Oncological PET/CT
Report template: F-18 FDG PET/CT (oncology, lymphoma) · PSMA PET/CT (prostate cancer) · SSTR PET/CT (Ga-68 DOTA peptides)
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Solve questions (26) →Contents
- 21.1 FDG PET/CT Basic Principles and Physiological Uptake
- 21.2 FDG PET/CT Indications (by Organ)
- 21.3 Treatment Response Assessment (PERCIST, RECIST)
- 21.4 Causes of False Positives and False Negatives
- 21.5 Non-FDG PET Radiopharmaceuticals
- 21.6 SUV Calculation and Influencing Factors
- 21.7 Radiotherapy Planning and PET
- Key Points for the Board
- Current guidelines on this chapter's topics
Learning objectives and modules4 modules · about 2 h 55 min
Learning objectives
After this chapter you will be able to:
- Explain the cellular uptake mechanism and physiological distribution of FDG.
- Manage patient preparation and the factors that alter uptake (blood glucose, insulin, brown fat, treatments).
- State the main oncological indications and limits of FDG PET/CT.
- Assess treatment response with the PERCIST and RECIST criteria.
- Recognise the causes of false-positive and false-negative findings.
- Match non-FDG PET tracers with their targets and indications; explain the role of PET in radiotherapy planning.
Modules
The chapter is divided into study modules without changing the order of the text: read, watch the animations, then answer the questions linked to those headings.
- Module 121.1 FDG PET/CT Basic Principles and Physiological Uptake30 min · 1 animation · 12 questionsAnswer the questions →
- Module 221.2–21.3 FDG PET/CT Indications (by Organ) · Treatment Response Assessment (PERCIST, RECIST)50 min · 20 questionsAnswer the questions →
- Module 321.4–21.5 Causes of False Positives and False Negatives · Non-FDG PET Radiopharmaceuticals1 h 10 min · 32 questionsAnswer the questions →
- Module 421.6–21.7 SUV Calculation and Influencing Factors · Radiotherapy Planning and PET · Key Points for the Board25 min · 1 animation · 5 questionsAnswer the questions →
Times are estimates: 130 words per minute, 3 min per animation, 1.5 min per question.
MOST FREQUENTLY ASKED IN THIS CHAPTER
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FDG → entry into the cell via GLUT-1 → phosphorylation by hexokinase → cannot be dephosphorylated by glucose-6-phosphatase → metabolic trapping
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F-18 half-life: 110 minutes, cyclotron production, positron emission, 511 keV annihilation photons
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In obese patients SUVbw is artificially high → use SUVlbm (SUL)
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Physiological uptake: brain (most intense), myocardium (variable), urinary tract (excretion), tonsils, GI tract
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Brown fat: symmetric cervical-supraclavicular uptake → prevented with a warm environment + beta-blocker
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Myocardial suppression: prolonged fasting (≥12-18 hours) + high-fat diet + heparin → cardiac sarcoidosis/endocarditis protocol
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SPN: >8-10 mm nodule → PET indicated; SUVmax >2.5 suspicious for malignancy
21.1 FDG PET/CT Basic Principles and Physiological Uptake12 questions
Basic Properties of FDG
F-18 Fluorodeoxyglucose (FDG):
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Glucose analogue → enters the cell via GLUT (especially GLUT-1 and GLUT-3) transporters
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Phosphorylated in the cell by hexokinase → FDG-6-phosphate is formed
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FDG-6-phosphate cannot be dephosphorylated by glucose-6-phosphatase → metabolic trapping
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It cannot enter the later steps of glycolysis → accumulates in the cell
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Tumour cells have increased GLUT-1 expression and hexokinase activity → FDG uptake increases
A two-row flow chart between blood and a tumour cell: above, glucose enters by GLUT, becomes glucose-6-phosphate via hexokinase and goes on to glycolysis; below, FDG enters the same way and becomes FDG-6-phosphate, which cannot enter glycolysis or be reversed by glucose-6-phosphatase. A highlight moving along the arrows and boxes lighting up in turn show the order of conversion; trapped FDG-6-P is counted.
Continuous stream · no seeking
FDG enters and is phosphorylated like glucose, but FDG-6-P can neither enter glycolysis nor be reversed, so uptake reflects the cell's glucose use.
Source: mechanism from the book (21.1); an animated version of Figure 21.1. Molecule numbers and speeds representative.
How to use: a single click on the drawing pauses and resumes; use the time bar below to go to any point of the flow.
Did this animation help you understand the topic?
Figure 21.1: Metabolic trapping of FDG: entry into the cell via GLUT, phosphorylation by hexokinase, and inability to be dephosphorylated by glucose-6-phosphatase (schematic).
Physical Properties of F-18:
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Half-life: 110 minutes
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Decay: positron (β+) emission
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Positron range: ~1 mm (in water)
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Annihilation: two 511 keV gamma photons → emitted at 180°
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Production: cyclotron (O-18 enriched water target)
Patient Preparation
Fasting:
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At least 4 hours of fasting (ideally 6 hours)
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Purpose: to lower insulin levels → reduce FDG uptake in muscle and fat → increase tumour/background contrast
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Water may be drunk (unsweetened)
Blood Glucose:
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Blood glucose should be checked before injection
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Threshold (EANM 2025): if plasma glucose is <11 mmol/L (~200 mg/dL) the scan is performed; if ≥11 mmol/L it should ideally be rescheduled, taking the patient's circumstances into account (in poorly controlled diabetes hyperglycaemia is not an absolute contraindication). In clinical trial protocols the upper limit may be 7-8.3 mmol/L (126-150 mg/dL). Glucose should not be below 4 mmol/L (~70 mg/dL); insulin is not given to lower glucose
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High blood glucose → competitive inhibition → tumour FDG uptake falls → false negative
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Insulin management is important in diabetic patients → short-acting insulin should be given at least 4 hours before injection (so as not to increase muscle uptake)
Other Preparation:
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Avoid strenuous exercise (for at least 6 hours, preferably 24 hours beforehand)
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Avoid a cold environment (to prevent brown fat activation)
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Waiting in a warm environment (brown fat precaution)
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Diazepam (5 mg IV, 10 min before FDG) or propranolol (80 mg orally, 2 hours before) has been tried for brown fat; results are conflicting. Routine sedation is not needed in adults; it may be considered to reduce muscle uptake in head and neck tumours or for claustrophobia
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60 minutes waiting after FDG injection (uptake time)
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Rest in a quiet, dark, warm room during the waiting period
EANM Recommendations (FDG):
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Activity: calculated with the formula 14 × weight / time per bed position (min); in children at least 26 MBq; 19 µSv/MBq; bladder wall dose 130 µGy/MBq. EANM 2025: the product of activity and time per bed position should not fall below the value in the guideline table; these values are for short axial FOV/analogue systems, and on digital and long axial FOV systems the EARL procedure is followed
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At least 4 hours of fasting and adequate hydration; blood glucose should be <11 mmol/L (~200 mg/dL)
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There should be 4-6 hours between insulin and FDG injection; an insulin pump is switched off at least 4 hours beforehand
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Waiting times: at least 10 days after chemotherapy (preferably 3 weeks), >2 weeks after growth factor (G-CSF), 2-3 months after radiotherapy, at least 6 weeks after surgery
Figure 21.2: Timeline of patient preparation before FDG PET/CT and recommended minimum waiting times after treatment (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"Why does FDG accumulate in the cell?"
→ It is phosphorylated by hexokinase but cannot be dephosphorylated by glucose-6-phosphatase → metabolic trapping.
▸
"Enzyme that increases FDG uptake?"
→ Hexokinase.
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"Transporter that carries FDG into the cell?"
→ GLUT-1 (upregulated in most tumours).
Physiological FDG Uptake
Knowing physiological uptake is critical for distinguishing it from pathological uptake.
Organs with High Physiological Uptake:
| Organ/Tissue | Mechanism | Feature |
|---|---|---|
| Brain | High glucose metabolism (GLUT-3) | Grey matter >> white matter |
| Myocardium | Uses fatty acids when fasting, glucose when fed | Variable uptake (depends on fasting state) |
| Urinary tract | Renal excretion | Renal pelvis, ureter, bladder intense |
| Tonsils/Waldeyer ring | Lymphoid tissue | Symmetric, bilateral |
| Gastrointestinal tract | Smooth muscle activity, lymphoid tissue | Stomach, bowel variable |
| Liver | Basal metabolism | Homogeneous, moderate |
| Spleen | Lymphoid tissue | Lower than or equal to liver |
| Bone marrow | Haematopoietic activity | Homogeneous, low-moderate |
Variable/Artefactual Uptake:
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Brown fat: cervical, supraclavicular, paravertebral, mediastinal → symmetric, bilateral → increases in a cold environment → can be reduced with a beta-blocker or a warm environment
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Muscle uptake: talking → laryngeal muscles; chewing → masseter/pterygoid; tension → neck muscles
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To reduce muscle uptake, talking, chewing and chewing gum are avoided during the uptake period; a benzodiazepine (diazepam) helps with anxiety-related muscle tension
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Uterus: variable with the menstrual cycle (increased at ovulation and menstruation)
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Lactation: bilateral increased uptake in the lactating breast
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Thymus: rebound hyperplasia in young patients and after chemotherapy
Figure 21.3: Physiological and variable/artefactual FDG uptake sites (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"If the exam asks about symmetric cervical-supraclavicular FDG uptake?"
→ Think of brown fat.
▸
"How is myocardial FDG uptake suppressed?"
→ Prolonged fasting (≥12-18 hours) + high-fat/low-carbohydrate diet + heparin (fatty acid mobilisation). This protocol is used especially for the assessment of cardiac sarcoidosis and endocarditis (→ Chapter 14).
FDG Excretion
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Primary route: renal excretion (glomerular filtration)
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About 20% of the injected dose is excreted in the urine in the first 2 hours
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Bladder activity → may mask pelvic lesions → is rarely a problem with adequate hydration; delayed imaging or furosemide is rarely needed, and the risk of urinary tract infection from bladder catheterisation may outweigh its benefit (EANM 2025)
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Hepatic excretion: minimal
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Report content (EANM v3.0, 2025): in addition to the common items (see 27), blood glucose (with time of measurement), body weight measured on the day, height and sex, antidiabetic drugs, corticosteroids and growth factors, uptake interval. If quantitative values are given, the metric (SUVmax, SUVpeak or SULpeak) and whether it is glucose-corrected; the liver reference (3 cm VOI; a mean SUV outside 1.3-3.0 or SUL outside 1.0-2.2 suggests a technical problem and quantitative interpretation is reconsidered); MTV/TLG and the segmentation method if used. Follow-up reports mirror the baseline format and state clearly whether new lesions are present; for Deauville and Lugano in lymphoma see 20
21.2 FDG PET/CT Indications (by Organ)13 questions
Lung Cancer
Non-Small Cell Lung Cancer (NSCLC):
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Characterisation of a solitary pulmonary nodule (SPN):
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FDG PET/CT is indicated for nodules >8-10 mm
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SUVmax >2.5 → high suspicion of malignancy
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CT findings favouring benignity: central, diffuse, laminated or concentric, or popcorn calcification, and fat within the nodule (hamartoma). Eccentric or punctate calcification does not exclude malignancy. No change in size of a solid nodule for at least 2 years favours benignity (slow-growing lepidic adenocarcinoma and carcinoid can mislead)
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False negatives: carcinoid, bronchioloalveolar carcinoma (lepidic adenocarcinoma), low-grade tumours, nodules <8 mm
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Pure ground-glass (subsolid) nodules mostly take up little FDG, so PET is not useful for characterising them; PET and contrast-enhanced CT are used mainly for solid nodules
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False positives: granuloma, infection, inflammation
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Staging: assessment of mediastinal lymph nodes and distant metastases
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Treatment response: after neoadjuvant chemotherapy
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Detection of recurrence: post-treatment follow-up
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Radiotherapy planning: definition of tumour volume (GTV)
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Prognosis: in NSCLC the SUVmax of the primary tumour is an independent prognostic factor (high SUV is associated with shorter survival); metabolic response after treatment predicts survival better than size response on CT
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Approach to SPN: if the pre-test probability is high, proceed directly to tissue diagnosis or resection; PET/CT is most useful for solid nodules ≥8 mm with intermediate (indeterminate) pre-test probability. Because the probability of malignancy in PET-negative nodules is still ~5-10%, CT follow-up is performed
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The meaning of a negative PET depends on pre-test probability: if the probability is high (e.g. 80%), the probability of malignancy remains ~15% even with a negative PET and tissue diagnosis is needed. PET is most cost-effective when pre-test probability and CT appearance are discordant
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Mediastinal staging: PET/CT has a high NPV and can detect metastases in normal-sized lymph nodes (~15%); PET-positive nodes may be false positive because of granuloma or anthracosis and should be confirmed by EBUS or mediastinoscopy
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If the mediastinum is negative on PET/CT, the tumour is peripheral and ≤3 cm, and there is no N1, invasive mediastinal staging is not needed; if the tumour is central or >3 cm, if N1 is suspected, or if FDG uptake of the primary is low, EBUS or mediastinoscopy is performed even with a negative PET (ESTS)
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Distant staging: an FDG-avid pleural effusion suggests malignancy; for adrenal and bone metastases PET is more sensitive than CT and bone scintigraphy; for brain metastases contrast-enhanced MRI is preferred because of the high cortical uptake
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Adrenal mass: SUVmax ≥~3.1 or an adrenal/liver SUV ratio >~1.5 suggests metastasis; lipid-poor adenoma and phaeochromocytoma may be false positive, small or necrotic metastases false negative
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Malignant pleural mesothelioma takes up FDG; in most benign pleural processes SUV is <2. The value of PET in showing local extent is limited; its main contribution is to prevent unnecessary thoracotomy by showing extrathoracic metastases. Localised fibrous tumour of the pleura mostly takes up little FDG
Small Cell Lung Cancer (SCLC):
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Useful for distinguishing limited from extensive stage
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Routine use is not as widespread as in NSCLC
Colorectal Cancer
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Limited role in primary tumour staging (colonoscopy and CT take priority)
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Liver metastases: resectability assessment → PET/CT may detect additional metastatic foci
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In metastasectomy candidates PET/CT changes management in ~30% of cases by showing extrahepatic disease; CT is more sensitive for small (<1 cm) lung metastases, and contrast-enhanced MRI for detecting and characterising liver lesions
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Rising CEA: when no lesion is found on conventional imaging
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Detection of recurrence: strongest indication → sensitivity 90-95%
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False negatives: mucinous adenocarcinoma → low FDG uptake
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If incidental focal colonic FDG uptake is seen, colonoscopy is recommended (adenoma and carcinoma are common); diffuse or segmental uptake is mostly physiological or related to colitis or metformin use
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In rectal cancer PET/CT is superior to CT for distinguishing presacral scar from recurrence; early after RT inflammation may cause false positives, while focal uptake persisting months later suggests recurrence
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RT-related inflammatory FDG uptake may last up to ~6 months; therefore assessment for presacral recurrence is more reliable at least 6 months after the end of RT
Lymphoma
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Staging, interim and end-of-treatment response assessment (→ cross-reference with Chapter 20)
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The Deauville score and Lugano classification are used
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Distinguishing FDG-avid from FDG-non-avid lymphoma is important
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Primary CNS lymphoma: despite high physiological cortical uptake, it mostly takes up FDG more intensely than the cortex; this feature helps distinguish it from toxoplasmosis in immunosuppressed patients
Melanoma
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Staging of stage III and higher melanoma
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Routine PET/CT is not recommended in stage I-II (low yield)
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Detection of in-transit and distant metastases
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False negatives: small metastases (<5 mm), especially pulmonary micronodules
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The scan field should extend from head to toes (for metastases in the distal extremities); PET does not replace SLNB. CT is superior for subcentimetre lung nodules and MRI for brain metastases
Breast Cancer
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Not used routinely for primary diagnosis (mammography, US and MRI take priority)
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Staging of locally advanced (stage III) and metastatic (stage IV) breast cancer
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EANM-SNMMI 2024 (no special type breast cancer): in baseline staging the role of FDG PET/CT starts at stage IIB: not recommended in stage I, may be useful in clinical stage IIA (T1N1 or T2N0), recommended in stage IIB (preferably before surgery), III (including inflammatory) and IV. It is done instead of, not together with, conventional imaging (bone scan, chest CT, liver US or abdominal CT); in a randomised trial it was superior to that combination on its own. Response is reported on an accredited system with PERCIST, EORTC or, during immunotherapy, the EANM criteria; early metabolic response is particularly useful in non-metastatic triple-negative and HER2-positive tumours. With suspected recurrence (clinical or laboratory) and equivocal conventional imaging it shows the site and extent of recurrence. SUV, MTV and TLG are prognostic
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Treatment response assessment
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Limited sensitivity for axillary lymph node assessment (micrometastases may be missed)
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Lobular carcinoma: FDG uptake may be lower than in ductal carcinoma → false negative
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Other causes of false negatives: tumour <1 cm, well-differentiated (tubular) carcinoma and carcinoma in situ. High FDG uptake is associated with aggressive biology and poor prognosis
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In early-stage disease FDG PET does not replace SLNB for axillary staging. For bone metastases FDG is more sensitive for lytic and bone scintigraphy for blastic lesions; the two methods are complementary
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An FDG-avid axillary node has a high PPV (high specificity, low sensitivity); after biopsy confirmation axillary treatment can be planned. In axillary adenocarcinoma of unknown primary, breast MRI is the first choice
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In ER-positive patients, a transient rise in FDG uptake on days 7-10 after tamoxifen (metabolic flare) is not progression; it predicts response to hormone therapy
Head and Neck Cancers
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Staging and treatment planning
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Cancer of unknown primary (CUP): metastatic cervical lymph node + unknown primary → PET/CT may detect the primary focus (25-30%)
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Assessment of recurrence after treatment → ≥12 weeks after treatment (to let inflammation subside)
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In a clinically N0 neck a negative PET does not exclude occult metastasis (~20-30% have occult metastases, most <1 cm); therefore SLNB or elective dissection is needed. The main contribution of PET is to show distant metastases and synchronous second primaries
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In head and neck SCC, distant metastases are most often in the lung (followed by bone and liver); a solitary lung nodule must be distinguished as metastasis or (smoking-related) second primary
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A negative PET/CT ~12 weeks after CRT has a high NPV; planned neck dissection can be avoided in these patients (PET-NECK trial)
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Radiotherapy planning
Oesophageal Cancer
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Staging: detection of distant metastases
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Response to neoadjuvant treatment
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EUS is superior for local staging (T and N staging)
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For regional lymph nodes EUS is more sensitive and PET more specific (nodes close to the primary may not be separable from tumour activity). False positives occur in reflux or radiation oesophagitis, false negatives in small or well-differentiated tumours
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Sensitivity for detecting the primary tumour is high (~90-95%), but PET cannot distinguish wall layers and so cannot perform T staging; T1 (especially T1a) tumours are often not detected
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A high baseline SUV and failure to achieve a metabolic response to neoadjuvant therapy indicate poor prognosis; an early fall in SUV (~week 2) identifies responders (MUNICON)
Thyroid Cancer
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Routine FDG PET/CT is not indicated in differentiated thyroid cancer (RAI scanning takes priority)
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High thyroglobulin + negative RAI scan → FDG PET/CT indicated ("flip-flop" phenomenon)
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The sensitivity of FDG PET/CT increases with Tg level; according to ATA 2025 it is used particularly in high-risk patients with elevated Tg (generally >10 ng/mL) and a negative radioiodine scan. TSH stimulation (rhTSH) may increase sensitivity somewhat; detection of FDG-avid disease often changes management
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FDG PET/CT is useful in anaplastic and medullary thyroid cancer
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Oncocytic (Hürthle) and poorly differentiated carcinomas mostly do not take up RAI but take up FDG; FDG PET/CT is therefore valuable for staging and follow-up. FDG uptake is a marker of poor prognosis
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The most sensitive PET agent for recurrent MTC is F-18 FDOPA; FDG is useful especially in disease with a short calcitonin or CEA doubling time (aggressive) and carries prognostic value
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Flip-flop: loss of differentiation → NIS expression falls (no RAI uptake) → GLUT-1 rises (FDG uptake)
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Incidental thyroid FDG uptake: focal uptake carries a malignancy risk of ~30-35%; US ± FNAB is performed. Diffuse bilateral uptake is mostly due to chronic (Hashimoto) thyroiditis or Graves disease and is assessed together with thyroid function tests
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In a nodule with indeterminate cytology (Bethesda III/IV), a negative FDG PET/CT, with its high NPV, reduces unnecessary diagnostic surgery (EfFECTS randomised controlled trial); oncocytic (Hürthle) nodules are often false positive
Figure 21.4: Flip-flop phenomenon in thyroid cancer: with loss of differentiation, NIS (RAI) uptake falls and GLUT-1 (FDG) uptake rises (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"High thyroglobulin, negative RAI scan → what do you do?"
→ Request FDG PET/CT. This is the "flip-flop" phenomenon → the tumour has dedifferentiated → does not take up iodine but takes up FDG. This is a marker of poor prognosis.
Pancreatic Cancer
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Detection and staging of the primary tumour
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Distinguishing chronic pancreatitis from pancreatic cancer (limited; both may take up FDG)
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Hyperglycaemia from the frequently associated diabetes lowers sensitivity; sensitivity is low for periampullary tumours and peritoneal implants. Inflammation is usually diffuse and cancer focal; chronic pancreatitis mostly does not take up FDG, so malignancy should be sought in FDG-avid chronic pancreatitis
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Detection of distant metastases
Ovarian Cancer
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Limited role in primary staging (surgical staging is the gold standard)
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Detection of recurrence: rising CA-125 + negative conventional imaging → PET/CT useful
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Sensitivity is low for peritoneal micrometastases (<5 mm); a negative PET does not make second-look surgery unnecessary. In premenopausal women ovarian uptake may be cycle-related and physiological
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Peritoneal metastases (ESGAR/ESUR/PSOGI/EANM 2024; ovarian and colorectal cancer): FDG PET/CT is acquired according to the EANM tumour imaging guideline and combining it with a diagnostic-quality CT is highly recommended; the protocol is the same for ovarian and colorectal cancer. The imaging estimate of the peritoneal cancer index (PCI) often underestimates the surgical PCI; small and mucinous implants can be missed. Because physiological bowel uptake is low with FAPI, comparative studies found higher sensitivity and PCI estimates with FAPI PET than with FDG (97.7% vs 72.1% in one study)
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Treatment response assessment
Testicular Cancer
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In seminoma: assessment of a residual mass (residual mass >3 cm after chemotherapy)
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In non-seminoma: PET/CT is not reliable (mature teratoma does not take up FDG → false negative)
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Seminoma takes up more FDG than non-seminoma; uptake in the normal testis is variable. For residual seminoma after chemotherapy, PET should be performed no earlier than ~6-8 weeks afterwards because of inflammation
BOARD TIP
▸
"Residual mass after chemotherapy for testicular tumour + PET?"
→ PET/CT is useful in seminoma (for a residual mass >3 cm). In non-seminoma PET/CT is not reliable → mature teratoma does not take up FDG → surgical exploration is needed.
Other Tumours
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Renal cell carcinoma: FDG is limited by renal excretion → low sensitivity for the primary tumour; useful for detecting metastases
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RCC: tumour thrombus takes up FDG, bland thrombus does not; for (lytic) bone metastases FDG PET/CT is more sensitive than bone scintigraphy. A high SUVmax indicates poor prognosis, and an early fall in SUV after TKI predicts response; CT is the standard staging method
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Prostate cancer: low FDG sensitivity → PSMA PET/CT or choline PET/CT is preferred (→ Chapter 21.5)
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Hepatocellular carcinoma: well-differentiated HCC → low FDG uptake; poorly differentiated → high uptake
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In HCC, C-11 acetate (like choline) is taken up at a high rate by well-differentiated tumour; used together with FDG they are complementary (dual tracer)
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Cholangiocarcinoma: FDG sensitivity is high in the mass-forming intrahepatic type and low in the periductal-infiltrating (hilar or extrahepatic) type; sensitivity for lymph nodes is limited. Staging is done mainly with contrast-enhanced CT and MRI/MRCP; PET contributes by showing distant metastases
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In cholangiocarcinoma FDG sensitivity is ~85% in the nodular type and ~20% in the infiltrative type; gallbladder carcinoma mostly takes up FDG. Stents and cholangitis cause false positives, and sensitivity for carcinomatosis is limited
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Sarcomas: staging, grade assessment, treatment response
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GIST: contrast-enhanced CT is the standard method for staging and follow-up; FDG PET shows imatinib response days or weeks before size change. A small-bowel GIST of the same size is more aggressive than a gastric GIST
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Cervical cancer: staging (especially lymph node metastasis), radiotherapy planning
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In locally advanced cervical cancer PET/CT is more sensitive than MRI and CT for pelvic and para-aortic nodes (para-aortic involvement extends the RT field); metabolic response ~3 months after CRT is a strong prognostic marker
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Gastric cancer: mucinous and signet ring cell (diffuse) types have low FDG uptake and false negatives occur
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In gastric cancer T staging is done with EUS and CT; the intestinal type takes up more FDG than the diffuse type. For N staging PET is specific but insensitive; sensitivity for peritoneal metastases is low (~30-50%), and contrast-enhanced CT is more sensitive
•
Bladder cancer: because urinary activity hides the primary tumour, PET/CT is used mainly to look for lymph node and distant metastases in muscle-invasive disease; hydration, furosemide and delayed imaging help
•
Plasma cell disorders (EANM 2024): per the IMWG, whole-body low-dose CT is first line for suspected MGUS and smouldering myeloma, low-dose CT or FDG PET/CT for suspected active myeloma; whole-body MRI for solitary plasmacytoma of bone and FDG PET/CT for extramedullary plasmacytoma. FDG PET/CT shows lytic lesions ≥5 mm; sensitivity ~90%, specificity 70-100%. 10-20% of newly diagnosed patients are FDG-negative because of low hexokinase-2 expression and cannot be followed with PET; MRI is more sensitive for diffuse marrow involvement. Reporting uses IMPeTUs: diffuse marrow (5-point Deauville scale), number and site of focal lesions (skull, spine, extra-spinal; 0, 1-3, 4-10, >10), paramedullary and extramedullary disease, fractures. Poor prognosis: >3 focal lesions, focal SUVmax >4.2, extramedullary and paramedullary disease. FDG PET/CT is the preferred method for post-treatment response (it normalises earlier than MRI); complete metabolic response is marrow and focal uptake equal to or below liver (Deauville ≤3); a positive PET in conventional complete response indicates worse PFS. Extramedullary disease is present in 5-11% at diagnosis and >20% at relapse; it is sought with PET even in MRD-negative patients. In smouldering myeloma, PET positivity without osteolysis is not yet a myeloma-defining event
21.3 Treatment Response Assessment (PERCIST, RECIST)7 questions
RECIST 1.1 (Response Evaluation Criteria in Solid Tumors)
Anatomical (CT-based) response criteria:
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Target lesions: at most 5 lesions (at most 2 per organ), longest diameter ≥10 mm (lymph node short axis ≥15 mm)
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Measurement: unidimensional (longest diameter)
Response Categories:
| Category | Criterion |
|---|---|
| Complete Response (CR) | Disappearance of all target lesions; lymph nodes short axis <10 mm |
| Partial Response (PR) | ≥30% decrease in the sum of target lesion diameters (relative to baseline) |
| Progressive Disease (PD) | ≥20% increase in the sum of target lesion diameters (relative to nadir) + absolute increase ≥5 mm OR new lesion |
| Stable Disease (SD) | Meets neither PR nor PD criteria |
PERCIST 1.0 (PET Response Criteria in Solid Tumors)
Metabolic (PET-based) response criteria:
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Measurement parameter: SULpeak (SUV corrected for lean body mass) → preferred
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Alternative: SUVmax or SUVpeak may be used
•
Target lesion: the most FDG-avid lesion (at most 5)
•
At baseline the SULpeak of the target lesion should be ≥1.5 × mean liver SUL + 2 SD
Response Categories:
| Category | Criterion |
|---|---|
| Complete Metabolic Response (CMR) | Complete resolution of FDG uptake in all lesions (below mean liver, to blood pool level) |
| Partial Metabolic Response (PMR) | ≥30% and ≥0.8 SUL unit decrease in SULpeak |
| Progressive Metabolic Disease (PMD) | ≥30% and ≥0.8 SUL unit increase in SULpeak OR new FDG-avid lesion |
| Stable Metabolic Disease (SMD) | Meets none of the CMR, PMR or PMD criteria |
RECIST vs PERCIST Comparison:
| Feature | RECIST 1.1 | PERCIST 1.0 |
|---|---|---|
| Basis | Anatomical (size) | Metabolic (FDG uptake) |
| Modality | CT | PET/CT |
| Measurement | Longest diameter (unidimensional) | SULpeak / SUVmax |
| PR threshold | ≥30% decrease in diameter | ≥30% decrease in SUL |
| PD threshold | ≥20% increase in diameter | ≥30% increase in SUL |
| Advantage | Widely accepted, standardised | Early response detection, functional |
| Disadvantage | Size may not change in necrotic tumour | Standardisation difficulties |
BOARD TIP
▸
"PR threshold in RECIST?"
→ 30% decrease (diameter).
▸
"PD threshold in RECIST?"
→ 20% increase (diameter) + absolute 5 mm.
▸
"PR and PD thresholds in PERCIST?"
→ Both 30% (decrease or increase). Trap: in RECIST the PR and PD thresholds differ (30% vs 20%); in PERCIST both are 30%.
Figure 21.5: Threshold values of the RECIST 1.1 and PERCIST 1.0 response categories.
Did this figure help you understand the topic?
Lymphoma-Specific Response Criteria
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Lugano/Deauville: in FDG-avid lymphomas → Deauville 5-point scale (→ cross-reference with Chapter 20)
•
IWC (International Working Criteria): older criteria, updated by Lugano
•
RECIST or PERCIST is not used in lymphoma → the Lugano classification is used
21.4 Causes of False Positives and False Negatives7 questions
Causes of False Positives
Non-malignant conditions showing FDG uptake:
1. Infection and Inflammation:
•
Active infection (pneumonia, abscess, tuberculosis, fungal infection)
•
Granulomatous diseases (sarcoidosis, histoplasmosis)
•
Inflammatory processes (pancreatitis, colitis, oesophagitis)
•
Mechanism: increased glycolysis in activated macrophages and neutrophils
2. Iatrogenic/Treatment-Related:
•
Postoperative inflammation (6-8 weeks)
•
Post-radiotherapy inflammation (radiation pneumonitis, oesophagitis) → wait 3 months
•
Post-chemotherapy inflammation
•
Talc pleurodesis → intense granulomatous reaction → may take up FDG for years
•
G-CSF → diffuse bone marrow and splenic uptake → wait 2-4 weeks
•
Bone marrow stimulation (erythropoietin)
3. Benign Tumours and Other:
•
Adenoma (colon, thyroid)
•
Fibrous dysplasia
•
Paget disease
•
Fracture healing
•
Desmoid tumour
•
Warthin tumour (parotid)
4. Physiological Variants:
•
Brown fat
•
Muscle uptake (talking, chewing, tension)
•
Menstrual cycle (endometrium, ovary)
•
Uterine leiomyoma, functional ovarian cyst and corpus luteum may also take up FDG
•
Thymic hyperplasia (rebound)
BOARD TIP
▸
"If the exam asks for the cause of a false positive on PET/CT, the most common answer?"
→ Infection/inflammation (increased glycolysis in activated macrophages).
▸
"PET after talc pleurodesis?"
→ Intense FDG uptake for years → false positive.
▸
"When should PET be done after G-CSF?"
→ At least 2-4 weeks later.
Causes of False Negatives
Malignant conditions showing no or low FDG uptake:
1. Tumour-Related:
•
Tumours with low metabolic activity:
–
Bronchioloalveolar carcinoma (lepidic adenocarcinoma)
–
Carcinoid tumour (low grade)
–
Mucinous adenocarcinoma (colorectal, ovarian)
–
Renal cell carcinoma (some subtypes)
–
Prostate cancer
–
Well-differentiated hepatocellular carcinoma
–
Lobular breast cancer
–
Mature teratoma
–
Low-grade sarcoma
2. Patient-Related:
•
Hyperglycaemia → competitive inhibition (most important cause)
•
Short uptake time (<60 minutes)
•
High insulin level → muscle/fat uptake increases, tumour uptake falls relatively
3. Technical:
•
Small lesion size (<7-8 mm) → partial volume effect
•
Motion artefact (respiratory motion → lung bases)
•
Attenuation correction errors
BOARD TIP
▸
"Tumours that do not take up FDG?"
→ Mnemonic BMLP-CHR: Bronchioloalveolar, Mucinous, Lobular breast, Prostate, Carcinoid, HCC (well-differentiated), Renal.
▸
"Most common patient-related cause of false negatives?"
→ Hyperglycaemia.
21.5 Non-FDG PET Radiopharmaceuticals25 questions
Ga-68 PSMA (Prostate-Specific Membrane Antigen)
•
Target: PSMA (type II transmembrane glycoprotein) → overexpressed on prostate cancer cells
•
Indication: prostate cancer staging, biochemical recurrence, metastasis detection
•
Advantage: much higher sensitivity than FDG (in prostate cancer)
•
Can detect the site of recurrence even at low PSA levels (PSA ≥0.2 ng/mL)
•
PSMA-negative tumours: prostate cancer with neuroendocrine differentiation
•
False positives: ganglia, Paget disease, fibrous dysplasia, some benign tumours
•
Link to therapy: patient selection for Lu-177 PSMA therapy (theranostics) (→ Chapter 26)
•
EANM: PSMA is a membrane metallopeptidase overexpressed in 90-100% of prostate cancer cells; small urea-based ligands are used for imaging
•
Indications: primary staging of high-risk disease, localisation of the site in biochemical recurrence, patient selection for PSMA-targeted radioligand therapy in mCRPC
•
Ga-68 PSMA: 1.8-2.2 MBq/kg (100-200 MBq); 20 µSv/MBq, i.e. ~2-4 mSv; the kidneys receive the highest organ dose
•
False positives: coeliac and cervical ganglia, benign bone lesions
•
F-18 PSMA-1007: because it is excreted almost entirely by the hepatobiliary route, urinary activity in the pelvis is low; however, non-specific uptake in benign bone lesions is more frequent than with PSMA-11
•
Fasting is not needed with F-18 PSMA agents; hydration, bladder voiding and, if needed, 10-20 mg IV furosemide are given. Cu-64 PSMA has lower urinary excretion and allows delayed imaging
•
Acquisition and reporting (EANM/SNMMI PSMA PET 2.0, 2023; PROMISE V2, 2023): the uptake time is ~60 minutes for most ligands. Lesion location is reported with the molecular TNM (miTNM); the PRIMARY score can be used for a focus in the prostate. PSMA expression score (only for lesions >10 mm): 0 = equal to or below blood pool, 1 = above blood pool and equal to or below liver, 2 = above liver and equal to or below parotid, 3 = above parotid. Scores 2-3 are regarded as positive for radioligand therapy; the highest and lowest scores in the patient are both reported. For F-18 PSMA-1007, which is excreted by the liver, the reference organ is the spleen instead of the liver. Because neuroendocrine liver metastases often lose PSMA expression, the liver is also assessed with cross-sectional imaging
F-18 PSMA (Piflufolastat – DCFPyL)
•
F-18 labelled PSMA ligand
•
Advantages over Ga-68 PSMA: longer half-life (110 min vs 68 min), cyclotron production (no generator needed), better image quality
•
FDA approved (2021)
–
FDA-approved PSMA PET agents (November 2026): Ga-68 PSMA-11 (December 2020), F-18 piflufolastat (Pylarify, May 2021; new formulation Pylarify TruVu, March 2026), Ga-68 gozetotide kits (Illuccix December 2021, Locametz March 2022, Gozellix March 2025), F-18 flotufolastat (rhPSMA-7.3, Posluma, May 2023; radiohybrid ligand). Indications: suspected metastasis in candidates for definitive therapy and suspected recurrence with rising PSA; Locametz and the other approved agents are also used to select patients for Lu-177 PSMA-617. Cu-64 SAR-bisPSMA (a bivalent ligand) received FDA breakthrough therapy designation for biochemical recurrence in November 2026; phase 3 is ongoing
•
Report content (EANM/SNMMI PSMA 2.0; PROMISE V2; E-PSMA): in addition to the common items (see 27), last PSA and its date, ISUP grade, previous treatments (especially androgen deprivation therapy and its duration), ligand used, uptake interval, diuretic and bladder voiding. Findings: lesions by miTNM (miT, miN, miM and extent of bone involvement), with measurements where needed; PSMA expression score for lesions >10 mm (see above); a likelihood category for each lesion and overall (E-PSMA or PSMA-RADS); PSMA-avid benign or unrelated findings are listed separately
C-11 / F-18 Choline
•
Target: cell membrane synthesis (phosphatidylcholine)
•
Indication: prostate cancer (widely used in the pre-PSMA era), HCC
•
C-11 choline: T½ 20 minutes → requires an on-site cyclotron
•
F-18 fluoromethylcholine (FCH): T½ 110 minutes → more practical
•
Its use in prostate cancer has declined with the spread of PSMA PET/CT
•
HCC: choline uptake is high in well-differentiated HCC (FDG low) → complementary role
•
EANM: uptake reflects increased membrane phospholipid synthesis and choline kinase activity; the main indication is restaging in biochemical recurrence (detection rate 54.8% in 3203 patients)
•
Activity: F-18 FCH 4 MBq/kg (50-400 MBq, 20 µSv/MBq); C-11 choline 400-600 MBq (4.4 µSv/MBq)
•
In HCC, sensitivity rises up to 93% when C-11 choline and FDG are used together
•
Intense physiological uptake: salivary glands, kidneys, pancreas and bladder; inflammation and BPH cause false positives
BOARD TIP
▸
"Which PET agent is better in well-differentiated HCC?"
→ Choline (FDG uptake is low).
▸
"Poorly differentiated HCC?"
→ FDG is taken up better. Dual-tracer approach: choline + FDG → reflects the degree of differentiation of HCC.
F-18 NaF (Sodium Fluoride)
•
Target: binds to bone hydroxyapatite crystals (chemisorption onto the bone surface)
•
Indication: detection of bone metastases
•
Alternative to Tc-99m MDP/HDP bone scintigraphy → higher sensitivity and specificity
•
Advantage: higher bone/background ratio, faster imaging, PET resolution
•
Disadvantage: cost, availability
•
Details → cross-reference with Chapter 15
Ga-68 DOTATATE / DOTATOC / DOTANOC
•
Target: somatostatin receptors (SSR type 2 > type 5)
•
Indication: staging and treatment planning of neuroendocrine tumours (NET)
•
Far superior sensitivity to Octreoscan (In-111 pentetreotide)
•
Link to therapy: patient selection for Lu-177 DOTATATE (PRRT) (theranostics)
•
Details → cross-reference with Chapter 13.3
F-18 FAZA / F-18 FMISO (Hypoxia Imaging)
•
Target: tumour hypoxia
•
Mechanism: in hypoxic cells nitroimidazole compounds are reduced and trapped in the cell
•
Indication: radiotherapy planning → hypoxic tumours are radioresistant → dose escalation or use of radiosensitisers
•
Clinical use is at the research level, limited in routine practice
•
Other research agents: Cu-64 ATSM (hypoxia), annexin V (apoptosis; binds phosphatidylserine), F-18 galacto-RGD (αvβ3 integrin; angiogenesis)
F-18 FLT (Fluorothymidine)
•
Target: thymidine kinase-1 (TK-1) → DNA synthesis/cell proliferation
•
Mechanism: thymidine analogue → retained in cells in S phase
•
Indication: assessment of tumour proliferation rate, early treatment response
•
Advantage: not taken up in inflammation as much as FDG → more specific
•
Disadvantage: high physiological uptake in bone marrow and liver
•
In most tumours FLT uptake (SUV) is lower than that of FDG; background activity in normal brain is low, but tumour uptake depends on disruption of the blood-brain barrier
•
Clinical use is at the research level
F-18 FAPI (Fibroblast Activation Protein Inhibitor)
•
Target: fibroblast activation protein (FAP) → overexpressed on cancer-associated fibroblasts (CAF) in the tumour stroma
•
Advantages:
–
Very low physiological background uptake (brain, liver, GI tract → minimal)
–
High tumour/background ratio
–
Imaging possible 10 minutes after injection (rapid uptake)
–
Useful in tumours where FDG is limited (peritoneal carcinomatosis, gastric cancer, pancreatic cancer, cholangiocarcinoma)
•
Disadvantages:
–
FAP expression is not tumour-specific → may also be taken up in benign conditions such as wound healing, fibrosis and arthritis
–
Not yet FDA approved (at the research stage; clinical use increasing rapidly)
•
Ga-68 FAPI is also used (Ga-68 labelled version)
•
EANM: independent of glucose metabolism and does not require fasting; uptake is high in breast, pancreatic, colon, gastric, lung and hepatobiliary cancers, and low in lymphoma and myeloma
•
Effective dose is ~1.4-1.6 mSv/100 MBq (rapid renal excretion); fibrosis, ischaemia, inflammation and wound healing cause false positives
•
SNMMI/EANM FAP PET guideline (2024): the recommended uptake time is 20-60 min for Ga-68-labelled FAPIs and 30-90 min for F-18-labelled ones (60 min for F-18 FAPI-74); many centres use 60 min to match FDG, SSTR and PSMA. No fasting is needed and the bladder is emptied before the scan; activity can be reduced 2-4-fold on digital and long axial field-of-view systems. Oncological indications: gastrointestinal adenocarcinoma, pancreatic ductal adenocarcinoma, oesophageal, head and neck, thyroid, lung, ovarian and breast cancer; staging, restaging, response and selection for FAP-targeted therapy. Pitfalls: degenerative joint and spine disease, wound healing, fibrosis (heart, liver, lung, myelofibrosis), atherosclerosis/arteritis, oesophagitis, IgG4-related disease, inflammatory bowel disease; the premenopausal uterus and breast tissue; FAP expression in tumours is heterogeneous
BOARD TIP
▸
"Most important advantage of FAPI over FDG?"
→ Very low physiological background → minimal uptake in brain, liver and GI tract → superior contrast for tumours in these regions.
▸
"What does FAPI target?"
→ Not the tumour cell but the fibroblasts in the tumour stroma (CAF).
F-18 Fluciclovine (Axumin)
•
Target: amino acid transport (ASCT2 and LAT-1 transporters)
•
Indication: biochemical recurrence of prostate cancer
•
Leucine analogue → enters the cell but is not incorporated into protein
•
Minimal urinary excretion → superior to FDG for pelvic assessment
•
Its use is declining with the spread of PSMA PET/CT
•
FDA approved (2016)
•
EANM: a synthetic amino acid transported by LAT1 and ASCT2; 370 MBq is given (not adjusted for weight or age); imaging starts 3-5 minutes after injection
•
Preparation: at least 4 hours of fasting; avoid strenuous exercise the day before; the bladder should not be emptied within 30-60 min before injection
•
Malignancy criterion: uptake in soft tissue or a lymph node equal to or higher than bone marrow (a lower threshold is used for lesions <1 cm)
•
In bone, lytic lesions show more uptake; sclerotic lesions without uptake are assessed with NaF, bone scintigraphy, MRI or PSMA
Other Targeted Agents (EANM)
Ga-68 PentixaFor (CXCR4):
•
A cyclic pentapeptide antagonist that binds selectively to CXCR4; 100-200 MBq (1.85-4 MBq/kg), ~2.3 mSv for 150 MBq; imaging is performed after 60 ± 15 min
•
Contrast is high in multiple myeloma, mantle cell lymphoma and marginal zone lymphoma; in primary aldosteronism the accuracy for detecting an aldosterone-producing adenoma is 93.3% (a non-invasive alternative to adrenal vein sampling)
•
Pitfall: physiological uptake in the spleen and bone marrow is high
Tc-99m MIBI Breast Imaging (MBI):
•
Early uptake reflects proliferation, and washout reflects P-gp/MDR-mediated drug resistance
•
MBI is more sensitive than standard scintimammography, especially for lesions <1 cm and for multiple or contralateral lesions; MRI remains the first additional modality
•
Uses: supplementary screening in dense breasts, local extent, response to neoadjuvant therapy, biopsy guidance, risk stratification by background parenchymal uptake (BPU)
•
Activity: on a standard gamma camera 740-1110 MBq, on MBI/CZT systems 300-600 MBq; 9 µSv/MBq. BI-RADS-like categories are used (3 follow-up, 4-5 biopsy)
•
Classic scintimammography: injection is given in the arm opposite the lesion (in a foot vein if bilateral disease is suspected); prone lateral (pendant breast) and supine anterior images are acquired at 5-10 minutes. Medial lesions may be missed on lateral views; sensitivity in the axilla is low
•
False negatives: <1 cm, hypocellular, lobular and in situ tumours
•
False positives: fibroadenoma (especially cellular ones), fibrocystic change or atypical hyperplasia, papilloma, inflammation or abscess, recent biopsy or surgery
•
Positron emission mammography (PEM): breast-dedicated, compression, high-resolution (~2 mm) PET imaging with FDG
–
Two types of breast-dedicated PET: PEM with two opposed flat-panel detectors (the patient sits and the breast is lightly compressed as in mammography) and ring-type dedicated breast PET (dbPET; the patient lies prone and the breast hangs through an opening in the bed into a ring detector)
–
SUV cannot be measured with PEM; the PEM uptake value (PUV) is used instead. The SUVmax of ring-type dbPET agrees better with whole-body PET (reported correlation 0.84-0.94, versus 0.78 for PUVmax)
–
Lesions close to the chest wall may fall in the blind area of ring-type dbPET; PEM has an advantage near the chest wall. The reported minimum acquisition times are 5 minutes for dbPET and 7 minutes for PEM
–
When performed with the same FDG given for whole-body PET/CT it adds no radiation. For one PEM system an in-plane resolution of 2.4 mm (whole-body PET/CT ~5-7 mm) and a pooled sensitivity of 87% and specificity of 85% have been reported; because of the radiation dose, the ACR did not recommend PEM for screening (as of 2014)
Tumour Imaging with Tc-99m(V)-DMSA and Tl-201 (historical)
•
Tc-99m(V)-DMSA: a pentavalent complex, different from the DMSA used for renal imaging; it is prepared at high pH (~7.5) by adding NaHCO₃ to the kit. It was used mainly in medullary thyroid carcinoma: about 370 MBq, imaging at 2 hours. Lesion sensitivities in MTC of ~95% (MIBG 11%; 1988) and 95% versus 47% for MIBI and 19% for Tl-201 (1996) have been reported; it shows soft tissue metastases but may miss some bone lesions
•
In brain tumours, (V)-DMSA and Tl-201 showed about 93% and 88% of lesions respectively; delayed washout of (V)-DMSA from the tumour was related to histological grade, whereas no significant difference was seen with Tl-201 (1997)
•
Tl-201: a potassium analogue. Early tumour uptake relates to blood flow and disruption of the blood-brain barrier; delayed uptake relates to entry into viable tumour cells via Na⁺/K⁺-ATPase. For its use in the brain, see Chapter 19 (recurrence versus radiation necrosis; lymphoma versus toxoplasmosis in AIDS)
Summary Table of Non-FDG PET Radiopharmaceuticals
| Radiopharmaceutical | Target | Primary Indication | Theranostic Pair |
|---|---|---|---|
| Ga-68/F-18 PSMA | PSMA receptor | Prostate cancer | Lu-177 PSMA |
| Ga-68 DOTATATE | Somatostatin receptor (SSR2) | Neuroendocrine tumours | Lu-177 DOTATATE |
| F-18 NaF | Hydroxyapatite | Bone metastases | — |
| C-11/F-18 Choline | Membrane synthesis | Prostate, HCC | — |
| F-18 FAPI | FAP (tumour stroma) | Various solid tumours | — (research) |
| F-18 Fluciclovine | Amino acid transport | Prostate recurrence | — |
| F-18 FLT | Thymidine kinase-1 | Proliferation | — |
| F-18 FMISO/FAZA | Hypoxia | RT planning | — |
| F-18 FES | Oestrogen receptor | Breast cancer (ER+) | — |
| C-11 Methionine | Amino acid transport | Brain tumours | — |
F-18 FES (Fluoroestradiol)
•
Target: oestrogen receptor (ER)
•
Indication: in vivo assessment of ER expression in metastatic breast cancer
•
Detection of ER-positive lesions → prediction of response to endocrine therapy
•
FDA approved (2020)
•
Determines ER status non-invasively in metastases that cannot be biopsied
Figure 21.6: Cellular and tissue targets of non-FDG PET radiopharmaceuticals (schematic).
Did this figure help you understand the topic?
•
EANM: an oestradiol analogue that binds ER and SHBG with high affinity; in ER-positive lesions sensitivity is 86% and specificity 85%
•
FES-negative lesions with SUVmax <1.5 mostly do not respond to hormone therapy
•
Drug withdrawal: tamoxifen should be stopped at least 6 weeks and fulvestrant ~28 weeks beforehand
–
FDA label (2024): drugs that bind the ER are stopped at least 5 biological half-lives before (tamoxifen 8 weeks, fulvestrant 28 weeks, elacestrant 11 days); aromatase inhibitors and CDK4/6 inhibitors do not block FES binding and are not stopped. According to the guideline, even a 6-week break from fulvestrant is often enough to visualise ER-positive lesions; the full interval is awaited when quantitative measurement is needed. Breastfeeding is interrupted for 4 hours
•
Activity 111-280 MBq, uptake time 60 min; physiological uptake in the liver and biliary tract may hide liver metastases
–
SNMMI/EANM 2023: imaging can be done 20-80 min after injection (60 min suggested). Interpretation is mostly visual; uptake clearly above local background is positive, and SUVmax >1.5 suggests ER expression (quantitative values need careful calibration). The report also describes heterogeneity between lesions and concordance with a contemporaneous FDG PET when available; FES is also taken up by non-breast ER-positive tissue such as the uterus and ovaries
•
False positives: post-RT changes, fibrous dysplasia, fracture, meningioma, leiomyoma
•
A similar receptor PET: F-18 FDHT (fluoro-dihydrotestosterone) shows androgen receptor expression and target engagement of antiandrogen therapy in metastatic prostate cancer (research stage)
C-11 Methionine
•
Target: amino acid transport and protein synthesis
•
Indication: brain tumours (glioma grading, recurrence vs radionecrosis)
•
Advantage: low physiological uptake in the brain (unlike FDG) → high tumour/background ratio
•
Physiological uptake of C-11 methionine: pancreas (most intense), liver, salivary and lacrimal glands, bone marrow, pituitary, kidney and bladder, bowel; low in brain and lung. Normal pituitary activity in the sellar region should not be mistaken for tumour
•
Disadvantage: C-11 half-life 20 minutes → requires an on-site cyclotron
•
Alternative: F-18 FET (fluoroethyltyrosine) → T½ 110 min, more practical
Amino Acid PET in Brain Tumours (EANM, RANO/EANO):
•
Agents: F-18 FET, F-18 FDOPA, C-11 methionine, F-18 fluciclovine; they are taken up by Na⁺-independent LAT1/LAT2 transporters and their uptake is independent of the state of the BBB
•
In gliomas, because physiological cortical FDG uptake is high, FDG should be preferred only if amino acid agents are not available
•
Indications: differentiation of neoplastic from non-neoplastic lesions, tumour extent, biopsy targeting, surgical and RT planning, differentiation of treatment-related change from recurrence; differentiation of recurrence from radionecrosis in irradiated brain metastases
•
FET: 185-200 MBq; static imaging at 20-40 minutes, dynamic imaging 0-40/50 min; sensitivity 80-90%; specificity for recurrence vs radionecrosis 85-95%
•
The FDA approved F-18 FET (floretyrosine, Pixclara) in September 2026 to differentiate recurrent or progressive glioma from treatment-related change (adults and children older than 1 month; interpreted together with other findings); it is the first PET agent approved for glioma in the USA
•
Dynamic FET: grade III/IV glioma shows an early peak followed by a plateau or decline, grade I/II glioma a continuously rising curve
•
A negative FET lowers the probability of a high-grade tumour but does not exclude a low-grade astrocytic glioma
•
FDG in the brain: mean TBR ≥1.4 or maximum TBR ≥1.8 is used to distinguish low- from high-grade glioma; in irradiated metastases, delayed imaging at 2-4 hours gives sensitivity and specificity of 80-90% for recurrence vs radionecrosis
•
Brain metastases (EANM/EANO/RANO/SNMMI 2025): amino acid PET (FET, FDOPA, MET, fluciclovine) is recommended to differentiate recurrence from treatment-related change; pooled sensitivity 82% and specificity 84% in meta-analysis. Activity: FET and FDOPA 185-200 MBq, MET 370-555 MBq; FET static acquisition at 20 min for 20 min (dynamic 40-50 min), FDOPA at 10-20 min. The lesion TBR (SUVmax or SUVmean / contralateral healthy brain SUVmean) is reported; SUV performs better for fluciclovine. FDG is used only when amino acid tracers are unavailable, within a previously irradiated field and for primaries with high FDG uptake (delayed images at 3-5 h preferred); it is not used for metastases of mucinous adenocarcinoma, lobular breast cancer or renal cancer. Its value is limited for lesions <10 mm; scanning at least 1 month after RT or surgery reduces inflammation-related false positives
•
False positives on amino acid PET: inflammatory or demyelinating lesion, abscess, ischaemia, vascular malformation, reactive astrocytosis
•
FDG uptake correlates with the histological grade of glioma (low-grade gliomas are often FDG-negative)
•
Exception: juvenile pilocytic astrocytoma (WHO grade 1), despite its benign course, often takes up FDG intensely; it should not be mistaken for a high-grade tumour
•
Pilocytic astrocytoma may also show high uptake on amino acid PET; this is a pitfall in grade prediction
•
FDG interpretation: uptake of low-grade glioma is at white matter level, that of high-grade glioma at or above grey matter level. In meningioma uptake is variable (if high, the course is aggressive). Corticosteroids reduce the metabolism of normal cortex but do not markedly change tumour uptake
•
Meningioma (EANM/EANO/RANO/SNMMI 2024): meningiomas strongly express SSTR2 and healthy brain uptake is low; SSTR PET (Ga-68 DOTATATE/DOTATOC, Cu-64 DOTATATE, F-18 SiTATE) is used for differential diagnosis, defining extent at the skull base and in bone, surgical and RT planning, and separating recurrence from scar. SUV <2.3 (Ga-68 DOTATATE) excludes meningioma with high probability; rare SSTR-negative meningiomas and granulomatous inflammation/neurosarcoidosis are pitfalls. PRRT (Lu-177 DOTATATE, 4 cycles 8 ± 2 weeks apart) is an investigational option when surgical and RT options are exhausted and SSTR PET within the last 2 months is positive
21.6 SUV Calculation and Influencing Factors4 questions
Definition of SUV (Standardised Uptake Value)
SUV is a quantitative measure of FDG uptake in a lesion. It is a value normalised on the assumption of homogeneous distribution throughout the body.
Formula:
SUV = Tissue activity concentration (kBq/mL) / [Injected activity (kBq) / Body weight (g)]
Try it in the calculator: SUV / SUL →
•
SUV = 1 → homogeneous distribution (the value expected if distributed equally throughout the body)
•
SUV > 1 → uptake above the expected average in that region
•
EANM 2025: SUL is the recommended quantitative measure. Weight is measured directly before every scan. In response assessment, blood glucose is measured with a validated method and SUL is given with and without glucose correction; because glucose is normalised to 5.0 mmol/L, the two values are practically identical on average
SUV Variants
| Variant | Correction Factor | Feature |
|---|---|---|
| SUVbw (body weight) | Body weight | Most widely used, standard |
| SUVlbm (lean body mass) = SUL | Lean body mass | More accurate in obese patients; preferred in PERCIST |
| SUVbsa (body surface area) | Body surface area | Less commonly used |
| SUVmax | — | Highest pixel value within the ROI; simple but noise-sensitive |
| SUVpeak | — | Mean within a 1 cm³ spherical ROI; less noise-sensitive |
| SUVmean | — | Mean value within the ROI; depends on ROI drawing |
BOARD TIP
▸
"Most commonly used SUV?"
→ SUVmax (in clinical practice).
▸
"Preferred in PERCIST?"
→ SULpeak (peak value corrected for lean body mass).
▸
"Which SUV is more accurate in an obese patient?"
→ SUVlbm (SUL) → because fat does not take up FDG, correcting for body weight makes SUV artificially high.
A PET slice of a lesion is shown voxel by voxel with an SUV profile across it; SUVmax is marked as the highest voxel and SUVpeak as the mean of a 1 cm³ sphere; in the second step the threshold contour, MTV, SUVmean and TLG are computed for the chosen threshold.
Continuous stream · no seeking
Key point: SUVmax is a single voxel and sensitive to noise, SUVpeak is more stable; the partial volume effect lowers the true value of a small lesion; MTV and SUVmean depend on the threshold chosen, and TLG = MTV × SUVmean.
Source: book (SUVmax single voxel; SUVpeak 1 cm³ spherical VOI, PERCIST; SUVmean VOI average; 41% threshold MTV; TLG = MTV × SUVmean). Model (example data): 2 mm voxels, 7 mm radius sphere (true SUV 12, background 1), PET resolution FWHM 6 mm, noise illustrative (4% + 0.05). MTV is the voxels above the threshold connected to the highest voxel; TLG in SUV·mL.
How to use: a single click on the drawing pauses and resumes; in the second step ↑ ↓ change the threshold; ← → change steps.
Did this animation help you understand the topic?
Figure 21.7: Comparison of SUVmax, SUVpeak and SUVmean measurement in the same lesion (schematic).
Factors Affecting SUV
A. Patient-Related Factors:
| Factor | Effect | Mechanism |
|---|---|---|
| Hyperglycaemia | SUV ↓ | Competitive inhibition → FDG uptake falls |
| Obesity | SUVbw ↑ (artificial) | Fat does not take up FDG → correct with SUVlbm |
| Insulin | SUV ↓ (tumour), ↑ (muscle) | Insulin increases muscle/fat uptake |
| Brown fat | SUV ↑ (false) | Cold environment → UCP-1 activation |
| Body composition | Variable | Muscle/fat ratio affects SUV |
B. Technical Factors:
| Factor | Effect | Explanation |
|---|---|---|
| Uptake time | SUV ↑ (as time increases) | In most tumours FDG uptake keeps rising after 60 min |
| Extravasation | SUV ↓ | FDG remains at the injection site → systemic dose falls |
| Cross-calibration of clocks | Variable | Dose calibrator and PET scanner clocks must be synchronised |
| Reconstruction algorithm | Variable | OSEM vs FBP → different SUV values |
| Partial volume effect | SUV ↓ | In small lesions (<2-3 × resolution) SUV is underestimated |
| Attenuation correction | Variable | CT-based correction errors affect SUV |
| Scatter correction | Variable | Inadequate correction → erroneous SUV |
C. Biological Factors:
•
Tumour heterogeneity → different SUV values within the same tumour
•
Necrosis → low SUV (no viable tumour cells)
•
Hypoxia → HIF-1α-mediated increase in glycolysis (Pasteur effect) → SUV may increase
•
Tumour grade → generally high grade = high SUV (there are exceptions)
Figure 21.8: Technical factors affecting SUV: uptake time and partial volume effect in small lesions (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"Patient factor that most affects SUV?"
→ Blood glucose level.
▸
"What is needed to compare SUV between follow-up PETs?"
→ Same scanner, same reconstruction, same uptake time, same blood glucose level → standardisation is critical.
SUV Threshold Values
•
SUVmax >2.5: suspicion of malignancy in a solitary pulmonary nodule (sensitivity ~95%, specificity ~80%)
•
This threshold is not a definitive diagnostic criterion → it must be assessed in clinical context
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Low-grade tumours may have SUV <2.5 (false negative)
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Inflammatory lesions may have SUV >2.5 (false positive)
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SUV alone is not sufficient to diagnose malignancy → biopsy is the gold standard
21.7 Radiotherapy Planning and PET1 questions
Role of PET/CT in Radiotherapy Planning
Tumour Volume Definition:
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GTV (Gross Tumour Volume): macroscopic tumour volume → PET defines the borders of metabolically active tumour
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BTV (Biological Target Volume): PET-based biological target volume
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PET can define tumour borders more accurately than CT:
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It can distinguish tumour within atelectasis (lung cancer)
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It can show viable tissue in necrotic tumour
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It can detect lymph node metastasis independent of size criteria
Clinical Applications:
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Lung cancer: most common use → GTV definition, mediastinal lymph node assessment, atelectasis-tumour differentiation
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Head and neck cancer: targeting of primary tumour and lymph nodes
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Cervical cancer: lymph node metastasis → extension of the treatment field
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Oesophageal cancer: tumour length and lymph node assessment
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Lymphoma: involved-site radiotherapy (ISRT) planning
PET-Based Volume Definition Methods:
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Fixed SUV threshold: SUV ≥2.5 or a set threshold value
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Percentage threshold: 40-50% of SUVmax
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Gradient-based: the point where the uptake gradient is steepest
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Adaptive threshold: threshold adjusted automatically to background
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There is not yet a consensus on a standard method
Figure 21.9: PET in radiotherapy planning: distinguishing tumour within atelectasis and tumour diameters defined by different threshold methods (schematic).
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BOARD TIP
▸
"Greatest contribution of PET/CT to RT planning?"
→ Distinguishing tumour within atelectasis (lung cancer) and detecting metabolically active lymph nodes.
▸
"How does the GTV generally change with PET compared with CT?"
→ In some patients it shrinks (atelectasis is excluded), in others it grows (additional lymph nodes are added).
PET During Treatment (Adaptive RT)
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PET during treatment → modification of the treatment plan according to tumour response
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Dose escalation: additional dose to hypoxic or resistant regions (dose painting)
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Dose de-escalation: dose reduction in responding regions → normal tissue sparing
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Still at the research stage, limited in routine clinical practice
4D-PET/CT (Respiratory-Gated PET)
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Reduces artefacts caused by respiratory motion
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Respiratory motion blurs the lesion (smearing); contrast and SUV are underestimated and metabolic volume overestimated. Respiratory phase mismatch between PET and CT causes attenuation correction artefacts
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Useful especially for lesions at the lung bases and in the upper abdomen
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Contributes to defining the ITV (Internal Target Volume)
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Makes SUV measurement more accurate (motion blurring is reduced)
Key Points for the Board
FDG Basic Principles:
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FDG → entry into the cell via GLUT-1 → phosphorylation by hexokinase → cannot be dephosphorylated by glucose-6-phosphatase → metabolic trapping
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F-18 half-life: 110 minutes, cyclotron production, positron emission, 511 keV annihilation photons
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In obese patients SUVbw is artificially high → use SUVlbm (SUL)
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Physiological uptake: brain (most intense), myocardium (variable), urinary tract (excretion), tonsils, GI tract
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Brown fat: symmetric cervical-supraclavicular uptake → prevented with a warm environment + beta-blocker
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Myocardial suppression: prolonged fasting (≥12-18 hours) + high-fat diet + heparin → cardiac sarcoidosis/endocarditis protocol
Organ-Based Indications – Key Points:
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SPN: >8-10 mm nodule → PET indicated; SUVmax >2.5 suspicious for malignancy
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Colorectal: strongest indication is detection of recurrence; mucinous type → false negative
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Thyroid: high Tg + negative RAI → FDG PET/CT (flip-flop phenomenon → poor prognosis)
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Testis: PET is useful for a residual mass >3 cm in seminoma; not reliable in non-seminoma (mature teratoma)
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Prostate: low FDG sensitivity → PSMA PET/CT preferred
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HCC: well-differentiated → takes up choline (not FDG); poorly differentiated → takes up FDG
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Head and neck CUP: PET/CT can detect the primary focus in 25-30%
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PET after RT: no earlier than 3 months (to let inflammation subside)
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Incidental focal thyroid FDG uptake → malignancy risk ~30-35% → US ± FNAB; diffuse bilateral uptake → usually thyroiditis/Graves
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Incidental focal colonic FDG uptake → colonoscopy (adenoma/carcinoma); diffuse/segmental → physiological, colitis or metformin
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Negative PET/CT ~12 weeks after head and neck CRT → planned neck dissection can be avoided (PET-NECK)
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Metabolic flare on days 7-10 after tamoxifen in ER+ breast cancer → not progression, a predictor of hormone response
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Pilocytic astrocytoma (WHO grade 1) takes up FDG intensely → should not be mistaken for a high-grade tumour
RECIST vs PERCIST:
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RECIST 1.1: anatomical (CT), PR ≥30% decrease, PD ≥20% increase + 5 mm
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PERCIST 1.0: metabolic (PET), PR/PD: ≥30% and ≥0.8 SUL unit change in SULpeak, parameter SULpeak
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RECIST/PERCIST are not used in lymphoma → Lugano/Deauville is used
False Positives:
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Most common: infection/inflammation (increased glycolysis in activated macrophages)
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Talc pleurodesis → takes up FDG for years
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G-CSF → diffuse bone marrow/splenic uptake → wait 2-4 weeks
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After surgery → wait 6-8 weeks
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Rebound thymic hyperplasia (young patients after chemotherapy)
False Negatives:
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Mnemonic BMLP-CHR: Bronchioloalveolar, Mucinous, Lobular breast, Prostate, Carcinoid, HCC (well diff.), Renal
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Most common patient factor: hyperglycaemia
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Technical: small lesion (<8 mm) → partial volume effect
Theranostic Pairs (PET and SPECT):
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Ga-68 PSMA → Lu-177 PSMA (prostate cancer)
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Ga-68 DOTATATE → Lu-177 DOTATATE (NET)
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I-123/I-131 MIBG → I-131 MIBG therapy (phaeochromocytoma, neuroblastoma)
Non-FDG PET Agents – Special Cases:
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FAPI: very low background, targets tumour stroma (CAF), not yet FDA approved
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FES: oestrogen receptor, ER status in metastatic breast cancer (FDA approved 2020)
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C-11 Methionine / F-18 FET: brain tumours → low background in the brain (unlike FDG)
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F-18 Fluciclovine: prostate recurrence; use declining with PSMA
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F-18 NaF: bone metastases, sensitivity superior to Tc-99m MDP
SUV Key Points:
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SUVmax: most widely used in clinical practice; simple but noise-sensitive
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SULpeak: preferred in PERCIST
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Patient factor that most affects SUV: blood glucose
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Standardisation is critical for follow-up PETs: same scanner, same reconstruction, same uptake time
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Patient preparation: ≥4-6 hours fasting, blood glucose <150-200 mg/dL, 60 min uptake time, warm/quiet environment
RT Planning:
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Greatest contribution of PET: atelectasis-tumour differentiation + detection of metabolically active lymph nodes
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GTV definition methods: fixed SUV threshold, percentage threshold (40-50%), gradient-based, adaptive threshold → no consensus yet
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4D-PET: respiratory gating → reduces motion artefact, useful for lesions at the lung bases and in the upper abdomen
Additional Notes from EANM Guidelines:
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FDG: glucose <11 mmol/L; wait ≥10 days after CT, >2 weeks after G-CSF, 2-3 months after RT, ≥6 weeks after surgery
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PSMA: Ga-68 100-200 MBq; ganglia and benign bone lesions are false positives; PSMA-1007 hepatobiliary excretion
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Fluciclovine: 370 MBq, imaging after 3-5 min; lytic > sclerotic uptake
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FES: SUVmax <1.5 → no response to hormone therapy expected; fulvestrant is stopped ~28 weeks beforehand
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Brain tumour: amino acid PET (FET/FDOPA/MET) superior to FDG; dynamic FET early peak → high grade
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PentixaFor (CXCR4): myeloma, MCL, MZL; APA detection in primary aldosteronism
Current guidelines on this chapter's topics
The latest guidelines and consensus documents on the procedures covered in this chapter (official EANM index and primary sources, November 2026). Comparison of the text with these versions is in progress; consult the guideline itself for details.
- 2025[18F]FDG PET/CT: EANM procedure guidelines for tumour imaging: version 3.0 (opens in a new tab)
- 2024SNMMI Procedure Standard/EANM Practice Guideline for Fibroblast Activation Protein (FAP) PET (opens in a new tab)
- 2024SNMMI Procedure Standard/EANM Practice Guideline for Estrogen Receptor Imaging of Patients with Breast Cancer Using 16α-[18F]Fluoro-17β-Estradiol PET (opens in a new tab)
- 2024Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA) (opens in a new tab)
- 2024Imaging of peritoneal metastases of ovarian and colorectal cancer: joint recommendations of ESGAR, ESUR, PSOGI, and EANM (opens in a new tab)
- 2023PSMA PET/CT: joint EANM procedure guideline/SNMMI procedure standard for prostate cancer imaging 2.0 (opens in a new tab)
- 2023International EANM-SNMMI-ISMRM consensus recommendation for PET/MRI in oncology (opens in a new tab)
- 2023Second Version of the Prostate Cancer Molecular Imaging Standardized Evaluation Framework (PROMISE V2) (opens in a new tab)
- 2022SNMMI Procedure Standard/EANM Practice Guideline for Molecular Breast Imaging with Dedicated γ-Cameras (opens in a new tab)
- 2022Joint EANM/SNMMI/ESTRO practice recommendations for the use of 2-[18F]FDG PET/CT external beam radiation treatment planning in lung cancer V1.0. (opens in a new tab)
- 2021E-PSMA: the EANM standardized reporting guidelines v1.0 for PSMA-PET (opens in a new tab)
- 2021EANM guideline on the role of 2-[18F]FDG PET/CT in diagnosis, staging, prognostic value, therapy assessment and restaging of ovarian cancer, endorsed by the American College of Nuclear Medicine (ACNM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the International Atomic Energy Agency (IAEA) (opens in a new tab)
- 2020EANM / SNMMI Practice Guideline for [18F]FDG PET/CT External Beam Radiotherapy Treatment Planning in Uterine Cervical Cancer (opens in a new tab)
- 2019[18F]Fluciclovine PET/CT: joint EANM and SNMMI procedure guideline for prostate cancer imaging—version 1.0 (opens in a new tab)
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