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

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.