Gastrointestinal

Hepatocellular carcinoma: screening, staging, and treatment

Clinical Overview and When to Suspect Hepatocellular Carcinoma

— Cirrhosis of any etiology (HCV, HBV, alcohol, MASH, hemochromatosis, PBC, autoimmune, alpha-1 antitrypsin)

— Chronic HBV without cirrhosis in Asian men >40, Asian women >50, Africans >20, family history of HCC, or high HBV DNA

— Aflatoxin exposure, often synergistic with HBV

— Stage 3 fibrosis from MASH even without overt cirrhosis (emerging surveillance candidate)

— New decompensation in previously compensated cirrhosis (ascites, encephalopathy, variceal bleed)

— Rising AFP or new liver mass on routine imaging

— Unexplained weight loss, RUQ pain, early satiety in a patient with known liver disease

— Paraneoplastic clues: erythrocytosis (EPO), hypoglycemia (IGF-2), hypercalcemia (PTHrP), watery diarrhea

Hepatocellular carcinoma (HCC) is the dominant primary liver malignancy in adults and the fastest-rising cause of cancer death in the US, driven by chronic HCV, NAFLD/MASH, alcohol, and HBV.

Arises almost exclusively in a background of chronic liver disease, especially cirrhosis (>90% of US cases). NAFLD-related HCC can occur in non-cirrhotic livers but is uncommon.

Key risk substrates to anchor suspicion:

When to suspect in clinic:

Step 3 management: In any cirrhotic with new ascites, hepatic decompensation, or portal vein thrombosis, order multiphasic contrast imaging to rule out HCC — decompensation is the most common "missed" trigger on board stems.

Board pearl: HCC is one of the few solid tumors that can be diagnosed radiographically without biopsy when classic LI-RADS 5 features are present in an at-risk patient — biopsy is not required and may risk seeding.

Mortality is high because diagnosis is often late; outpatient surveillance is the single highest-yield intervention an internist controls. Frame every cirrhotic visit around surveillance adherence, vaccination (HAV/HBV), and modifiable risk reduction (alcohol cessation, weight loss, HCV cure, HBV suppression).

Presentation Patterns and Key History

— Asymptomatic surveillance finding: nodule on q6-month ultrasound in a known cirrhotic

— Decompensation of stable cirrhosis: new ascites, jaundice, hepatic encephalopathy, or variceal bleed in a patient previously well-controlled

— RUQ pain or palpable mass: bulky tumor, capsular stretch, or hemorrhage

— Acute abdomen with hemoperitoneum: ruptured HCC, more common in large subcapsular tumors — mortality is high

— Paraneoplastic syndrome: erythrocytosis, hypoglycemia (often refractory), hypercalcemia, diarrhea, dermatomyositis

— Constitutional: weight loss, anorexia, low-grade fever, fatigue

— Hepatitis B/C status, prior treatment, sustained virologic response date

— Alcohol quantification (AUDIT-C), duration, current use

— Metabolic risk: BMI, T2DM, dyslipidemia, OSA — drivers of MASH

— Family history of HCC or HBV (vertical transmission cohorts)

— Iron overload symptoms, transfusion history, IV drug use, tattoos

— Aflatoxin-relevant exposures (immigration from endemic regions)

— Anabolic steroids, oral contraceptives (more for adenoma, but ask)

— Prior imaging and AFP trends — trajectory matters more than single value

HCC is clinically silent in early stages — this is precisely why surveillance, not symptoms, drives diagnosis. By the time symptoms appear, curative options are often lost.

Common presentation patterns on Step 3 stems:

Key history to elicit:

Key distinction: A cirrhotic with new-onset portal vein thrombosis should be assumed to have tumor thrombus from HCC until proven otherwise — order multiphasic CT/MRI urgently, not just anticoagulation.

Board pearl: Refractory hypoglycemia in a cirrhotic patient = think large HCC secreting IGF-2; check imaging before chasing endocrine causes.

Document surveillance adherence at every hepatology and PCP visit; non-adherence is the single biggest predictor of advanced-stage diagnosis and is a quality metric in value-based liver care programs.

Physical Exam Findings and Hemodynamic Assessment

— Spider angiomata, palmar erythema, gynecomastia, testicular atrophy

— Caput medusae, Cruveilhier-Baumgarten venous hum

— Dupuytren contracture, parotid enlargement (alcohol)

— Muscle wasting (sarcopenia is a transplant criterion modifier)

— Jaundice, scleral icterus, fetor hepaticus

— Hepatomegaly with a hard, nodular, sometimes pulsatile liver edge — pulsatility from arterial hypervascularity is classic

— Arterial bruit over the liver (~25% of advanced HCC) — high specificity

— Hepatic friction rub — capsular involvement

— Sudden ascites (often bloody on tap) or rapid worsening of existing ascites

— Right supraclavicular (Virchow) node — metastatic

— Ruptured HCC: tachycardia, hypotension, peritonitis, falling Hgb in a cirrhotic — emergent surgery/embolization

— Variceal hemorrhage as the decompensating event — apply standard resuscitation: 2 large-bore IVs, restrictive transfusion to Hgb 7, octreotide, ceftriaxone prophylaxis

Most early HCC has no specific exam findings — the exam reflects the underlying cirrhosis. The board task is recognizing decompensation layered on chronic stigmata.

Stigmata of chronic liver disease (background, always document):

Features suggesting HCC specifically:

Hemodynamic assessment matters in two scenarios:

CCS pearl: A cirrhotic presenting with shock + abdominal distension + drop in hematocrit — order STAT contrast CT abdomen, type & cross 4 units, consult IR for transarterial embolization of ruptured HCC; do not delay for AFP.

Step 3 management: Quantify decompensation at every visit using Child-Pugh (bilirubin, albumin, INR, ascites, encephalopathy) and MELD-Na — these drive both prognosis and treatment eligibility (resection vs. transplant vs. systemic therapy).

Board pearl: Bloody ascites on paracentesis in a cirrhotic is HCC until proven otherwise — send fluid for cytology, but proceed directly to multiphasic imaging.

Diagnostic Workup — Initial Labs and Surveillance Imaging

— Abdominal ultrasound ± AFP every 6 months

— Populations: all cirrhotics (Child-Pugh A/B, and C only if transplant candidate), plus non-cirrhotic HBV high-risk groups (Asian M >40, Asian F >50, African >20, family history, high HBV DNA)

— Do not screen Child-Pugh C non-transplant candidates — no survival benefit

— Cutoff ≥20 ng/mL raises suspicion; >200 ng/mL in a cirrhotic with a mass is highly suggestive

— AFP alone is not adequate — ~30% of HCCs are AFP-non-secretors

— Trend matters: a rising AFP in HCV cirrhosis warrants imaging even if absolute value is "normal"

— False positives: active hepatitis flare, pregnancy, germ cell tumors

— CBC (thrombocytopenia from portal HTN, erythrocytosis paraneoplastic)

— CMP (bilirubin, AST/ALT, alk phos, albumin)

— INR, PT (synthetic function)

— AFP, AFP-L3, DCP (des-gamma-carboxy prothrombin) if available — higher specificity

— Hepatitis serologies (HBsAg, HBV DNA, anti-HCV, HCV RNA)

— Iron studies, ceruloplasmin, alpha-1 antitrypsin if etiology unclear

— <1 cm: repeat US in 3-6 months (most are regenerative/dysplastic)

— ≥1 cm: proceed to multiphasic contrast CT or MRI with LI-RADS reporting

Surveillance protocol (AASLD) for at-risk adults:

AFP interpretation:

Initial labs in suspected HCC:

If ultrasound detects a nodule:

Step 3 management: Do not order AFP as a standalone screening test — it lacks sensitivity. Pair with ultrasound, and escalate to multiphasic imaging for any nodule ≥1 cm or rising AFP.

Board pearl: A normal AFP does not exclude HCC. Imaging is the decision-maker.

Key distinction: Ultrasound is for surveillance; multiphasic CT/MRI is for diagnosis and staging — never confuse the two roles on the exam.

Diagnostic Workup — Advanced and Confirmatory Studies

— Phases: arterial, portal venous, delayed (washout)

— Classic HCC signature: arterial hyperenhancement + portal/delayed washout + capsule appearance

— LR-1/2: definitely/probably benign — routine surveillance

— LR-3: intermediate probability — short-interval follow-up imaging

— LR-4: probably HCC — multidisciplinary review, often treat

— LR-5: definitely HCC — no biopsy required, proceed to staging/treatment

— LR-M: probably malignant, not specific to HCC — biopsy

— LR-TIV: tumor in vein — diagnostic of HCC with venous invasion

— LI-RADS LR-M or atypical imaging in a non-cirrhotic liver

— Discordance between imaging and clinical context

— Required for systemic therapy enrollment in some protocols

— Risks: bleeding (cirrhotic coagulopathy), needle-tract seeding (~2%)

— CT chest (lung is the #1 extrahepatic met site)

— Bone scan if symptoms or alk phos elevated

— Brain MRI only if symptomatic

— Assess portal vein, hepatic vein, IVC for tumor thrombus

— BCLC (Barcelona Clinic Liver Cancer) is the dominant system — integrates tumor burden, liver function (Child-Pugh), and performance status to dictate treatment

— AJCC TNM is used adjunctively, especially post-resection

— Child-Pugh class, MELD, platelet count, HVPG (hepatic venous pressure gradient — <10 mmHg favors resection), volumetric CT of future liver remnant

Multiphasic contrast-enhanced CT or MRI is the diagnostic gold standard:

LI-RADS categories (Liver Imaging Reporting and Data System):

When to biopsy:

Staging workup for confirmed HCC:

Staging systems:

Functional liver reserve assessment before resection:

Step 3 management: In a cirrhotic with an LR-5 lesion, do not biopsy — proceed to multidisciplinary tumor board for BCLC-stratified treatment.

Board pearl: Tumor thrombus in the portal vein distinguishes HCC from bland thrombosis on imaging — look for arterial enhancement within the thrombus.

Risk Stratification and BCLC-Driven Treatment Logic

— BCLC 0 (very early): single nodule ≤2 cm, Child-Pugh A, PS 0 → ablation or resection

— BCLC A (early): single ≤5 cm or ≤3 nodules each ≤3 cm, preserved function → resection, transplant, or ablation

— BCLC B (intermediate): multinodular, no vascular invasion, no extrahepatic spread → TACE (transarterial chemoembolization)

— BCLC C (advanced): portal invasion or extrahepatic spread, PS 1-2 → systemic therapy (atezolizumab + bevacizumab first-line)

— BCLC D (terminal): PS >2 or Child-Pugh C non-transplant → best supportive care

— Preserved liver function (Child-Pugh A, MELD low)

— Limited tumor burden

— No macrovascular invasion or extrahepatic disease

— Single lesion ≤5 cm, OR

— Up to 3 lesions, each ≤3 cm, AND

— No vascular invasion, no extrahepatic spread

— Patients within Milan receive MELD exception points to prioritize listing

— Expanded criteria (UCSF) used at select centers

— Non-cirrhotic HCC

— Compensated cirrhotics with single tumor, no portal HTN (HVPG <10, platelets >100k, normal bilirubin)

BCLC staging maps directly to treatment — memorize this framework:

Curative-intent options require:

Transplant criteria — Milan criteria (highest yield):

Resection preferred over transplant in:

Step 3 management: Every newly diagnosed HCC should be discussed at a multidisciplinary tumor board (hepatology, surgery, transplant, IR, oncology, radiation) — this is now a quality metric in NCI-designated and value-based care contracts.

Key distinction: Resection removes tumor but leaves diseased liver (recurrence ~70% at 5 years); transplant treats both tumor and cirrhosis (recurrence <15%) — favored when Milan-eligible with significant portal HTN.

Board pearl: Portal vein tumor thrombus = BCLC C, not curable surgically — systemic therapy or clinical trial.

Pharmacotherapy — Systemic Therapy First-Line and Beyond

— Atezolizumab (anti-PD-L1) + bevacizumab (anti-VEGF) — IMbrave150 trial showed superior OS vs sorafenib

— Prerequisite: EGD within 6 months to screen/treat varices before bevacizumab (bleeding risk)

— Contraindications: untreated varices, recent GI bleed, autoimmune disease for atezolizumab, uncontrolled HTN

— Durvalumab + tremelimumab (HIMALAYA trial) — option when bevacizumab contraindicated

— Sorafenib or lenvatinib (oral multikinase inhibitors) — historical first-line, still used when immunotherapy contraindicated

— Regorafenib (after sorafenib progression)

— Cabozantinib

— Ramucirumab (if AFP ≥400)

— Nivolumab ± ipilimumab, pembrolizumab

— Sorafenib/lenvatinib: hand-foot skin reaction, hypertension, diarrhea, fatigue

— Bevacizumab: hypertension, proteinuria, bleeding (especially variceal), thromboembolism, GI perforation

— Immune checkpoint inhibitors: immune-related hepatitis, colitis, pneumonitis, thyroiditis, hypophysitis — treat with high-dose steroids

Systemic therapy is reserved for BCLC C (advanced HCC with vascular invasion or extrahepatic spread) or progression after locoregional therapy in BCLC B.

Eligibility requires Child-Pugh A liver function and PS 0-1; Child-Pugh B is controversial and trial-dependent.

First-line standard of care:

Alternative first-line:

Second-line and beyond:

Major adverse effects to monitor:

Step 3 management: Before starting atezolizumab/bevacizumab, order EGD, baseline BP, UA for proteinuria, TSH, LFTs. Re-check LFTs and TSH every cycle.

Board pearl: New transaminitis in a patient on checkpoint inhibitor = immune-mediated hepatitis — hold drug, start prednisone 1-2 mg/kg, rule out viral reactivation. Do not restart bevacizumab/atezolizumab combination if grade ≥3 hepatitis recurs.

Key distinction: HCC is chemotherapy-resistant — traditional cytotoxics like doxorubicin and 5-FU are not standard.

Procedures — Ablation, TACE, TARE, Resection, Transplant

— Radiofrequency ablation (RFA) or microwave ablation (MWA)

— Best for tumors ≤3 cm; equivalent to resection for very small (<2 cm) lesions

— Avoid near major vessels (heat sink), bowel, or gallbladder

— Ideal patient: single tumor, no portal HTN, Child-Pugh A, adequate future liver remnant (≥30% normal, ≥40% cirrhotic)

— Post-op recurrence ~70% at 5 years — driven by underlying cirrhosis

— Best long-term outcome when eligible — treats tumor + cirrhosis

— Bridging therapy (TACE, ablation) used while on waitlist to prevent dropout

— Downstaging beyond Milan with TACE/Y-90 can re-establish eligibility

— Catheter delivery of chemo (doxorubicin) + embolic material via hepatic artery

— Exploits HCC's arterial blood supply (normal liver is portal-fed)

— Contraindicated in main portal vein thrombosis, decompensated cirrhosis, extrahepatic disease

— Yttrium-90 microspheres — alternative to TACE, especially with segmental portal vein thrombosis (TACE contraindicated there)

— Lower post-embolization syndrome than TACE

— Increasingly used for tumors not amenable to ablation or as bridge to transplant

Locoregional and surgical options form the backbone of curative and intermediate-stage treatment.

Percutaneous ablation (BCLC 0/A, small tumors):

Surgical resection (BCLC 0/A):

Liver transplantation (BCLC A, Milan criteria):

Transarterial chemoembolization (TACE) (BCLC B):

Transarterial radioembolization (TARE / Y-90):

Stereotactic body radiotherapy (SBRT):

CCS pearl: For a cirrhotic with multinodular HCC, preserved liver function, and no vascular invasion → order TACE consult with IR, schedule follow-up multiphasic MRI at 4-6 weeks to assess response (mRECIST criteria).

Board pearl: Post-TACE syndrome (fever, RUQ pain, nausea, transaminitis) is expected for 3-7 days — supportive care, not infection workup unless prolonged or febrile neutropenia.

Special Populations — Elderly and Renal/Hepatic Impairment

— Chronologic age alone is not a contraindication to curative therapy

— Assess functional status, frailty (Fried criteria), sarcopenia, comorbidity burden, and cognitive status before resection or transplant

— Many transplant centers cap listing at age 70-75, though selected fit patients up to 75 are listed

— Ablation and TACE are well-tolerated in elderly; resection morbidity rises sharply

— Goals-of-care discussion early — especially with BCLC C disease

— Child-Pugh A: full menu — resection, transplant, ablation, TACE, systemic therapy

— Child-Pugh B: limited curative options; TACE selectively; systemic therapy controversial; transplant remains an option if Milan-eligible

— Child-Pugh C: transplant only (if Milan-eligible); otherwise best supportive care

— MELD-Na drives transplant prioritization; HCC patients within Milan receive MELD exception points that increase every 3 months

— Contrast considerations: gadolinium-based MRI agents — avoid group 1 agents (gadodiamide) in eGFR <30; macrocyclic agents (gadobutrol, gadoteridol) preferred

— Iodinated contrast: standard NSF/AKI precautions

— Hepatorenal syndrome in advanced cirrhosis — terlipressin (now FDA-approved in US), albumin, midodrine + octreotide

— Sorafenib and lenvatinib do not require renal dose adjustment, but tolerability worse in CKD

— Bevacizumab: monitor proteinuria; hold if >2 g/day or nephrotic

Elderly patients (>75):

Hepatic impairment (the central issue in HCC):

Renal impairment:

Step 3 management: Before any HCC therapy decision, stage liver function (Child-Pugh, MELD-Na) and renal function (eGFR, UA for proteinuria) — both reshape the treatment algorithm.

Board pearl: A Child-Pugh C cirrhotic with HCC outside Milan = comfort care/hospice. Aggressive therapy worsens outcomes. This is a recurring ethics/management vignette.

Special Populations — Pregnancy, HBV Vertical Transmission, and Pediatric Considerations

— Most often in women with chronic HBV or cirrhosis

— AFP is elevated physiologically in pregnancy — interpret with caution

— Imaging: ultrasound and non-contrast MRI preferred; avoid gadolinium (especially first trimester); CT only if essential

— Management individualized: resection feasible in 2nd trimester; systemic therapy generally deferred; bevacizumab and TKIs are teratogenic (category D/X)

— Transplant during pregnancy is exceptional; usually post-delivery

— All pregnant women: HBsAg screening at first prenatal visit

— If HBsAg+: check HBV DNA; if >200,000 IU/mL, give tenofovir in 3rd trimester (week 28)

— Newborn of HBsAg+ mother: HBIG + HBV vaccine within 12 hours of birth, complete series

— This reduces lifetime HCC risk dramatically — single most impactful primary prevention

— Rare; consider in children with chronic HBV, tyrosinemia, biliary atresia, glycogen storage disease, Alagille

— Hepatoblastoma, not HCC, is the dominant pediatric liver tumor under age 5 — AFP markedly elevated, associated with Beckwith-Wiedemann and FAP

— Young patients (15-35), no underlying cirrhosis, normal AFP

— Often elevated neurotensin and B12 binding protein

— Treatment: surgical resection is mainstay; systemic options limited

HCC in pregnancy is rare but high-yield:

HBV vertical transmission prevention (critical Step 3 outpatient task):

Pediatric HCC:

Fibrolamellar HCC — distinct entity:

Step 3 management: Every pregnant patient with chronic HBV → check HBV DNA, refer to hepatology, plan tenofovir at 28 weeks if viral load >200,000 IU/mL, ensure birth dose vaccine and HBIG protocol with L&D team.

Board pearl: Young adult, no cirrhosis, normal AFP, large liver mass = fibrolamellar HCC — proceed to resection, not biopsy-and-systemic-therapy.

Key distinction: Hepatoblastoma (kids, AFP very high) vs HCC (older, cirrhosis) vs fibrolamellar (young adult, no cirrhosis, normal AFP).

Complications and Adverse Outcomes

— Tumor rupture with hemoperitoneum — sudden RUQ pain, shock, hemoglobin drop in a cirrhotic; mortality 25-75%. Emergent transarterial embolization by IR is first-line; surgery if unstable.

— Portal vein tumor thrombus — accelerates decompensation, precludes curative therapy, defines BCLC C

— Biliary obstruction — from tumor invasion or hilar mass; presents as painless jaundice

— Paraneoplastic syndromes: hypoglycemia (IGF-2), erythrocytosis (EPO), hypercalcemia (PTHrP), watery diarrhea, dermatomyositis

— Metastases: lung > bone > adrenal > brain

— Post-TACE syndrome: fever, RUQ pain, nausea, transaminitis — self-limited

— Liver failure post-resection: "small-for-size syndrome" if remnant <30%

— Post-ablation: hemorrhage, bile leak, abscess, pleural effusion

— TKI toxicities: hand-foot syndrome, HTN, fatigue, diarrhea

— Bevacizumab: variceal bleeding, proteinuria, thromboembolism, GI perforation, impaired wound healing (hold 4-6 weeks pre-op)

— Checkpoint inhibitor irAEs: hepatitis, colitis, pneumonitis, endocrinopathies, dermatitis

— Variceal hemorrhage (especially with bevacizumab)

— Ascites and SBP — diagnostic paracentesis (PMN >250 = SBP, treat with ceftriaxone + albumin day 1 and day 3)

— Hepatic encephalopathy — lactulose, rifaximin

— Hepatorenal syndrome

— Tumor recurrence (~10-15%), often within 2 years

— Immunosuppression complications (CNI nephrotoxicity, PTLD, infections)

Tumor-related complications:

Treatment-related complications:

Cirrhosis-related complications worsened by HCC:

Post-transplant:

CCS pearl: A cirrhotic with HCC on bevacizumab presenting with hematemesis — stop bevacizumab, resuscitate, octreotide drip, ceftriaxone, urgent EGD, plan band ligation. Do not restart bevacizumab after variceal bleed.

Board pearl: Refractory hypoglycemia + large liver mass = IGF-2-secreting HCC paraneoplastic; treat hypoglycemia with dextrose + glucocorticoids, definitive therapy is tumor control.

When to Escalate Care — ICU, Consults, and Transitions

— Ruptured HCC with hemodynamic instability

— Massive variceal hemorrhage in HCC patient

— Grade III-IV hepatic encephalopathy with airway compromise

— Severe immune-related adverse events (myocarditis, pneumonitis with hypoxia, colitis with perforation)

— Acute-on-chronic liver failure with multi-organ involvement

— Hepatology: any new HCC diagnosis, decompensation, transplant evaluation

— Transplant surgery: Milan-eligible candidates, expedited listing

— Interventional radiology: TACE, Y-90, ablation, tumor rupture embolization, portal vein thrombosis evaluation

— Surgical oncology / HPB surgery: resection candidates

— Medical oncology: BCLC C systemic therapy initiation

— Radiation oncology: SBRT candidates, bone metastases palliation

— Palliative care: BCLC D, Child-Pugh C non-transplant, symptom burden — early integration improves outcomes

— Standard of care for every new HCC

— Required for transplant listing in most US centers

— Documentation is a quality metric and often a payer requirement

— Discharge after TACE: ensure follow-up imaging at 4-6 weeks (mRECIST), labs at 1-2 weeks

— Post-resection: surveillance imaging q3 months × 2 years, then q6 months

— Post-transplant: lifelong immunosuppression, surveillance for recurrence and de novo cancers

— Hand-off from inpatient to outpatient: medication reconciliation, surveillance schedule, transplant clinic appointment within 1-2 weeks — common transition-failure point on Step 3

ICU-level triggers:

Urgent consults:

Multidisciplinary tumor board:

Transitions of care:

Step 3 management: At discharge of any newly diagnosed HCC patient, schedule tumor board discussion, hepatology follow-up within 2 weeks, and ensure imaging/labs are ordered before discharge — do not rely on PCP to initiate.

CCS pearl: "Consult social work" and "schedule transplant evaluation" are valid orders on CCS cases for Milan-eligible candidates — psychosocial readiness is part of listing.

Key Differentials — Other Liver Mass Lesions

• Multiple liver masses can mimic HCC; distinguishing them on imaging and clinical context is high-yield.
• Hepatic hemangioma:
— Most common benign liver lesion
— Imaging: peripheral nodular enhancement with centripetal fill-in on contrast phases
— Asymptomatic; no treatment needed; do not biopsy (bleeding risk)
• Focal nodular hyperplasia (FNH):
— Young women, often incidental
— Central scar on MRI with delayed enhancement
— No malignant potential; no resection unless symptomatic
— Not associated with OCP use (unlike adenoma)
• Hepatic adenoma:
— Reproductive-age women on OCPs, anabolic steroid users, glycogen storage disease
— Risk of hemorrhage and malignant transformation to HCC (especially β-catenin mutated, >5 cm, males)
— Stop OCPs, resect if >5 cm or symptomatic
• Cholangiocarcinoma (intrahepatic):
— Risk factors: PSC, liver flukes (Clonorchis, Opisthorchis), hepatolithiasis, Caroli disease
— Imaging: delayed enhancement (opposite of HCC's arterial enhancement + washout)
— Elevated CA 19-9, not AFP
— LI-RADS LR-M category
• Hepatic abscess:
— Fever, RUQ pain, leukocytosis
— Pyogenic (E. coli, Klebsiella — Klebsiella in Asian/diabetic patients with metastatic complications) or amebic (Entamoeba histolytica, travel history)
— Treatment: drainage + antibiotics (pyogenic), metronidazole (amebic, often no drainage needed)
• Regenerative and dysplastic nodules:
— Common in cirrhosis; precursors to HCC
— Imaging follow-up at 3-6 months
• Key distinction: HCC = arterial enhancement + washout	Cholangiocarcinoma = delayed enhancement	Hemangioma = peripheral nodular fill-in	FNH = central scar
• Board pearl: OCP-using woman with a liver mass + hemoperitoneum = ruptured hepatic adenoma, not HCC. Stop OCPs, embolize, resect.

Key Differentials — Metastatic Disease and Systemic Mimics

— Colorectal (most common; check CEA, colonoscopy)

— Pancreatic, gastric, breast, lung, neuroendocrine, melanoma, ovarian

— Multiple lesions, non-cirrhotic liver → metastases

— Single hypervascular lesion in cirrhotic liver → HCC

— Hypovascular metastases (colon, pancreas): hypoenhancing on arterial phase

— Hypervascular metastases (neuroendocrine, RCC, melanoma, thyroid) can mimic HCC — biopsy if no risk factors for HCC

— AFP: HCC, germ cell, hepatoblastoma

— CEA: colorectal, gastric

— CA 19-9: pancreatic, cholangiocarcinoma

— Chromogranin A: neuroendocrine

— Hepatic congestion from right heart failure — nutmeg liver pattern, pulsatile flow

— Budd-Chiari syndrome: hepatic vein thrombosis; caudate lobe hypertrophy on imaging; hypercoagulable workup (JAK2, PNH, antiphospholipid)

— Sinusoidal obstruction syndrome (post-HSCT, bush teas)

— Sarcoidosis, granulomatous hepatitis — multiple small lesions

— Fungal microabscesses in immunocompromised

— Lymphoma (especially in transplant patients — PTLD), leukemia

— Amyloidosis — hepatomegaly with mildly elevated alk phos out of proportion to other LFTs

Metastatic liver disease is far more common than primary HCC in the US — always consider in non-cirrhotic livers.

Most common primaries metastasizing to liver:

Imaging clues:

Tumor markers:

Non-neoplastic mimics:

Systemic infiltrative disease:

Step 3 management: In a non-cirrhotic patient with multiple liver lesions, search for an extrahepatic primary first — CT chest/abdomen/pelvis, age-appropriate cancer screening, tumor markers, then targeted biopsy.

Key distinction: A solitary hypervascular lesion in a cirrhotic = HCC pathway (LI-RADS). Multiple lesions in a non-cirrhotic = metastatic workup. Do not anchor on HCC without the risk substrate.

Board pearl: New "HCC-like" lesion in a patient with known colon cancer history → it's a metastasis until proven otherwise — biopsy and check CEA.

Secondary Prevention and Long-Term Plan

— HCV: achieve sustained virologic response with direct-acting antivirals (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) — reduces but does not eliminate HCC risk; continue surveillance lifelong if cirrhotic

— HBV: tenofovir or entecavir indefinitely in cirrhotic or high viral load; goal is undetectable HBV DNA

— Alcohol: complete abstinence; offer naltrexone, acamprosate, behavioral support, AA referral

— MASH: weight loss (7-10%), Mediterranean diet, exercise, control T2DM (consider GLP-1 agonists, pioglitazone), statins are safe and beneficial

— Hemochromatosis: therapeutic phlebotomy to ferritin <50

— Vaccinations: HAV, HBV (if susceptible), pneumococcal (PCV20 or PCV15→PPSV23), annual influenza, COVID, RSV ≥60, Tdap, shingles ≥50, HPV per age

— Avoid hepatotoxins: acetaminophen max 2 g/day, no NSAIDs (renal/variceal bleed risk), no herbal supplements (kava, comfrey)

— Variceal screening: EGD at cirrhosis diagnosis; nonselective beta-blocker (carvedilol, propranolol, nadolol) or band ligation for medium/large varices

— Osteoporosis screening: DEXA — cirrhotics at high risk

— Post-curative therapy: multiphasic CT/MRI + AFP q3 months × 2 years, then q6 months

— Recurrence often within first 2 years

Secondary prevention reduces recurrence and addresses ongoing liver injury — this is the outpatient cornerstone of Step 3 management.

Etiology-specific control (the highest-impact intervention):

General health maintenance in cirrhosis:

Post-treatment surveillance:

Step 3 management: Every HCC patient discharge plan should include: HCV/HBV treatment status, alcohol counseling, vaccination update, variceal screening, surveillance imaging schedule, and PCP communication letter within 7 days.

Board pearl: Achieving HCV SVR reduces HCC risk by ~70% but does not zero it in cirrhotics — continue lifelong surveillance.

Follow-Up, Monitoring, and Counseling

— Multiphasic CT or MRI + AFP every 3 months for 2 years, then every 6 months

— CT chest annually for first 2 years (lung metastases)

— Most recurrences occur in first 2 years

— Multiphasic imaging at 4-6 weeks to assess response (mRECIST: modified Response Evaluation Criteria — measures viable enhancing tumor, not just total size)

— Repeat TACE if residual viable disease

— Imaging every 8-12 weeks

— Labs every cycle: CBC, CMP, TSH (checkpoint inhibitors), UA (bevacizumab), BP

— AFP trend useful in AFP-secreting tumors

— Lifelong immunosuppression monitoring (tacrolimus levels)

— Surveillance imaging q3-6 months × 5 years

— Screen for de novo malignancies (skin, PTLD, head & neck) — annual dermatology

— Cardiovascular and metabolic risk management (immunosuppression worsens HTN, diabetes, dyslipidemia)

— Alcohol cessation — most important modifiable factor; document at every visit

— Weight management in MASH-related HCC — refer to dietitian, consider bariatric surgery in Child-Pugh A with morbid obesity post-transplant

— Medication safety: acetaminophen ≤2 g/day, avoid NSAIDs, review supplements

— Sexual health, fertility: TKIs and chemotherapy require contraception; bevacizumab teratogenic

— Mental health: high depression rates in cancer + cirrhosis; screen with PHQ-9

— Advance care planning: code status, healthcare proxy — initiate early, especially BCLC C/D

— Prehabilitation before resection/transplant: nutrition optimization, exercise, sarcopenia reversal — improves outcomes

Post-curative therapy surveillance (resection, ablation, transplant):

Post-locoregional therapy (TACE/TARE):

On systemic therapy:

Post-transplant:

Counseling priorities:

Rehabilitation:

Step 3 management: At every HCC follow-up visit, document surveillance imaging adherence, AFP trend, alcohol status, vaccination status, and code status — these are quality metrics and high-yield Step 3 deliverables.

Board pearl: mRECIST, not RECIST, is the standard for assessing HCC response to locoregional therapy because viable tumor is defined by enhancement, not size.

Ethical, Legal, and Patient Safety Considerations

— Six-month sobriety rule for alcohol-related liver disease is no longer absolute; many centers list earlier with multidisciplinary psychosocial assessment — board questions may test understanding that early listing without rigid 6-month rule is increasingly acceptable for selected patients

— Equitable allocation: MELD exception points for HCC have been recalibrated to prevent gaming

— Living donor transplantation requires separate informed consent and psychosocial evaluation of donor — donor autonomy is paramount, and donor must have independent advocacy team

— Decisional capacity in hepatic encephalopathy: a patient with grade II+ encephalopathy lacks capacity; identify healthcare proxy or surrogate per state hierarchy. Defer non-urgent decisions until encephalopathy resolves

— Locoregional therapy risks: explicit discussion of post-TACE syndrome, liver failure, tumor rupture

— Checkpoint inhibitor irAE counseling: patients must understand to report any new symptoms (cough, diarrhea, rash, fatigue) immediately

— HBV and HCV are reportable in all states — notify public health

— Partner notification and household screening for HBV — vaccinate susceptible contacts

— Highest-risk transition: hospital discharge after decompensation with new HCC diagnosis. Medication reconciliation (diuretics, lactulose, rifaximin, beta-blockers, antivirals) must be explicit

— Schedule hepatology follow-up within 2 weeks; ensure transplant referral isn't lost in handoff — this is a sentinel-event-level lapse

— HCC disproportionately affects Black, Hispanic, and Asian Americans; insurance status and language barriers correlate with delayed diagnosis and lower curative therapy rates

— Use professional interpreters, not family members, for consent

— BCLC C/D patients should have early palliative consult — improves quality of life and survival

— Hospice eligibility: Child-Pugh C with HCC outside transplant criteria typically qualifies

Transplant listing ethics:

Informed consent edge cases:

Mandatory reporting and public health:

Transition-of-care safety:

Health equity:

Goals-of-care and palliative integration:

Step 3 management: A Child-Pugh C patient with HCC outside Milan asks about chemotherapy. Correct response: discuss goals of care, palliative care referral, hospice eligibility, and avoid futile therapy — this is a recurring ethics stem.

Board pearl: Bevacizumab requires pre-treatment EGD for variceal screening — failure to screen is a documented patient-safety lapse.

High-Yield Associations and Rapid-Fire Clinical Facts

— AFP — classic; ~70% sensitivity; >200 ng/mL highly suggestive in cirrhotic with mass

— AFP-L3 — fucosylated isoform, higher specificity

— DCP (PIVKA-II) — independent marker, elevated by warfarin (confounder)

— Erythrocytosis — EPO

— Hypoglycemia — IGF-2

— Hypercalcemia — PTHrP

— Watery diarrhea, dermatomyositis, gynecomastia

— HCC: arterial hyperenhancement + portal/delayed washout + capsule

— Hemangioma: peripheral nodular centripetal fill-in

— FNH: central scar with delayed enhancement

— Cholangiocarcinoma: delayed enhancement (opposite of HCC)

HCC tumor markers:

HCC paraneoplastic syndromes:

Fibrolamellar HCC: young, no cirrhosis, normal AFP, DNAJB1-PRKACA fusion, neurotensin elevated

Hepatic adenoma → HCC transformation: β-catenin mutation subtype, >5 cm, male sex

Aflatoxin: Aspergillus toxin, p53 R249S mutation, synergistic with HBV

Hemochromatosis: C282Y mutation, HCC risk ~20-fold; phlebotomy reduces but does not eliminate risk

Hepatitis B integration: causes HCC even without cirrhosis — unique among hepatitis viruses

Hepatitis C: HCC almost always requires cirrhosis; SVR with DAAs reduces but does not eliminate risk

MASH/NAFLD: rising fastest as HCC cause; can occur in non-cirrhotic livers, complicating surveillance

Imaging signatures:

Milan criteria: 1 ≤5 cm OR up to 3 ≤3 cm each, no vascular invasion, no extrahepatic spread

BCLC stages: 0/A curative, B = TACE, C = systemic, D = supportive

First-line systemic: atezolizumab + bevacizumab (after EGD for varices)

Surveillance: ultrasound ± AFP q6 months in cirrhotics and high-risk HBV

Step 3 management: Memorize the LI-RADS LR-5 imaging triad — it allows diagnosis without biopsy in at-risk patients.

Board pearl: Tumor thrombus in portal vein with arterial enhancement = HCC invading vasculature, not bland thrombosis — anticoagulation alone is wrong management.

Board Question Stem Patterns

— "55-year-old man with HCV cirrhosis treated to SVR 2 years ago. Most appropriate next step?"

— Answer: Continue ultrasound + AFP every 6 months indefinitely (SVR does not eliminate HCC risk in cirrhosis)

— Cirrhotic patient with 3-cm liver mass, arterial enhancement, portal washout, capsule

— Answer: No biopsy needed; refer to tumor board for staging and treatment

— Cirrhotic with single 4-cm HCC, Child-Pugh B, no portal HTN/vascular invasion

— Answer: Transplant evaluation (Milan-eligible)

— Previously stable cirrhotic with new ascites and 10-lb weight loss

— Answer: Multiphasic CT or MRI to evaluate for HCC, not just diuretic adjustment

— Cirrhotic with portal vein thrombus showing arterial enhancement

— Answer: HCC with vascular invasion, BCLC C — systemic therapy (atezolizumab + bevacizumab after EGD)

— Patient with advanced HCC about to start atezolizumab + bevacizumab

— Answer: EGD for variceal screening, BP, UA for proteinuria, TSH, LFTs

— Patient on pembrolizumab for HCC with new AST/ALT 8x ULN

— Answer: Hold checkpoint inhibitor, start prednisone 1-2 mg/kg, rule out viral hepatitis reactivation

— Cirrhotic with sudden RUQ pain, hypotension, hemoperitoneum

— Answer: Transarterial embolization by IR, resuscitate

— Cirrhotic with large liver mass and recurrent hypoglycemia

— Answer: HCC secreting IGF-2; treat with dextrose, glucocorticoids, tumor-directed therapy

— HBsAg+ pregnant woman, HBV DNA 500,000 IU/mL at 26 weeks

— Answer: Start tenofovir at 28 weeks, plan HBIG + birth-dose vaccine for infant

Pattern 1 — Surveillance trigger:

Pattern 2 — LI-RADS LR-5 diagnosis:

Pattern 3 — Milan criteria and transplant:

Pattern 4 — Decompensation as presentation:

Pattern 5 — Portal vein tumor thrombus:

Pattern 6 — Pre-systemic therapy workup:

Pattern 7 — Immune-related hepatitis:

Pattern 8 — Tumor rupture:

Pattern 9 — Paraneoplastic refractory hypoglycemia:

Pattern 10 — Pregnancy + HBV:

Step 3 management: When a stem describes a cirrhotic with any new finding, default to multiphasic imaging and tumor board — surveillance lapses are the most common trap.

Board pearl: "Biopsy the liver mass" is almost always wrong in a cirrhotic with classic LR-5 features.

One-Line Recap

Hepatocellular carcinoma is a cirrhosis-driven cancer where outpatient surveillance with q6-month ultrasound ± AFP, radiographic LI-RADS LR-5 diagnosis without biopsy, and BCLC-stratified treatment from curative resection/transplant/ablation through TACE to atezolizumab + bevacizumab determine survival.

Surveillance is the highest-yield clinician-controlled intervention: ultrasound ± AFP every 6 months in all cirrhotics (Child-Pugh A/B, and C if transplant candidate) and high-risk non-cirrhotic HBV — lifelong, even after HCV SVR.

Diagnosis is radiographic, not histologic, in the at-risk patient: multiphasic CT or MRI showing LI-RADS LR-5 features (arterial hyperenhancement + portal/delayed washout + capsule) confirms HCC; biopsy risks seeding and is reserved for atypical or non-cirrhotic cases.

Treatment follows BCLC staging absolutely: BCLC 0/A → resection, ablation, or transplant (Milan: 1 ≤5 cm or up to 3 ≤3 cm); BCLC B → TACE; BCLC C (vascular invasion or extrahepatic) → atezolizumab + bevacizumab after EGD for varices; BCLC D → palliative care and hospice.

Secondary prevention and longitudinal care drive outcomes: cure HCV with DAAs, suppress HBV with tenofovir/entecavir, eliminate alcohol, treat MASH aggressively, vaccinate (HAV, HBV, pneumococcal, influenza, COVID, shingles), screen varices, avoid hepatotoxins, integrate palliative care early, and never miss the transition-of-care touchpoint — schedule hepatology follow-up within 2 weeks of any decompensation or new diagnosis.

Board pearl: The single most tested decision in HCC vignettes is recognizing that radiographic LR-5 features in a cirrhotic warrant treatment, not biopsy, and that Milan criteria define transplant candidacy — anchor every stem to surveillance status, BCLC stage, Child-Pugh class, and Milan eligibility, and the answer will fall out.