise in chronic liver disease or normal liver	The presence of cirrhosis significantly increases the likelihood of HCC over metastases
Gross morphology	Well-defined, spherical nodules; cut surface varies by primary site (e.g., firm, mucinous, or necrotic)	HCC: Soft, tan-yellow mass, often with a pseudocapsule; iCCA: Firm, white mass with fibrotic stroma and capsular retraction	Capsular retraction suggests iCCA; a pseudocapsule is more typical of HCC; metastases lack a true capsule
Histologic pattern	Reflects the primary tumor morphology (e.g., glandular, mucinous, or neuroendocrine)	HCC: Thickened trabeculae of hepatocyte-like cells; iCCA: Irregular, malignant glandular structures with dense stroma	Tumor architecture in metastases mirrors the origin; HCC shows disrupted lobular architecture, while iCCA exhibits desmoplasia
Cytologic features	Variable: Mucin production, signet-ring cells, neuroendocrine differentiation, or squamous features, depending on primary	HCC: Polygonal cells with eosinophilic or clear cytoplasm, bile pigment may be present; iCCA: Columnar cells with intracellular mucin	Bile pigment is a hallmark of hepatocellular differentiation; mucin suggests cholangiocarcinoma or metastases
Reticulin staining	Reticulin framework usually preserved, outlining glandular or nested structures	HCC: Loss or fragmentation of reticulin due to thickened plates; iCCA: Often retains reticulin around malignant glands	Reticulin stain helps distinguish HCC (loss of framework) from metastases (preserved reticulin)
Vascular features	Lacks unpaired arteries; sinusoidal or vascular invasion typically at tumor-liver interface	HCC: Characteristically shows unpaired arteries and sinusoidal-like vasculature; iCCA: Tends to invade portal structures	Presence of unpaired arteries supports HCC; vascular invasion is common in both but more characteristic in HCC
Hepatocellular markers	Negative for hepatocytic markers such as HepPar1, arginase-1, and glypican-3	HCC: Typically, positive for HepPar1, arginase-1 (most specific), and glypican-3; iCCA: Generally negative for these markers	Hepatocytic marker panel (HepPar1, arginase-1, glypican-3) is essential to confirm HCC
Cytokeratin profile	Varies by origin, e.g., colorectal (CK20+/CDX2+), breast (CK7+/GATA3+), lung (CK7+/TTF-1+)	HCC: Usually CK7−/CK19−; iCCA: CK7+/CK19+ in most cases	CK7/CK19 positivity favors cholangiocarcinoma or metastases; CDX2 positivity suggests colorectal origin
Additional immunohistochemical markers	Site-specific, e.g., CDX2 (colorectal), TTF-1 (lung), GATA3 (breast). Polyclonal CEA shows diffuse membranous pattern in adenocarcinomas	HCC: Polyclonal CEA shows canalicular (beaded) staining; alpha-fetoprotein may be positive (approximately 50% cases); iCCA: May express carbohydrate antigen 19-9 and luminal CEA	Canalicular CEA pattern is characteristic of HCC; diffuse membranous pattern suggests adenocarcinoma
Imaging characteristics	Typically, hypovascular on arterial phase with rim or peripheral enhancement (target sign); enhancement less than liver in portal phase	HCC: Arterial phase hyperenhancement with washout in portal/delayed phases; iCCA: Peripheral rim enhancement with gradual centripetal fill-in	Imaging enhancement pattern is key: Hypervascular with washout favors HCC; rim enhancement with delayed fill suggests iCCA/metastasis
Other imaging features	Often multiple, no pseudocapsule, calcifications possible (especially in mucinous tumors); no background liver disease	HCC: Solitary, in cirrhotic liver, with pseudocapsule; iCCA: Subcapsular location, capsular retraction, peripheral biliary dilatation	Capsular retraction and biliary dilation are typical of iCCA; multiple lesions in non-cirrhotic liver favor metastases

CDX: Caudal-related homeobox; CEA: Carcinoembryonic antigen; CKA; Cytokeratin; HCC: Hepatocellular carcinoma; iCCA: Intrahepatic cholangiocarcinoma; TTF: Thyroid transcription factor.