Role of PET/CT in Hepatocellular Carcinoma

Introduction

Primary Liver Malignancies

• Primary liver cancer is the sixth most commonly diagnosed malignancy and the third leading cause of cancer-related death worldwide.
• Hepatocellular carcinoma (HCC) accounts for approximately 85–90% of cases of primary liver cancers and arises almost exclusively on a background of chronic liver disease.
• The remainder comprises intrahepatic cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma and rarer entities such as hepatoblastoma and angiosarcoma.

• The unifying clinical problem in HCC is that it develops within a liver that is already diffusely abnormal.
• Regenerative nodules, dysplastic nodules, fibrosis, steatosis and portal hypertension all complicate both detection and characterisation, and all influence the interpretation of metabolic imaging.

Hepatocellular Carcinoma

HCC is the archetypal inflammation-driven malignancy. Between 80% and 90% of patients have established cirrhosis at diagnosis, and the annual incidence of HCC in a cirrhotic liver is approximately 2–4%.

Risk Factors and Surveillance

Molecular Pathogenesis

Hepatocarcinogenesis is a multistep process progressing from chronic inflammation and regeneration through low- and high-grade dysplastic nodules to early and then progressed HCC. The molecular landscape is dominated by a small number of recurrent events:

• TERT promoter mutations — the earliest and most frequent genetic alteration, present in a majority of tumours and already detectable in dysplastic nodules.
• TP53 inactivation — associated with poor differentiation, aggressive behaviour and aflatoxin exposure.
• CTNNB1 activation — constitutive Wnt/β-catenin signalling, characteristically associated with well-differentiated, FDG-negative tumours and an immune-excluded phenotype.
• Chromatin remodelling genes (ARID1A, ARID2) and AXIN1 loss.
• Hepatitis B viral integration into the host genome, which can drive carcinogenesis independently of cirrhosis.
• Upregulation of VEGF, PDGF and FGF angiogenic signalling, the therapeutic target of the anti-angiogenic agents used in advanced disease.

These pathways are directly relevant to nuclear medicine. Tumours with β-catenin activation retain a well-differentiated, gluconeogenic hepatocyte phenotype and are typically FDG-negative, whereas dedifferentiated, TP53-mutated tumours upregulate glucose transporters and are strongly FDG-avid. The metabolic phenotype seen on PET is therefore a readout of the underlying molecular class.

Anatomy and Pathology

Segmental Anatomy

Surgical planning in HCC depends on the Couinaud classification, which divides the liver into eight functionally independent segments, each with its own portal pedicle and hepatic venous drainage. Segment I (caudate lobe) drains directly into the inferior vena cava and is therefore often spared or separately involved. The three hepatic veins define the four sectors; the portal bifurcation defines the transverse plane separating segments II/III/IVb/V/VI from I/IVa/VII/VIII.

Accurate segmental localisation on PET/CT requires fusion with the diagnostic contrast-enhanced study, since anatomical landmarks are poorly resolved on low-dose CT and are frequently distorted by cirrhotic architectural change like caudate hypertrophy and right lobe atrophy.

Histopathology

Growth Patterns and Architecture

• HCC recapitulates hepatocyte architecture to a variable degree.
• The classical trabecular pattern is most common, with tumour cells arranged in plates of increased thickness lined by sinusoidal endothelium.
• Pseudoglandular (acinar), compact and scirrhous patterns are also recognised.
• Loss of reticulin framework, stromal invasion and unpaired arteries are the key features distinguishing early HCC from high-grade dysplastic nodules.

Histological Variants

Grading

The Edmondson–Steiner system grades HCC from I (well differentiated, closely resembling normal hepatocytes) to IV (poorly differentiated, pleomorphic). The WHO recommends a three-tier well/moderate/poor scheme. Grade is the single most important determinant of FDG avidity and is also a strong predictor of microvascular invasion and post-treatment recurrence.

Clinical Presentation and Tumour Markers

Clinical Presentation

Early HCC is asymptomatic and is usually detected through surveillance of an at-risk population. Symptomatic presentation generally indicates advanced disease and includes right upper quadrant pain, weight loss, early satiety, a palpable mass, or decompensation of previously stable cirrhosis with new ascites, jaundice, variceal bleeding or encephalopathy.

Tumour Markers

Alpha-Fetoprotein

Alpha-fetoprotein (AFP) remains the most widely used serum marker. It is elevated in approximately 60% of patients with hepatocellular carcinoma, using a cutoff around 20 ng/mL. About 30–40% of patients have normal AFP, particularly with small or early-stage HCC. Modest elevations occur in active hepatitis, cirrhosis and regeneration. Values above 400 ng/mL in a patient with a liver mass are highly suggestive of HCC, and markedly elevated AFP correlates with larger tumour size, vascular invasion, poor differentiation and, importantly for nuclear medicine, with higher FDG avidity and a greater probability of extrahepatic disease.

Other Markers

• AFP-L3 — the fucosylated fraction of AFP; a higher proportion indicates greater malignant potential.
• Des-gamma-carboxy prothrombin (DCP / PIVKA-II) — complementary to AFP and associated with portal vein invasion; widely used in Japan.
• GALAD score — combines gender, age, AFP-L3, AFP and DCP; improves early detection over any single marker.

Surveillance and Non-Invasive Diagnosis

Surveillance

• All patients with cirrhosis of any aetiology, and selected non-cirrhotic hepatitis B carriers, should undergo six-monthly abdominal ultrasound, with or without AFP. Surveillance improves early detection and survival.
• An abnormal surveillance examination triggers diagnostic multiphasic CT or MRI—not PET/CT.
• PET/CT has no role whatsoever in surveillance — it is neither sensitive enough for small lesions nor justifiable in terms of cost and radiation exposure for a repeated examination.

Non-Invasive Diagnostic Criteria

HCC is the only major solid tumour that may be diagnosed definitively on imaging alone. In a patient with cirrhosis or chronic hepatitis B, an observation ≥ 10 mm demonstrating arterial phase hyperenhancement with washout on portal venous or delayed phases, with or without an enhancing capsule and threshold growth, is diagnostic of HCC. Biopsy is reserved for indeterminate lesions, lesions in a non-cirrhotic liver, and cases where histology will alter management.

The Liver Imaging Reporting and Data System (LI-RADS) formalises this into categories LR-1 (definitely benign) through LR-5 (definitely HCC), with LR-M for observations probably malignant but not HCC-specific and LR-TIV for tumour in vein. This algorithm is entirely CT- and MRI-based; PET has no place within it.

Staging of Hepatocellular Carcinoma

HCC is unique among solid tumours in that prognosis and treatment allocation depend not only on tumour burden but also on underlying liver function and performance status. A patient with a small resectable tumour and decompensated cirrhosis may have a worse prognosis than one with a larger tumour and preserved function. Any staging report — including a PET report — should be framed with this in mind.

Barcelona Clinic Liver Cancer (BCLC) System

AJCC TNM Classification

Primary Tumour (T)

Regional Lymph Nodes (N) and Distant Metastasis (M)

Regional nodes comprise the hilar, hepatoduodenal ligament, inferior phrenic and caval groups. N0 denotes no regional nodal metastasis and N1 regional nodal involvement. M0 and M1 denote the absence and presence of distant metastasis respectively. These are precisely the categories in which FDG PET/CT makes its greatest contribution, since the primary tumour is already well characterised by CT or MRI.

Stage Grouping

Assessment of Hepatic Reserve

The Child–Pugh classification (bilirubin, albumin, INR, ascites, encephalopathy) and the ALBI grade (albumin and bilirubin only, avoiding subjective variables) quantify hepatic reserve. Both independently predict survival and both modify the interpretation of any imaging finding: an occult metastasis detected on PET has very different consequences in a Child–Pugh A patient being considered for resection than in a Child–Pugh C patient.

Patterns of Tumour Spread

Intrahepatic Spread

HCC spreads within the liver by direct extension, by satellite nodules arising through portal venous dissemination, and by multicentric occurrence in a field of chronically injured hepatocytes. Distinguishing intrahepatic metastasis from synchronous multicentric primary disease is important prognostically but rarely possible on imaging alone.

Vascular Invasion

Vascular invasion is a hallmark of biologically aggressive HCC and exists along a continuum. Microvascular invasion, a histological diagnosis, is identified in approximately 15–40% of resected HCCs and is one of the strongest predictors of recurrence after resection or liver transplantation. Macrovascular invasion is radiologically evident at diagnosis in approximately 20–30% of patients and includes tumour thrombus within the portal vein, hepatic veins, or inferior vena cava. It defines BCLC stage C and generally excludes patients from conventional liver-transplantation pathways.

Portal vein tumour thrombus (PVTT) is the predominant form of macrovascular invasion, occurring in approximately 20–30% of patients at diagnosis; published series report rates as high as 35–40% in advanced HCC.

Hepatic vein tumour thrombus is less common, occurring in approximately 5–13% of patients, while extension into the inferior vena cava or right atrium is uncommon, generally reported in <5%.

Tumour thrombus typically expands the involved vessel, demonstrates internal arterial enhancement or neovascularity, and may show increased FDG uptake—particularly in poorly differentiated HCC. Bland thrombus usually lacks enhancing soft tissue and significant FDG uptake, although inflammatory uptake and coexistence of bland and tumour thrombus are recognized pitfalls.

Extension into the inferior vena cava and right atrium can be demonstrated effectively on whole-body PET/CT. PET/CT may depict the full craniocaudal extent of metabolically active thrombus and associated extrahepatic disease beyond the field of a dedicated liver examination.

Nodal and Distant Dissemination

Nodal metastases are detected in approximately 3–5% of patients at HCC diagnosis, increasing to 25–30% in autopsy series. Their presence indicates BCLC stage C disease and generally excludes conventional resection or transplantation.

Among patients with nodal spread, the principal sites are:

Paraaortic nodes: 45–50%

Porta-hepatis nodes: 30–35%

Periceliac nodes: 5–10%

Peripancreatic nodes: 5–10%

Nodal disease is frequently understaged on CT in cirrhotic patients, in whom reactive lymphadenopathy is common and size criteria perform poorly.

Hematogenous dissemination is detected in approximately 10–15% of patients at HCC diagnosis and is associated with BCLC stage C disease. The frequency increases substantially during disease progression.

Among patients with extrahepatic metastases, the principal hematogenous sites are:

Lungs: 40–55%; most common and may be too small for PET detection; diagnostic chest CT remains essential

Bones: 25–40%; lytic, hypervascular, and usually FDG-avid

Adrenal glands: 9–12%

Brain and other organs: usually <2%

Whole-body PET/CT is valuable for detecting unsuspected skeletal, adrenal, and other distant metastases.

Imaging of Hepatocellular Carcinoma

Imaging Work-up

The imaging pathway begins with surveillance ultrasound. A detected nodule ≥ 10 mm triggers multiphasic contrast-enhanced CT or MRI, which either establishes the diagnosis non-invasively or leads to biopsy. Staging is completed with chest imaging. PET/CT enters this pathway only when a specific question about extrahepatic disease, tumour biology or equivocal findings arises.

Ultrasound and Contrast-Enhanced Ultrasound

Ultrasound is the surveillance tool of choice: inexpensive, radiation-free and repeatable, though operator-dependent and limited in obese patients and in coarsely nodular cirrhotic livers. Contrast-enhanced ultrasound demonstrates arterial hyperenhancement with late, mild washout and is valuable for characterising a single indeterminate nodule, but cannot stage the whole patient.

Multiphasic Computed Tomography

A dedicated four-phase protocol — unenhanced, late arterial, portal venous and delayed — is required. The late arterial phase is critical for detecting hyperenhancement, and the delayed phase for demonstrating washout and capsule appearance. CT also provides the vascular roadmap for surgery and transarterial therapy and assesses portal hypertension, varices and volumetry of the future liver remnant.

Magnetic Resonance Imaging

MRI is the most sensitive modality for intrahepatic disease, particularly with hepatobiliary contrast agents such as gadoxetate disodium, which add a hepatobiliary phase in which HCC appears hypointense against enhancing background parenchyma. Diffusion-weighted imaging further improves detection of small lesions. For intrahepatic staging, MRI outperforms PET decisively and the two should not be regarded as competing tests.

Comparative Summary of Imaging Modalities

Treatment of Hepatocellular Carcinoma

Treatment allocation follows the BCLC framework, and understanding it is essential for reporting PET meaningfully — the value of any finding depends entirely on the decision it influences.

Curative-Intent Therapy

• Resection — for single tumours with preserved function, no clinically significant portal hypertension and an adequate future liver remnant.
• Liver transplantation — addresses both tumour and underlying cirrhosis. The Milan criteria (a single lesion ≤ 5 cm, or up to three lesions each ≤ 3 cm, without vascular invasion or extrahepatic spread) remain the reference standard, with several validated expansions.
• Ablation — radiofrequency or microwave ablation for tumours up to approximately 3 cm, with outcomes comparable to resection in very early disease.

Locoregional and Systemic Therapy

• Transarterial chemoembolisation (TACE) — standard of care for intermediate-stage multinodular disease with preserved liver function.
• Transarterial radioembolisation (TARE) with ⁹⁰Y microspheres — used for larger or portal-vein-invading tumours, for radiation segmentectomy in early disease, and for lobar hypertrophy induction before resection.
• Systemic therapy — immune checkpoint inhibitor combinations (atezolizumab with bevacizumab; durvalumab with tremelimumab) are first-line for advanced disease, with multikinase inhibitors such as lenvatinib and sorafenib as alternatives, and regorafenib, cabozantinib and ramucirumab in later lines.
• External beam radiotherapy — stereotactic body radiotherapy and proton therapy for selected unresectable tumours or vascular invasion.
• Palliative care — management of ascites, variceal bleeding, pain and nutritional decline.

Biological Basis of FDG Uptake in HCC

The behaviour of ¹⁸F-FDG in the liver is unlike that in any other organ, and the reason is biochemical rather than technical. Understanding it is the key to interpreting every PET study in HCC.

FDG enters the cell through glucose transporters and is phosphorylated by hexokinase to FDG-6-phosphate, which in most tissues cannot proceed further along glycolysis and is therefore metabolically trapped. Hepatocytes, however, are gluconeogenic cells and express high levels of glucose-6-phosphatase, the enzyme that reverses this step. In well-differentiated HCC, which retains the hepatocyte phenotype, FDG-6-phosphate is dephosphorylated and washes back out of the cell. These tumours additionally express low levels of GLUT1 and GLUT3, limiting tracer influx in the first place.

Superimposed on this is the high physiological background activity of normal liver parenchyma, which reduces lesion-to-background contrast even when a tumour is genuinely avid. The combination of low influx, active efflux and high background explains why FDG PET detects only a proportion of hepatocellular carcinomas.

Dedifferentiation reverses each of these mechanisms. High-grade tumours lose glucose-6-phosphatase activity, upregulate GLUT1 and hexokinase II, and become markedly FDG-avid. FDG uptake in HCC is therefore a biomarker of tumour grade and aggressiveness rather than a marker of the presence of tumour. This single principle underlies essentially every valid clinical application of PET in this disease.

Tracers

¹⁸F-FDG

¹⁸F-FDG remains the clinical standard and the only tracer supported by substantial outcome data in HCC. Although its sensitivity for the primary tumour is modest, its performance for extrahepatic disease is considerably better and its prognostic value is well established.

Lipogenic Tracers: ¹¹C-Acetate and Choline

Well-differentiated HCC upregulates fatty acid synthase and phospholipid membrane synthesis, and is therefore avid for ¹¹C-acetate and for ¹¹C- or ¹⁸F-choline — precisely the tumours that FDG misses. Poorly differentiated tumours show the reciprocal pattern. Combining a glycolytic with a lipogenic tracer raises overall detection sensitivity well above either agent alone, and the pattern of dual-tracer uptake itself reflects tumour differentiation and therefore recurrence risk. Systematic review evidence supports the concept, though it is not yet consensual and the short half-life of ¹¹C confines it to centres with an on-site cyclotron.

Fibroblast Activation Protein Inhibitors

FAPI tracers target cancer-associated fibroblasts within the tumour stroma rather than the malignant cell. Because normal hepatic parenchyma expresses very little fibroblast activation protein, background liver activity is near-absent, which addresses the principal technical limitation of FDG in this organ. Reported tumour-to-background ratios are consistently higher than with FDG, and FAPI detects a proportion of FDG-negative, well-differentiated tumours.

Other Agents

• ⁶⁸Ga-PSMA — prostate-specific membrane antigen is expressed in HCC tumour neovasculature; early cohorts suggest useful uptake and a possible theranostic route.
• ¹⁸F-FLT (proliferation), ¹⁸F-FMISO (hypoxia) and anti-glypican-3 agents remain research tools.

Summary of Tracers

Image Interpretation

Interpretation should be systematic and should always be performed alongside a diagnostic multiphasic study. The reference background region is placed in visually normal parenchyma remote from the lesion, from a large region of interest in the right lobe, avoiding vessels and treated areas.

Role of PET/CT in Diagnosis

No major guideline recommends FDG PET/CT for the diagnosis of HCC or for the characterisation of an indeterminate nodule in a cirrhotic liver. Multiphasic CT and, in particular, hepatobiliary contrast-enhanced MRI substantially outperform PET for lesion detection and characterisation, and sensitivity falls sharply for lesions below 1 cm because of partial volume effects and high background. Requesting PET to answer a diagnostic question in HCC reflects a misunderstanding of the modality.

PET nevertheless contributes to characterisation in defined circumstances: when a lesion is FDG-avid out of proportion to its morphological appearance, raising the possibility of a high-grade or non-hepatocellular malignancy; when intrahepatic cholangiocarcinoma or combined HCC-cholangiocarcinoma is in the differential; and when the clinical question is not whether tumour is present but how aggressive it is.

Differential Diagnosis

The tumour is characterised by neoangiogenesis with progressive loss of the normal portal venous supply and development of an unpaired arterial supply, which is the physiological basis of the arterial hyperenhancement and washout pattern used for non-invasive diagnosis.

Most specific CT combination for HCC: arterial-phase hyperenhancement + portal/delayed washout + enhancing capsule in an at-risk liver.

False Negatives

• Well-differentiated tumours retaining glucose-6-phosphatase activity — the commonest cause by a wide margin.
• Lesions smaller than approximately 1 cm, degraded by partial volume effects.
• Lesions near the hepatic dome affected by respiratory motion.
• Hyperglycaemia or recent insulin administration at the time of injection.
• High background parenchymal activity masking a modestly avid lesion.

False Positives

• Hepatic abscess, and inflammatory or infective pseudotumour.
• Post-procedural inflammation after ablation, chemoembolisation, radioembolisation, biopsy or surgery.
• Active hepatitis and granulomatous disease.
• Inflammatory hepatocellular adenoma.
• Reactive lymphadenopathy in the porta hepatis, common in chronic liver disease.
• Immune-related adverse events during checkpoint inhibitor therapy.

Role of PET/CT in Staging

Staging is where PET/CT earns its place in HCC. Its contribution is asymmetric: limited for the primary tumour, substantial for nodal and distant disease.

T Stage — Primary Tumour

• PET/CT contributes little to T staging. It cannot reliably determine tumour size, segmental extent, capsular involvement or relationship to vascular structures, all of which are better shown by multiphasic CT and MRI.
• Its one genuine T-stage contribution is the characterisation of venous filling defects: FDG uptake within a portal or hepatic venous thrombus indicates tumour thrombus rather than bland thrombus, changing the tumour to T4, reclassifying the patient to BCLC stage C and excluding transplantation.

N Stage — Regional Lymph Nodes

CT assessment relies predominantly on nodal size and morphology, which perform poorly in chronic liver disease because reactive periportal adenopathy is common. FDG PET/CT provides complementary metabolic information, with a reported sensitivity of approximately 70–90% for nodal metastases in selected cohorts. Specificity is generally high but may be reduced by inflammatory or granulomatous disease. Detection of metastatic regional nodes establishes N1 disease and AJCC stage IVA; distant nodal involvement constitutes M1/stage IVB disease. Either finding usually excludes transplantation and conventional curative-intent local therapy.

M Stage — Distant Metastases

This is the principal indication for PET/CT in HCC. Extrahepatic deposits arise from the dedifferentiated, FDG-avid clone and lie in tissues with low background activity, so sensitivity is far better than for the intrahepatic primary, and reported specificity is high. Pooled sensitivity is approximately 64%, with specificity around 93–95%; sensitivity is higher in poorly differentiated, FDG-avid tumours and varies according to the metastatic site. A negative examination does not exclude small-volume metastatic disease.

Skeletal Metastases

HCC bone metastases are characteristically osteolytic, expansile and hypervascular, often with a substantial soft-tissue component. Conventional ⁹⁹ᵐTc-diphosphonate bone scintigraphy therefore under-detects them, whereas FDG PET/CT identifies them reliably and additionally demonstrates the associated soft-tissue component, which is often the clinically important element when spinal cord compression or fracture risk is being assessed.

Pulmonary, Adrenal and Peritoneal Disease

The lungs are the most common site of extrahepatic spread, accounting for approximately 40–55% of metastatic cases. Pulmonary sensitivity is limited—approximately 40–60%—because subcentimetre nodules may be metabolically occult; careful review of the diagnostic CT component is essential. Whole-body PET/CT also detects adrenal metastases, present in approximately 9–12% of metastatic cases, as well as peritoneal deposits and occasional synchronous malignancies.

Diagnostic Accuracy

¹⁸F-FDG PET/CT has limited sensitivity for primary HCC—approximately 56–61%, because many small and well-differentiated tumours have uptake similar to background liver; however, its specificity is high at approximately 95–96%, and sensitivity improves in poorly differentiated, advanced and metastatic disease.

PET/CT in Patient Selection

Selection for Liver Transplantation

Conventional transplant selection criteria are morphological. They classify patients by lesion number and size and take no account of tumour biology. They consequently misclassify in both directions: a proportion of within-criteria tumours recur aggressively, while some beyond-criteria tumours behave indolently. FDG PET/CT introduces an independent biological axis to the same decision.

• PET-negative tumours, even when beyond conventional morphological criteria, have been reported to achieve recurrence-free survival approaching that of within-criteria disease.
• PET-positive tumours within Milan criteria carry a materially higher risk of post-transplant recurrence.
• Pre-transplant FDG avidity predicts early recurrence after both deceased-donor and living-donor transplantation, and correlates with microvascular invasion and cytokeratin 19 expression on the explant.
• Several transplant programmes, particularly in Asia, formally incorporate PET status into extended selection algorithms.

This is arguably the most clinically influential application of PET in HCC, because it can justify transplanting a patient who would otherwise be excluded, or counsel against a transplant likely to fail — decisions made against a background of profound organ scarcity.

Selection for Resection and Locoregional Therapy

Before hepatic resection, pre-operative FDG avidity independently predicts early recurrence, microvascular invasion and poorer disease-free survival. A markedly avid tumour should prompt reconsideration of the extent of resection, of peri-operative systemic strategies, and of the intensity of post-operative surveillance. Before transarterial or ablative therapy, the contribution is principally the exclusion of extrahepatic disease and the stratification of expected benefit.

A Practical Decision Framework

PET/CT in Response Assessment

Why Metabolic Assessment Is Useful After Treatment

Anatomical response assessment after locoregional therapy in HCC is unusually difficult. Retained lipiodol obscures the treated tumour after chemoembolisation; coagulative necrosis after ablation initially occupies the same volume as the original tumour; and radioembolisation produces a delayed response with peri-tumoural oedema and inflammation. Size-based criteria consequently perform poorly, and metabolic change generally precedes anatomical change.

After Chemoembolisation

Metabolic imaging can separate viable residual tumour from treated tissue earlier than size-based criteria, and both pre- and post-treatment FDG parameters carry prognostic information for survival after TACE. Imaging should be deferred for approximately four to six weeks to allow post-embolisation inflammatory uptake to settle.

After Radioembolisation

PET contributes at three separate points in the ⁹⁰Y pathway. Before treatment, FDG PET/CT excludes extrahepatic disease and characterises tumour biology. Immediately afterwards, ⁹⁰Y PET/CT provides higher resolution and better quantification of microsphere distribution than bremsstrahlung SPECT, enabling voxel-level dosimetry and confirmation of adequate tumour targeting. Subsequently, FDG PET/CT assesses metabolic response. An evidence-based review of 19 studies comprising 833 patients undergoing selective internal radiation therapy established the value of FDG PET in treatment planning, response evaluation and prognostication, and the same principles are applied in HCC practice. Response after radioembolisation is slower than after chemoembolisation, and assessment before approximately three months risks a false impression of failure.

After Ablation

PET/CT is not a standard follow-up modality after radiofrequency or microwave ablation, but published series indicate that it is sensitive and specific for residual or recurrent viable tumour at the ablation margin and may have advantages over contrast-enhanced ultrasound and CT in anatomically complex situations. A thin, uniform rim of uptake around the ablation cavity represents expected inflammatory change; nodular, eccentric or progressively increasing uptake indicates residual disease.

During Systemic and Immune Therapy

With immune checkpoint inhibition combined with anti-angiogenic therapy now standard in advanced disease, response assessment has become more complex. Metabolic response usually precedes anatomical change and PET can identify early non-responders. Interpretation must, however, account for pseudoprogression, for the flare phenomenon, and for immune-related adverse events — thyroiditis, colitis, pneumonitis, hypophysitis and sarcoid-like nodal reaction — which appear as new FDG-avid findings entirely unrelated to tumour progression and which the reporting physician has a responsibility to recognise and flag.

PET/CT in Restaging and Recurrence

Recurrence after curative-intent treatment is common — the majority of patients recur within five years of resection, reflecting both true recurrence and de novo tumour in a persistently diseased liver. Restaging serves to determine whether recurrence is intrahepatic and amenable to further local therapy, or disseminated.

• Rising AFP with negative or equivocal conventional imaging is the classic indication for whole-body FDG PET/CT.
• PET is particularly useful after transplantation, when immunosuppression and altered anatomy complicate conventional interpretation.
• It distinguishes post-surgical and post-ablation change from viable recurrent tumour when cross-sectional imaging is indeterminate.
• It identifies extrahepatic recurrence that would preclude repeat resection, re-ablation or salvage transplantation.

The same biological caveat applies: a well-differentiated recurrence may be metabolically silent, so a negative study in the face of a convincingly rising AFP should prompt dedicated hepatobiliary MRI rather than reassurance.

Prognostic Role of PET/CT

The prognostic literature in HCC is considerably more consistent than the diagnostic literature, and it is on this basis that PET has its strongest claim to clinical utility.

A meta-analysis of 22 studies comprising 1,721 patients found that a high tumour-to-liver SUV ratio was associated with significantly worse overall survival (HR 2.04) and markedly worse disease-free survival (HR 7.17), while a high absolute tumour SUV also predicted poorer overall survival (HR 1.53). A multicentre retrospective cohort of patients with BCLC stage C disease confirmed that the tumour-to-liver ratio was an independent predictor of overall survival in both intrahepatic and extrahepatic disease groups, and that FDG uptake in the primary tumour was significantly higher in patients with extrahepatic spread than in those with disease confined to the liver.

Quantitative PET Biomarkers

Guideline Recommendations

Guideline positions on PET/CT in HCC are notably consistent and notably conservative. All major societies agree that multiphasic contrast-enhanced CT or MRI is the primary imaging modality, that PET/CT has no role in diagnosis, and that its use should be confined to selected clinical scenarios in which the result will alter management.

NCCN

• Multiphasic contrast-enhanced CT or MRI is the standard for diagnosis and local staging.
• FDG PET/CT has limited sensitivity but high specificity in HCC and is not recommended routinely.
• PET/CT may be considered when extrahepatic disease is suspected or when conventional imaging is equivocal.
• PET/CT does not replace cross-sectional imaging for assessment of vascular involvement or technical resectability.

EASL

• Non-invasive diagnostic criteria on multiphasic CT or MRI remain the cornerstone of diagnosis.
• FDG PET/CT is not recommended for diagnosis or routine staging because of inadequate sensitivity for well-differentiated tumours.
• A role in the detection of extrahepatic disease in selected patients is acknowledged.
• PET is not endorsed as a standard component of transplant selection, although its prognostic value is recognised in the supporting evidence base.

AASLD

• Endorses the LI-RADS framework for diagnosis and reporting.
• Does not include FDG PET/CT within the diagnostic algorithm.
• Recognises that metabolic imaging may inform assessment of tumour biology in research and in selected transplant contexts.

ESMO

• Cross-sectional imaging is the standard investigation for staging.
• PET/CT is not routinely indicated in newly diagnosed HCC.
• PET may assist when distant metastatic disease is suspected clinically or biochemically.

APASL and Practice in Asia

Practice in the Asia-Pacific region, where hepatitis B-related HCC and living-donor transplantation are common, has been more receptive to metabolic imaging. Several centres routinely perform FDG PET/CT before living-donor transplantation and incorporate PET status into extended selection criteria, on the basis of the recurrence data discussed above.

Guideline Comparison

Emerging Tracers

The limitations of FDG in HCC — grade-dependent uptake and high hepatic background — have driven a search for tracers that target a different pathway or exploit a lower background.

FAPI PET/CT in HCC

Radiolabelled fibroblast activation protein inhibitors target cancer-associated fibroblasts within the tumour stroma rather than the malignant cell itself. Normal hepatic parenchyma expresses very little fibroblast activation protein, so background liver activity is minimal, directly addressing the greatest technical limitation of FDG in this organ.

Diagnostic Performance

FAPI PET/CT demonstrates substantially higher sensitivity for primary HCC, approximately 90–95%, with reported specificity around 85–90%, owing to its high tumour uptake and low normal-liver background. Head-to-head studies have reported primary-tumour sensitivities of approximately 94% for FAPI versus 69% for FDG, and nodal sensitivities of 97.9% versus 89.1%, respectively.

Advantages

• Very low physiological hepatic background and consequently high lesion conspicuity.
• Detection of well-differentiated, FDG-negative tumours.
• Improved delineation of intrahepatic extent and satellite nodules.
• No fasting requirement and independence from blood glucose.
• Potential to select patients for FAP-targeted radionuclide therapy.

Limitations and Current Position

• Uptake occurs in cirrhosis, fibrosis and inflammation — a particular concern in the chronically diseased liver in which HCC arises.
• Evidence remains predominantly single-centre and retrospective, with limited prospective data and almost no outcome data.
• No current guideline endorsement in HCC.
• Limited availability, with generator supply constraints for ⁶⁸Ga-labelled agents.

PSMA PET/CT

Prostate-specific membrane antigen is expressed in the neovascular endothelium of hepatocellular carcinoma rather than in the tumour cells themselves. Early clinical cohorts report avid uptake in a substantial proportion of lesions, including some that are FDG-negative, and raise the theoretical possibility of ¹⁷⁷Lu-PSMA-directed therapy. Evidence remains preliminary.

Other Investigational Agents

Future Directions

Radiomics

Radiomic analysis extracts high-dimensional texture, shape and intensity features from PET and CT data beyond what is visually apparent. In HCC the most promising applications are non-invasive prediction of microvascular invasion, of cytokeratin 19 and Ki-67 status, and of post-treatment recurrence risk. Reproducibility across scanners, reconstruction algorithms and segmentation methods remains the principal obstacle to clinical adoption.

Artificial Intelligence

Deep learning approaches are being developed for automated lesion segmentation in the cirrhotic liver, for background-adaptive quantification that corrects for variable parenchymal activity, and for multimodal models integrating PET, MRI, laboratory data and genomics into unified predictions of recurrence after resection or transplantation.

PET/MRI

PET/MRI is conceptually well suited to HCC because it combines the superior soft-tissue and hepatobiliary contrast of MRI — the reference standard for intrahepatic disease — with metabolic information in a single session and at reduced radiation exposure. Reported applications include prediction of cytokeratin 19 status and improved characterisation of lesions indeterminate on either modality alone. Cost, availability and acquisition time remain limiting.

Theranostics

HCC already possesses an established radionuclide therapy in ⁹⁰Y radioembolisation, and image-based personalised dosimetry using post-treatment ⁹⁰Y PET/CT is the most immediate theranostic opportunity, with mounting evidence that tumour-absorbed dose predicts response. Beyond this, FAP-directed therapy with ¹⁷⁷Lu-FAPI, PSMA-directed therapy and antigen-directed approaches against glypican-3 represent plausible future pairings of diagnostic and therapeutic agents, all currently investigational.

Frequently Asked Questions

Q Should every patient with HCC undergo PET/CT?

No. PET/CT is not a routine investigation in HCC and is not recommended by any major guideline for diagnosis or routine staging. It should be requested when a specific question — usually the presence of extrahepatic disease or the biological aggressiveness of the tumour — will change management.

Q Why is FDG PET so often negative in HCC?

Because well-differentiated HCC retains glucose-6-phosphatase activity, which dephosphorylates FDG-6-phosphate and allows it to wash out of the cell, and expresses low levels of GLUT1 and GLUT3. High physiological liver background compounds the problem.

Q Does a negative PET exclude HCC?

No, and this is the single most important caveat. A negative study is entirely compatible with a well-differentiated tumour. Diagnosis rests on multiphasic CT or MRI using LI-RADS criteria.

Q What does an intensely FDG-avid HCC signify?

Poor differentiation, a high proliferation index, an increased likelihood of microvascular invasion and cytokeratin 19 positivity, a higher probability of extrahepatic spread, and shorter overall and disease-free survival.

Q Can PET/CT distinguish tumour thrombus from bland portal vein thrombus?

Yes. FDG uptake within a portal venous filling defect supports tumour thrombus, whereas bland thrombus is metabolically inactive. The distinction changes stage and precludes transplantation.

Q Is PET useful before liver transplantation?

It is not formally endorsed in Western guidelines, but the evidence is substantial. PET-negative tumours beyond conventional morphological criteria behave favourably, while PET-positive tumours within criteria recur more frequently. Several programmes use it within extended selection algorithms.

Q Is PET better than bone scintigraphy for HCC skeletal metastases?

Yes. HCC bone metastases are lytic, expansile and osteoblast-poor, and are therefore under-detected by ⁹⁹ᵐTc-diphosphonate imaging. FDG PET/CT detects them reliably and demonstrates the associated soft-tissue component.

Q How soon after TACE, ablation or radioembolisation should PET be performed?

Approximately four to six weeks after chemoembolisation or ablation, and around three months after radioembolisation. Earlier imaging is confounded by post-procedural inflammatory uptake and, after ⁹⁰Y, by the inherently delayed response.

Q Is FAPI replacing FDG in HCC?

Not currently. FAPI offers markedly better tumour-to-background contrast in the liver and detects FDG-negative tumours, but uptake in cirrhosis and fibrosis, the predominance of retrospective single-centre data, and the absence of outcome evidence mean that FDG remains the reference tracer.

Q Does PET have a role in surveillance of cirrhosis?

No. Surveillance is performed with six-monthly ultrasound, with or without AFP. PET has no role in screening an at-risk population.

High-Yield Clinical Pearls

Selected References

1. Prognostic significance of parameters from pretreatment ¹⁸F-FDG PET in hepatocellular carcinoma: a meta-analysis. Abdominal Radiology 2016;41(1):33–41. doi:10.1007/s00261-015-0603-9

2. ¹⁸F-FDG PET/CT can predict survival of advanced hepatocellular carcinoma patients: a multicenter retrospective cohort study. Journal of Nuclear Medicine 2017;58(5):730–736.

3. Ghidaglia J, Golse N, Pascale A, Sebagh M, Besson FL. ¹⁸F-FDG/¹⁸F-choline dual-tracer PET behaviour and tumour differentiation in hepatocellular carcinoma: a systematic review. Frontiers in Medicine 2022;9:924824.

4. Exploring the efficacy of ¹⁸F-FDG PET/CT in hepatocellular carcinoma diagnosis: role of Ki-67 index and tumour differentiation. PMC10556170, 2023.

5. FDG-PET/CT imaging findings of hepatic tumours and tumour-like lesions based on molecular background. Japanese Journal of Radiology 2020;38:697–718. doi:10.1007/s11604-020-00961-1

6. The current role of PET-CT in the characterisation of hepatobiliary malignancies. HPB (Oxford); PMC2697862.

7. PET/CT in patients with liver lesions of different nature. Clinical and Translational Imaging 2014. doi:10.1007/s40336-014-0061-3

8. The prognostic value of ¹⁸F-FDG PET/CT for hepatocellular carcinoma treated with transarterial chemoembolisation. Theranostics 2014;4(7):736–744.

9. Lv J, Yin H, Mao W, Shi H. Investigating the value of pre-treatment ¹⁸F-FDG PET/CT in predicting the pathological characteristics of hepatocellular carcinoma and recurrence after liver transplantation. Abdominal Radiology 2021;46(6):2490–2497.

10. Diagnostic performances of PET/CT using fibroblast activation protein inhibitors in patients with primary and metastatic liver tumours: a comprehensive literature review. International Journal of Molecular Sciences 2024; PMC11241825.

11. Henrar RB, Vuijk FA, Burchell GL, Vahrmeijer AL, Oprea-Lager DE, et al. Diagnostic performance of radiolabelled FAPI versus [¹⁸F]FDG PET imaging in hepato-pancreato-biliary oncology: a systematic review and meta-analysis. International Journal of Molecular Sciences 2025;26(5):1978.

12. Prospective comparison of ⁶⁸Ga-FAPI versus ¹⁸F-FDG PET/CT for tumour staging in biliary tract cancers. Radiology 2022. doi:10.1148/radiol.213118

13. Annunziata S, Treglia G, Caldarella C, Galiandro F. The role of ¹⁸F-FDG-PET and PET/CT in patients with colorectal liver metastases undergoing selective internal radiation therapy with yttrium-90: a first evidence-based review. The Scientific World Journal 2014;2014:879469.

14. The role of ¹⁸F-FDG PET/CT in evaluating the efficacy of radiofrequency ablation in metastatic and primary liver tumours: preliminary results. PMC7885284.

15. The added value of ¹⁸F-FDG PET/MRI multimodal imaging in hepatocellular carcinoma for identifying cytokeratin 19 status. PubMed 37119293.