How do you differentiate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC) by imaging, laboratory, and treatment strategies?

Differentiating Hepatocellular Carcinoma from Intrahepatic Cholangiocarcinoma

The most critical distinction between HCC and ICC relies on contrast-enhanced imaging patterns: HCC shows arterial hyperenhancement with portal venous/delayed washout, while ICC demonstrates peripheral rim enhancement with progressive centripetal fill-in on delayed phases, and this imaging difference directly determines whether patients receive locoregional therapies (for HCC) versus surgical resection or systemic chemotherapy (for ICC). 1

Imaging Differentiation

Primary Imaging Characteristics

HCC demonstrates arterial hyperenhancement followed by washout in the portal venous or delayed phase, which can be diagnosed non-invasively in cirrhotic patients with nodules >1 cm using multiphasic CT or MRI. 1

ICC typically appears as a hypodense mass with peripheral rim enhancement in the arterial phase, followed by progressive centripetal contrast fill-in on delayed phases (target appearance), reflecting the tumor's fibrous stroma. 1

Specific Imaging Features by Modality

CT/MRI Protocol Requirements

• Standard imaging must include unenhanced, arterial, portal venous, and delayed phases to capture the characteristic enhancement patterns. 1
• On MRI, ICC appears hypointense on T1-weighted and hyperintense on T2-weighted images, with central hypointensity corresponding to fibrosis. 1
• HCC in cirrhotic patients can be diagnosed without biopsy if typical vascular hallmarks are present on one imaging modality for lesions 1-2 cm, or if AFP >200 ng/mL accompanies characteristic imaging for lesions >2 cm. 1, 2

Critical Imaging Pitfalls

• CEUS shows overlap between HCC and ICC vascular profiles, making it less suitable for definitive differentiation despite its utility in HCC diagnosis within cirrhosis. 1
• Small duct-type ICC (arising in cirrhosis) frequently mimics HCC radiologically, with up to 11.4-63% of ICC cases receiving false-positive HCC diagnoses on imaging alone. 1
• FDG-PET is not recommended for HCC diagnosis and has limited utility for small (<1 cm) ICC lesions. 1

Laboratory Differentiation

Tumor Markers

AFP is elevated (>200 IU/mL) in a minority of HCC cases but has poor sensitivity (39-65%) and variable specificity (76-97%), making it unreliable as a standalone diagnostic tool. 1

CA 19-9 and CEA are more commonly elevated in ICC than HCC, though these markers lack sufficient specificity for definitive diagnosis. 1

Clinical Context Markers

• HCC occurs predominantly in cirrhotic livers (95-98% Child-Pugh A in clinical trials), with risk factors including hepatitis B, hepatitis C, and alcoholic liver disease. 3
• ICC can occur in non-cirrhotic livers and is associated with primary sclerosing cholangitis, hepatolithiasis, and liver fluke infection. 1

Pathological Differentiation When Biopsy Required

Indications for Biopsy

Biopsy is mandatory for all patients proceeding to systemic chemotherapy, radiation therapy, or clinical trial enrollment, and when imaging remains atypical or inconclusive after multiphasic contrast studies. 1

Biopsy should be avoided in three scenarios: (1) patients ineligible for any therapy due to comorbidity, (2) decompensated cirrhotics on transplant waiting lists, and (3) resectable lesions where surgical specimen will provide definitive diagnosis. 1

Histopathological Features

HCC diagnosis requires identification of trabecular alterations (>2 cells broad), pseudoglands, reticulin loss, and increased nuclear/cytoplasmic ratio, with immunohistochemistry using glutamine synthetase, glypican-3, and HSP70 (2/3 positivity = 70% sensitivity, 100% specificity). 1

ICC shows adenocarcinoma with tubular/papillary structures and variable fibrous stroma, requiring differentiation from metastatic adenocarcinoma using cytokeratin panels: ICC is K7(+), K19(+), K20(-). 1

Combined HCC-CC must be distinguished from pure HCC because it requires different therapeutic approaches; however, mixed features may not be visible on biopsy, and significant CK19 expression indicates poor prognosis in HCC. 1

Immunohistochemistry Panel

• For HCC: Hepatocytic markers (Hep Par 1, arginase 1, ABCB11), CD34 for sinusoidal capillarization, and the glutamine synthetase/glypican-3/HSP70 panel. 1
• For ICC differentiation from metastases: K7/K19/K20 panel, with additional markers (CDX2/SATB2 for colon, TTF-1/napsin A for lung, GATA3 for breast). 1

Treatment Strategy Differences

HCC Treatment Approach

Surgical resection or liver transplantation remains the primary curative option for early HCC, with transplant criteria being single lesion ≤5 cm or up to 3 lesions ≤3 cm (Milan criteria), achieving 5-year survival of 70-80%. 2, 3

Locoregional therapies (radiofrequency ablation, transarterial chemoembolization) are appropriate for unresectable HCC in patients with preserved liver function (Child-Pugh A/B). 1, 3

Sorafenib 400 mg twice daily is the established systemic therapy for advanced HCC, demonstrating median overall survival of 10.7 months versus 7.9 months with placebo (HR 0.69, p=0.00058). 3

ICC Treatment Approach

Surgical resection is the only curative option for localized ICC, with 5-year survival of 30-40%, significantly lower than HCC due to different tumor biology. 1, 2

Systemic chemotherapy (gemcitabine-based regimens) is first-line for unresectable or metastatic ICC, with targeted therapies (FGFR inhibitors, IDH inhibitors) reserved for patients harboring specific mutations. 1

Locoregional therapies have limited efficacy in ICC compared to HCC and are not standard treatment, though transarterial procedures may be considered in highly selected cases. 1

Critical Treatment Implications

Misdiagnosing ICC as HCC and treating with HCC-directed locoregional therapies results in suboptimal outcomes, as ICC requires systemic chemotherapy or surgical resection for any meaningful survival benefit. 1

The presence of cirrhosis and characteristic imaging allows non-invasive HCC diagnosis and immediate treatment initiation, whereas ICC typically requires tissue confirmation before systemic therapy, potentially delaying treatment. 1

Tumor seeding risk from biopsy is 2.7% with median interval of 17 months, but this is manageable and does not affect overall survival, making biopsy safe when clinically indicated. 1