HCC vs IHCC - Clinical Reasoning

HL

HepatoLogic Clinical Reasoning

100% Local • No External API

Integrated Symbolic Differentiation & Treatment Eligibility for HCC, iCCA, Combined & Collision Tumors

Rule-Based Symbolic Decision Support • LI-RADS, EASL, ILCA & NCCN Aligned

Comprehensive Integrated Approach to Differentiating HCC vs. iCCA

Accurately distinguishing Hepatocellular Carcinoma (HCC) from Intrahepatic Cholangiocarcinoma (iCCA)—as well as recognizing Combined HCC-CCA (cHCC-CCA), Collision Tumors, and Synchronous Lesions—requires integrating patient demographics, liver reserve, risk factors, tumor markers, and multimodal imaging. This tool guides you step-by-step and runs a transparent symbolic rule engine to determine diagnosis, biopsy needs, and treatment eligibility.

How the Diagnostic & Treatment Pathway Works

The assessment is broken into four simple clinical steps followed by automated symbolic reasoning.

Step 1

Demographics & Fitness

Documents ECOG performance status, Child-Pugh liver reserve, portal hypertension (CSPH), future liver remnant (FLR), and variceal bleeding risk.

Governs surgical & systemic safety

Step 2

Clinical History & Risk

Evaluates pre-test probability from cirrhosis, chronic HBV/HCV, MASH, PSC, hepatolithiasis, liver flukes, prior malignancy, and active cholangitis.

Establishes LI-RADS eligibility

Step 3

Labs & Tumor Markers

Integrates AFP, AFP-L3, PIVKA-II/DCP, CA 19-9, CEA, bilirubin, ALP/GGT cholestasis, and platelets—including cholangitis confounder checks.

Detects dual or confounded markers

Step 4

Imaging, PET & Genomics

Captures CT/MRI dynamic phases (APHE, washout vs. delayed stromal enhancement), CEUS, DWI/HBP, MRCP, capsular retraction, and spatial architecture.

Separates LR-5, LR-M & mixed tumors

Analyze

Reasoning & Eligibility

Generates the diagnostic phenotype, biopsy strategy, rule-by-rule explanation, and eligibility across Resection, Transplant, Ablation, TACE/TARE, and Systemic therapy.

Complete MDT report output

Explore Pre-Configured Clinical Scenarios

Select any representative patient scenario below to load its clinical parameters and inspect the reasoning output.

Scenario 1 LI-RADS LR-5

Classic Resectable HCC

3.2 cm solitary mass in HBV cirrhosis (Child-Pugh A, no portal hypertension). Non-rim APHE, washout, enhancing capsule, AFP 420 ng/mL.

Scenario 2 LI-RADS LR-M

Classic Mass-Forming iCCA (FGFR2+)

5.8 cm mass in non-cirrhotic PSC liver. Rim APHE, delayed central stromal enhancement, capsular retraction, ductal dilatation, regional nodes.

Scenario 3 Mixed Phenotype

Combined HCC-iCCA (cHCC-CCA)

Single heterogeneous tumor with intimate admixture of arterialized washout and delayed fibrotic enhancement, plus elevated AFP and CA 19-9.

Scenario 4 Dual-Zone Cleft

Hepatic Collision Tumor

Two contiguous but sharply distinct tumor zones within one mass separated by a visible cleft, showing discordant MRI and FDG/FAPI PET uptake.

Scenario 5 Multicentric

Synchronous HCC + iCCA

Separate intrahepatic nodules with discordant kinetics—one classic LR-5 arterialized nodule and a second targetoid LR-M mass with duct dilatation.

Scenario 6 Safety Gate Test

Obstructive Cholangitis & Varices

Targetoid mass presenting with acute cholangitis (CA 19-9 1,850 U/mL, Bilirubin 8.4 mg/dL) and untreated high-risk gastroesophageal varices.

Patient Clinical Assessment

Complete the four clinical domains below, then click Analyze Case to run the reasoning engine.

Load Example Case: -- Choose a preset scenario -- 1. Classic Resectable HCC (LR-5) 2. Classic iCCA (LR-M, FGFR2+) 3. Combined HCC-iCCA (cHCC-CCA) 4. Hepatic Collision Tumor 5. Synchronous HCC + iCCA 6. Obstructive Cholangitis Confounder

Step 1 of 4

Demographics, Functional Status & Hepatic Reserve

These factors determine surgical resectability, transplant candidacy, and systemic therapy safety.

Patient Age Range & Presentation Surveillance-Detected Nodule (Asymptomatic) Incidental Mass on Routine Imaging Weight Loss, Pain, or Cholestatic Jaundice Hepatic Decompensation (Ascites / Encephalopathy)

ECOG Performance Status ECOG 0–1 (Preserved Fitness) ECOG 2 (Borderline / Restricted) ECOG 3–4 (Frail / Best Supportive Care)

Child-Pugh Hepatic Reserve Class Child-Pugh A (Well-Compensated Reserve) Child-Pugh B (Moderately Impaired) Child-Pugh C (Decompensated Cirrhosis)

Future Liver Remnant (FLR) & Anatomy Adequate FLR (≥30% normal or ≥40% cirrhotic) Borderline FLR (Needs PVE / Downstaging) Inadequate FLR / Bilobar Prohibitive Anatomy

Variceal / Bleeding / Immunotherapy Risk No Untreated High-Risk Varices (Cleared for Anti-VEGF) Untreated High-Risk Varices / Active Bleeding Risk Severe Autoimmune Contraindication to Immunotherapy

Clinically Significant Portal HTN (CSPH)

Splenomegaly, varices, ascites, or HVPG ≥10 mmHg

Step 2 of 4

Clinical History, Liver Background & Risk Factors

Cirrhosis strongly increases the prior probability of HCC but does not exclude iCCA or cHCC-CCA. Non-cirrhotic livers can still develop HCC (especially in chronic HBV or MASH).

Factors Favoring Hepatocellular (HCC) Context

Cirrhosis or Advanced Chronic Hepatic Fibrosis

Any etiology (qualifies patient for CT/MRI LI-RADS application)

Chronic Hepatitis B / C, Alcohol, or MASH / NASH

Includes non-cirrhotic chronic HBV, hemochromatosis, AIH, or A1AT deficiency

Factors Favoring Biliary (iCCA) or Alternative Context

Biliary Disease (PSC, Hepatolithiasis, Choledochal Cyst, Flukes)

Primary sclerosing cholangitis, recurrent pyogenic cholangitis, liver flukes

History of Extrahepatic Primary Malignancy

Colorectal, pancreatic, breast, lung, or neuroendocrine primary (raises metastasis differential)

Active Cholangitis or Untreated Biliary Obstruction

Important: Falsely elevates CA 19-9 and requires biliary drainage prior to systemic chemotherapy

Optional: Quick Clinical Note Keyword Extractor (Local Only) Extracts clinical features automatically

Step 3 of 4

Tumor Markers & Laboratory Profile

Marked AFP/AFP-L3/PIVKA-II elevation supports HCC, whereas CA 19-9/CEA with cholestatic liver tests favors iCCA. Co-elevation of both AFP and CA 19-9 raises suspicion for combined cHCC-CCA or collision tumor.

Alpha-Fetoprotein — AFP (ng/mL) Normal <20; ≥200 strongly supports HCC component

AFP-L3 (%) & PIVKA-II / DCP Elevated (Supports Hepatocellular Differentiation) Normal / Not Elevated Normal biomarkers do not exclude HCC

CA 19-9 (U/mL) ≥100 favors iCCA if obstruction/cholangitis excluded

Carcinoembryonic Antigen — CEA (ng/mL) ≥5.0 ng/mL supports cholangiocellular or metastatic etiology

Total Bilirubin (mg/dL) Used for hepatic reserve & biliary obstruction check

ALP & GGT Cholestatic Profile Normal or Mildly Elevated Markedly Cholestatic Pattern (High ALP/GGT) More common in duct-invading or mass-forming iCCA

Platelet Count (×10³/μL) <100 ×10³/μL suggests portal hypertension

Step 4 of 4

Multimodal Imaging (CT/MRI/CEUS/MRCP/PET), Staging & Genomics

The highest-yield combination favoring iCCA over atypical HCC is rim/peripheral APHE + progressive delayed central enhancement, particularly with capsular retraction, biliary dilatation, or lymphadenopathy.

A. Spatial Topology & Multiphasic Enhancement Kinetics

Lesion Spatial Topology (Single vs. Combined vs. Collision vs. Synchronous) Single Mass — Uniform / Classic Phenotype Throughout Single Mass — Intimately Intermixed / Transitional (Combined cHCC-CCA pattern) Single Mass — Two Contiguous Distinct Zones with Visible Cleft/Interface (Collision pattern) Separate Distinct Liver Lesions with Discordant HCC & iCCA Kinetics (Synchronous pattern)

Index Lesion Diameter (cm)

Arterial Phase Enhancement (APHE) Non-rim APHE (Arterialized HCC Feature) Rim or Peripheral Irregular APHE (LR-M / iCCA Feature) Dual-Zone (Non-rim APHE in one region + Rim APHE in another) Hypo- or Iso-enhancing

Portal Venous & Delayed Phase Non-peripheral Washout (Classic HCC Feature) Progressive Centripetal Delayed Enhancement (Fibrous Stroma / iCCA) Simultaneous Washout + Delayed Fibrotic Enhancement (Mixed) No Washout / Persistent Enhancement

Contrast-Enhanced Ultrasound (CEUS) Non-rim APHE with Late (≥60s) & Mild Washout (HCC) Rim APHE or Early (<60s) & Marked Washout (LR-M / iCCA) CEUS Not Performed

B. Morphology, DWI, Hepatobiliary Phase & Ancillary Clues

Tumor Margins, Capsule & Internal Architecture Round/Oval Expansile with Enhancing Capsule / Mosaic Irregular, Lobulated or Infiltrative (No Capsule) Capsule-like Margin with Internal Fibrotic/Targetoid Stroma

MRI DWI, T2 & Hepatobiliary Phase (HBP) Heterogeneous DWI Restriction & Uniform HBP Hypointensity Targetoid DWI, Targetoid T2 (Dark Fibrotic Center) & Targetoid HBP Spatially Discordant DWI / T2 / HBP Across Tumor Zones HBP Iso-/Hyperintense (Well-diff or β-catenin-activated HCC)

Hepatic Capsular Retraction Present Intralesional Fat, Hemorrhage, or Nodule-in-Nodule Threshold Growth (≥50% size increase in ≤6m)

C. Biliary Tree (MRCP), Vascular Behavior, Staging, PET & Molecular Markers

Bile Ducts & MRCP Assessment No Upstream Biliary Dilatation or Encasement Segmental/Lobar Ductal Dilatation & Duct Encasement Intraductal Tumor Extension

Portal / Hepatic Vein Behavior No Macrovascular Invasion or Encasement Enhancing Expansile Tumor-in-Vein (TIV — Favors HCC) Fibrotic Vessel Encasement / Narrowing (Favors iCCA) Both Expansile TIV and Biliary/Vascular Encasement

Nodal & Extrahepatic Disease Extent Solitary & Liver-Confined Multifocal Liver-Confined / Satellite Nodules Regional Porta Hepatis Lymphadenopathy Extrahepatic Metastases (Peritoneum, Lung, Bone, Adrenal)

FDG & FAPI PET/CT Findings PET Not Performed / Low Avidity Moderate-Intense FDG + Prominent Desmoplastic CAF FAPI Uptake Spatially Discordant FDG/FAPI Uptake Between Tumor Zones

Actionable Molecular / Genomic Profile (If Biopsy Performed) Pending / Not Yet Profiled (Order NGS if iCCA or cHCC-CCA suspected) FGFR2 Fusion or Rearrangement (Pemigatinib / Futibatinib eligible) IDH1 Mutation (Ivosidenib eligible) BRAF V600E Mutation (Dabrafenib + Trametinib eligible) HER2 (ERBB2) Amplification / Overexpression (HER2-Targeted eligible) NTRK Fusion (Larotrectinib / Entrectinib / Repotrectinib eligible) MSI-H / dMMR or TMB-High (Checkpoint Inhibitor eligible) RET Fusion or KRAS G12C Mutation (Matched Targeted Therapy eligible)

Integrated Diagnostic & Treatment Eligibility Report

Generated deterministically from clinical history, hepatic reserve, laboratory biomarkers, and multimodal imaging.

LI-RADS: LR-5 Classic Hepatocellular Carcinoma (HCC)

Classic Expansile Arterialized Hepatocellular Carcinoma (LR-5)

Multi-Modal Feature Alignment

Favors HCC (Arterial / Capsule): 90%

Favors iCCA (Targetoid / Stroma): 10%

Mixed / Combined / Collision Clues: 0%

Conditional Treatment Eligibility & Modality Matrix

Evaluated across diagnostic certainty, hepatic reserve (Child-Pugh/CSPH/FLR), ECOG status, vascular/biliary anatomy, and tumor stage.

CURATIVE INTENT

Supportive & Parallel Care Checklist:

Treat underlying HBV/HCV, optimize nutrition and alcohol abstinence, screen/manage gastroesophageal varices prior to anti-VEGF therapy, and ensure biliary drainage if obstruction or cholangitis is present.

Recommended Imaging Surveillance & Follow-up:

Biopsy & Histopathology Strategy

NOT MANDATORY

Immunohistochemistry (IHC) Panel: Hepatocellular: Arginase-1, HepPar-1, Glypican-3, canalicular pCEA | Cholangiocellular: CK7, CK19, MOC31

Symbolic Reasoning Rule Trace

Transparent step-by-step clinical logic triggered by this patient's findings.

0 Rules Fired

Structured Radiology & Multidisciplinary Tumor Board Report

Ready to paste into clinical documentation or MDT notes.

Clinician Sign-Off & Override

This system provides clinical decision support. Record the attending clinician or tumor board disposition below.

Clinician / Tumor Board ID

Disposition Accept Diagnostic & Treatment Pathway Modify: Schedule Multi-Region Biopsy First Override per Multidisciplinary Consensus

Clinical Note

Local Session Log 0 Entries

High-Yield Multi-Modal Distinction: HCC vs. iCCA

Practical rule: HCC usually behaves as an expansile arterialized hepatocellular mass (non-rim APHE, washout, capsule, fat, mosaic, tumor-in-vein), whereas iCCA behaves as a fibrotic/desmoplastic mass (rim APHE, progressive delayed central enhancement, capsular retraction, targetoid diffusion, biliary dilatation, regional nodes).

Diagnostic Domain	Favors HCC (LR-5 Phenotype)	Favors iCCA (LR-M Fibrotic Phenotype)
Clinical Setting & Risk	Cirrhosis, chronic HBV/HCV, alcohol, MASH/NASH, hemochromatosis, AIH, aflatoxin, A1AT	Primary sclerosing cholangitis (PSC), hepatolithiasis, choledochal cyst, liver flukes, chronic biliary disease
Arterial Phase (APHE)	Non-rim arterial phase hyperenhancement (APHE)	Rim or peripheral APHE (often thick or irregular)
Portal / Delayed Phase	Non-peripheral washout ± enhancing capsule/pseudocapsule	Progressive, persistent, or centripetal delayed enhancement of fibrous stroma
CEUS Kinetics	Non-rim hyperenhancement; late (≥60s) and mild washout	Rim enhancement; early (<60s) and marked washout
Morphology & Capsule	Round/oval expansile, encapsulated; mosaic architecture; intralesional fat or hemorrhage	Irregular, lobulated or infiltrative; central fibrosis; hepatic capsular retraction
Biliary & Vascular	Enhancing expansile tumor-in-vein (portal/hepatic vein); duct dilatation uncommon	Segmental/lobar ductal dilatation, duct encasement, fibrotic vessel narrowing/encasement
DWI, T2 & HBP MRI	Heterogeneous DWI restriction; mild-moderate T2; HBP hypointense (well-diff may be iso/hyper)	Targetoid DWI restriction (cellular rim, fibrotic center); targetoid T2 & HBP
Tumor Markers & LFTs	AFP, AFP-L3, PIVKA-II/DCP elevation	CA 19-9 & CEA elevation (reassess CA 19-9 after treating cholangitis/obstruction); cholestatic ALP/GGT
FDG & FAPI PET/CT	Variable FDG (well-diff often low; poorly-diff avid); lower/variable FAPI unless scirrhous	Moderate-intense FDG uptake (useful for staging nodes/mets); prominent FAPI uptake in desmoplastic stroma

Collision, Combined (cHCC-CCA) & Synchronous Tumors

1. Synchronous HCC and iCCA (Allen & Lisa Type 1)

Separate HCC and iCCA lesions occurring in different segments of the same liver with distinct enhancement patterns. Do not assume simple multifocal HCC when separate lesions exhibit discordant LR-5 and LR-M phenotypes.

2. Collision Tumor (Allen & Lisa Type 2 / Goodman Type I)

Two histologically independent primary tumors (biclonal origin) that arise separately and grow to directly abut/collide within the same mass with a clear fibrous interface/cleft and no true transition zone. Excluded from true monoclonal cHCC-CCA by the 2018 International Consensus & 2019 WHO 5th Edition; requires multi-region core biopsy sampling both distinct viable zones.

3. Combined HCC-iCCA (Allen & Lisa Type 3 / Goodman Type II / WHO 5th Ed.)

Single primary neoplasm (monoclonal/biphenotypic progenitor origin) containing intimate admixture/transition of hepatocellular (Arginase-1, HepPar-1, Glypican-3) and cholangiocellular (CK7, CK19, MOC31) differentiation. Categorize as LR-M; transplantation is non-standard.

Actionable iCCA Biomarkers & Targeted Systemic Therapies

Molecular Alteration	Matched Biomarker-Directed Therapy
First-Line Standard Backbone	Gemcitabine + Cisplatin + Durvalumab
FGFR2 Fusion / Rearrangement	Pemigatinib or Futibatinib
IDH1 Mutation	Ivosidenib
BRAF V600E	Dabrafenib + Trametinib
HER2 (ERBB2) Positive	HER2-Directed Therapy (Trastuzumab + Pertuzumab / Zanidatamab / T-DXd)
NTRK Fusion	Larotrectinib, Entrectinib, or Repotrectinib
MSI-H / dMMR / TMB-High	Immune Checkpoint Inhibitor Therapy
RET Fusion / KRAS G12C	Selpercatinib (RET) / Adagrasib or Sotorasib (KRAS G12C)

Verified Peer-Reviewed Literature & Nosology

Key Literature References by Diagnostic & Pathological Category

Authoritative pathology consensus statements, historical classifications, and international clinical practice guidelines defining each category in this reasoning engine.

Diagnostic Category	Pathological & Nosological Status	Primary Peer-Reviewed Literature References
1. Hepatic Collision Tumor (Contiguous HCC + iCCA with Cleft)	Real Biclonal Dual-Origin Entity Originally classified as Allen & Lisa Type 2 (1949) and Goodman Type I ("Collision Tumor") (1985). Formally separated from true monoclonal cHCC-CCA in the 2018 International Consensus & 2019 WHO 5th Ed.	• Allen RA, Lisa JR. Combined liver cell and bile duct carcinoma. Am J Pathol. 1949;25(4):647–655. PMID: 18152860. (Defined Type 2 contiguous colliding tumors vs. Type 1 separate & Type 3 admixed). • Goodman ZD, Ishak KG, Langloss JM, Sesterhenn IA, Rabin L. Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study. Cancer. 1985;55(1):124–135. PMID: 2578078. (Defined Type I "Collision Tumors" vs. Type II "Transitional Tumors"). • Brunt E, Aishima S, Clavien PA, et al. cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentiation. Hepatology. 2018;68(1):113–126. doi:10.1002/hep.29789. PMID: 29360137. (Explicitly distinguishes collision tumors of two independent primaries from true cHCC-CCA).
2. Combined HCC-CCA (cHCC-CCA) (Classical & Intermediate-Cell Types)	Monoclonal Biphenotypic Primary Single primary tumor showing intimate admixture of hepatocytic and cholangiocytic differentiation (Allen & Lisa Type 3 / Goodman Type II).	• Brunt E, Aishima S, Clavien PA, et al. cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentiation. Hepatology. 2018;68(1):113–126. PMID: 29360137. • Sempoux C, Kakar S, Kondo F, Schirmacher P. Combined hepatocellular-cholangiocarcinoma and undifferentiated primary liver carcinoma. In: WHO Classification of Tumours: Digestive System Tumours, 5th ed. Lyon: IARC Press; 2019:260–262. • Beaufrère A, Calderaro J, Paradis V. Combined hepatocellular-cholangiocarcinoma: an update. J Hepatol. 2021;74(5):1212–1224. doi:10.1016/j.jhep.2021.01.035. PMID: 33545267.
3. Synchronous Double Primary (HCC + iCCA) (Separate Intrahepatic Nodules)	Multicentric Independent Primaries Originally Allen & Lisa Type 1 (separate nodules of HCC and iCCA arising synchronously in the same liver without physical contact).	• Allen RA, Lisa JR. Combined liver cell and bile duct carcinoma. Am J Pathol. 1949;25(4):647–655. PMID: 18152860. (Type 1: separate synchronous nodules). • Jung KS, Chun KH, Choi GH, et al. Synchronous development of intrahepatic cholangiocarcinoma and hepatocellular carcinoma in different sites of the liver with chronic B-viral hepatitis. Gut Liver. 2013;7(5):609–614 / Cao J, et al. Synchronous double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma: a case series and review. World J Surg Oncol. 2013;11:276.
4. Hepatocellular Carcinoma (HCC) & LI-RADS LR-5 / LR-M	Hepatocytic Malignancy & Non-Invasive Imaging Criteria Defines LR-5 major features vs. LR-M targetoid features and BCLC/EASL curative vs. systemic pathways.	• European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol. 2025;82(2):315–374 (updating J Hepatol 2018;69:182–236). • Singal AG, Llovet JM, Yarchoan M, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78(6):1922–1965. PMID: 37199193. • Chernyak V, Fowler KJ, Kamaya A, et al. Liver Imaging Reporting and Data System (LI-RADS) Version 2018: Imaging of Hepatocellular Carcinoma in At-Risk Patients. Radiology. 2018;289(3):816–830. PMID: 30251931.
5. Intrahepatic Cholangiocarcinoma (iCCA) & Molecular Targets	Biliary Epithelial / Desmoplastic Malignancy Defines mass-forming/small-duct vs. large-duct iCCA, surgical lymphadenectomy, TOPAZ-1 1L regimen, and FGFR2/IDH1/BRAF/HER2 targeted therapy.	• European Association for the Study of the Liver & International Liver Cancer Association (EASL-ILCA). EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol. 2023;79(1):181–208. doi:10.1016/j.jhep.2023.03.010. PMID: 37084797. • Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(2):127–140. PMID: 36372281. • Oh DY, Ruth He A, Qin S, et al. (TOPAZ-1 Investigators). Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid. 2022;1(8):EVIDoa2200015.