Nuclear Medicine in Melanoma

1. The clinical problem

Cutaneous melanoma spreads first to regional lymph nodes in most patients, but it can also skip to any organ, including the brain. The oncologist needs imaging to answer four questions: are the regional nodes involved, is there distant disease, is systemic treatment working, and has the disease come back? Nuclear medicine answers the first with lymphoscintigraphy and sentinel lymph node biopsy (SLNB), and the other three largely with ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT).

Staging system in force: AJCC eighth edition

Current European Society for Medical Oncology (ESMO 2024), European Association of Dermato-Oncology (EADO 2024) and uveal melanoma (ESMO with the European Reference Network for rare adult solid cancers, ESMO–EURACAN 2026) guidelines stage melanoma with the eighth edition of the American Joint Committee on Cancer (AJCC8) system. Its key features for the imager are:

Mitotic rate is no longer a T criterion, and pathological stage IA now includes T1bN0. Stage IIC (T4b N0) has a 5-year melanoma-specific survival of about 82%, lower than stage IIIA, which is why thick ulcerated primaries are now staged and treated almost like node-positive disease.

Where nuclear medicine changes management

• SLNB: the most accurate nodal staging test; the status of the sentinel lymph node (SLN) sets stage III and the eligibility for adjuvant therapy.
• FDG PET/CT staging: decides between surgery, neoadjuvant therapy and systemic therapy when nodes are clinically involved or distant disease is suspected.
• Response and duration of therapy: FDG PET/CT is widely used to judge response to ICIs (anti-PD-1, programmed cell death protein 1; anti-CTLA-4, cytotoxic T-lymphocyte-associated protein 4) and BRAF/MEK inhibitors, and a complete metabolic response is increasingly used to support stopping therapy.

2. Tracers and why they work

Radiocolloids and receptor-targeted tracers for lymphatic mapping

Particles injected into the dermis enter the initial lymphatics and are trapped in the first draining node by macrophage phagocytosis or by particle size. Small particles move fast but pass on to second-echelon nodes; large particles move slowly and stay at the injection site. The choice is largely regional (European Association of Nuclear Medicine, EANM, guideline, endorsed by the Society of Nuclear Medicine and Molecular Imaging, SNMMI):

FDG

Cutaneous melanoma metastases are usually intensely FDG-avid, which makes FDG PET/CT the most sensitive single test for distant spread. It fails in predictable places: micrometastases in nodes (below the resolution of PET, which is why SLNB remains the nodal test), the brain (high cortical glucose use), small lung nodules (lost to partial-volume effects, although CT shows them) and the liver in uveal melanoma, where many metastases have low uptake. In the ESMO–EURACAN uveal guideline FDG PET/CT sensitivity for liver metastases ranges from 41% to 88% and falls to 11% for small lesions found on MRI.

What replaces FDG when it fails

• Occult nodal disease: SLNB with lymphoscintigraphy; nodal ultrasound for surveillance.
• Brain: contrast-enhanced MRI.
• Small lung nodules: the CT component, reported in lung windows.
• Uveal melanoma liver metastases: liver MRI with diffusion-weighted sequences.

3. Indications by clinical scenario

4. Evidence at a glance

Abbreviations: RCT, randomised controlled trial; HR, hazard ratio; PFS, progression-free survival; OS, overall survival; CMR, complete metabolic response.

5. Patient preparation and acquisition

Lymphoscintigraphy (EANM guideline, Bluemel 2015)

1. History and examination: prior excision (with histology), surgery or trauma in the region, pregnancy or breastfeeding. A clinically suspicious node needs fine-needle aspiration first; a node replaced by tumour may not take up tracer and can give a false-negative map.
2. Timing: same-day or day-before protocols have similar detection and false-negative rates. Do not inject in theatre, because drainage in melanoma can be delayed, aberrant or to several basins.
3. Injection: intradermal wheals, usually four or more aliquots of 0.1–0.2 ml around the primary or on each side of the excision scar, within 1 cm of it; 25–27 gauge needle. Avoid subcutaneous injection. In head and neck melanoma use four deposits around the lesion; on a limb, at least medial and lateral deposits.
4. Activity: no consensus; published activities range from about 5 to 120 MBq depending on the interval to surgery. Aim for a residual activity at operation that still gives good probe counts (above about 10 MBq); prepare albumin nanocolloid at ≥100 MBq/ml so that 20 MBq fits in 0.2 ml.
5. Dynamic images: start immediately, 10–20 min at one frame per minute (128 × 128), with the patient positioned for the region; for hand, forearm, foot or leg primaries follow the channels to the elbow or knee to catch epitrochlear or popliteal nodes.
6. Early and delayed statics: 5-min anterior and lateral views (256 × 256) over all possible basins; for the trunk, both axillae and both groins, or a neck-to-groin sweep. Delayed 3–5 min views at 1–3 h identify the nodes to mark.
7. SPECT/CT: should be done for head and neck primaries, is highly recommended for the groin and recommended for the axilla; it finds interval nodes, separates nodes close to the injection site and gives depth.
8. Skin marking: mark every sentinel node in each basin in the operating position, with depth; do not mark nodes clearly identified as second echelon.

FDG PET/CT in melanoma

• Standard preparation: fasting for at least 4 h (EANM; SNMMI 4–6 h) and imaging at 60 min (55–75 min) after injection, as in the EANM and SNMMI tumour guidelines.
• Field of view: include the skull base on every response study so that hypophysitis is not missed; the guideline allows extended vertex-to-feet imaging in melanoma, and it is essential when the primary or known disease is on the scalp or limbs (EANM/SNMMI/ANZSNM 2022).
• Serial studies: same scanner, same uptake time and same reconstruction, ideally on a system accredited by EANM Research Ltd (EARL), so that changes in SULpeak (peak standardised uptake value normalised to lean body mass) are real.
• Record for the reader: dates of surgery, SLNB, radiotherapy and the start of ICI, BRAF/MEK inhibitors or steroids, and any symptoms of colitis, thyroiditis or arthritis.
• Brown fat: common in young, slim patients and in cold rooms; keep the patient warm before injection, because supraclavicular and paravertebral brown fat can mimic nodal disease.

6. Interpretation

Reading a lymphoscintigram

• Sentinel node: a node receiving a lymphatic channel directly from the primary (the strongest criterion), or the first node to appear. It is often, but not always, the hottest.
• Late nodes in another basin are also sentinel nodes, unless the dynamic images show that they fill from an earlier node.
• False positives: skin or urine contamination (very hot and focal; check with a second view or SPECT/CT), second-echelon nodes read on late images only, lymphatic lakes.
• False negatives: two adjacent nodes read as one, a node masked by the injection site, poor drainage (massage, warming or limb exercise can help; drainage is slower in patients over 50).
• Report: tracer, activity, injection sites, image times; number, basin and depth of each sentinel node; second-echelon nodes; interval nodes; any node enlarged on CT without uptake.

Reading FDG PET/CT

Report distant disease by AJCC M category, because M1d (brain) and M1c (visceral) change treatment. Look specifically at skin and subcutaneous tissue (in-transit and satellite disease), bowel wall, bone, adrenals, spleen and muscle. Check the CT for sub-centimetre lung nodules that are too small to show uptake, and state that brain assessment needs MRI.

Immune-related adverse events on FDG PET/CT

Immune-related adverse events (irAEs) are common with ICIs, particularly with ipilimumab plus nivolumab. In 31 patients on this combination, 36 PET findings suggested an irAE and 29 (80%) were confirmed clinically; the PET finding came first in 7%, and endocrinopathies (36%) and enterocolitis (35%) were the commonest.

Wording the conclusion

• Answer the clinical question first (stage, response category and the criteria used).
• Separate tumour findings from immune findings: 'new symmetric hilar and mediastinal nodes in a patient whose metastases are responding: favour sarcoid-like reaction'.
• When progression is doubtful early on ICIs, write 'unconfirmed progressive metabolic disease' and recommend a repeat scan in 4–8 weeks if the patient is clinically stable.

7. Response assessment and follow-up

Criteria in use

Five sets of FDG criteria are in use: the 1999 European Organisation for Research and Treatment of Cancer (EORTC) criteria, PET Response Criteria in Solid Tumours (PERCIST 1.0), and three immunotherapy adaptations: PET Response Evaluation Criteria for Immunotherapy (PERCIMT), immunotherapy-modified PERCIST (imPERCIST5) and immune PERCIST (iPERCIST). SUL is the SUV normalised to lean body mass.

PERCIST and EORTC were built for cytotoxic therapy and treat any new FDG-avid metastasis as progression. The immunotherapy-adapted criteria were each derived in small retrospective cohorts (41 to 60 patients; iPERCIST in non-small cell lung cancer), and the EANM/SNMMI/ANZSNM guideline states that there are not yet enough data to choose between them. In practice, state which criteria you used and apply them consistently.

Atypical response patterns on ICIs

• Pseudoprogression: a transient increase in lesion size, uptake or number followed by response, seen in up to about 10% of patients, most often with anti-CTLA-4 therapy in melanoma and usually in the first 4–6 weeks.
• Dissociated response: some lesions respond while others grow; local treatment of the growing lesions with continued ICI can be appropriate.
• Hyperprogression: accelerated growth after starting ICIs; no agreed definition.
• Guideline advice: if progression versus pseudoprogression is uncertain, especially on the first scan, repeat FDG PET/CT 4–8 weeks later in a clinically stable patient and continue treatment meanwhile (EANM/SNMMI/ANZSNM 2022).

The 1-year scan and stopping anti-PD-1 therapy

In 104 patients with baseline and 1-year PET and CT on anti-PD-1-based therapy, CT showed complete response in only 28%, but PET showed CMR (EORTC criteria) in 75%, including 68% of CT partial responders. Five years after the 1-year scan, progression-free survival was 90% with CMR versus 54% without, and 88% versus 59% among CT partial responders. A residual mass on CT without FDG uptake therefore usually means inactive tissue.

This evidence is retrospective. The ECOG-ACRIN Cancer Research Group PET-Stop trial (NCT04462406) is testing prospectively whether stopping anti-PD-1 therapy at 12 months after a negative FDG PET/CT, or a negative biopsy of a residual avid lesion, is safe; primary completion is expected in 2027. The UK DANTE trial of stopping at 1 year versus continuing has so far been reported only as a conference abstract; it closed early, was underpowered, and its investigators advised that 2 years remain the standard. Report 1-year scans with a clear CMR or non-CMR statement.

BRAF/MEK inhibitors and combinations

PERCIST applies to targeted therapy as to any systemic treatment. The immunotherapy-adapted rules for new lesions were derived in patients on ICIs, so they should not be borrowed for patients on BRAF/MEK inhibitors alone; state the criteria used in every report.

Surveillance

There is no consensus on imaging surveillance after resection (ESMO IV, B). In the Xing meta-analysis, PET/CT had the best accuracy for distant recurrence (sensitivity 86%, specificity 91%) and ultrasound for nodal recurrence (96%, 99%). ESMO leaves the schedule to national guidance, EADO proposes a stage-based schedule, and neither mandates PET over CT; nodal ultrasound is the test for an observed sentinel-node-positive basin. Uveal melanoma follows its own schedule: liver ultrasound every 6–12 months for at least 5 years in low-risk patients and liver MRI every 4–6 months for at least 10 years in high-risk patients.

8. Theranostics and emerging tracers

No radioligand therapy is approved for melanoma. Melanin and melanocortin-1 receptor targets are attractive because they are specific to melanocytic tissue, but both depend on differentiation, and uveal and mucosal melanomas are the main populations under study.

9. Structured report example

10. Take-home points

1. Stage with AJCC8; Breslow thickness, ulceration and nodal status drive every imaging decision.
2. Lymphoscintigraphy is a dynamic study: watch the channels, image every possible basin, use SPECT/CT, and mark every sentinel node including interval nodes, but not second-echelon nodes.
3. After a positive sentinel node, stage with CT or FDG PET/CT and brain MRI; the basin is followed with ultrasound, not dissected.
4. Do not use FDG PET/CT for stage I–IIA disease; use it from stage IIB, for clinically detected nodes and for stage IV.
5. On ICIs, symmetric hilar nodes, diffuse colitis, thyroiditis and splenic activation are usually immune effects. Confirm doubtful progression 4–8 weeks later and name the criteria used.
6. A CMR at 1 year of anti-PD-1 therapy predicts long-term control and is used to support stopping treatment, pending prospective trial results.
7. In uveal melanoma, liver MRI comes first.

Test yourself

5 quick questions. Pick an answer to see the explanation.

References

1. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-92.
2. Amaral T, Ottaviano M, Arance A, et al. Cutaneous melanoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025;36(1):10-30.
3. Garbe C, Amaral T, Peris K, et al. European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics - Update 2024. Eur J Cancer. 2025;215:115152.
4. Garbe C, Amaral T, Peris K, et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2024. Eur J Cancer. 2025;215:115153.
5. Wong SL, Faries MB, Kennedy EB, et al. Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology clinical practice guideline update. J Clin Oncol. 2018;36(4):399-413.
6. Piperno-Neumann S, Angi M, Ascierto PA, et al. Uveal melanoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open. 2026;11(4):106888.
7. Bluemel C, Herrmann K, Giammarile F, et al. EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma. Eur J Nucl Med Mol Imaging. 2015;42(11):1750-66.
8. Stoffels I, Boy C, Pöppel T, et al. Association between sentinel lymph node excision with or without preoperative SPECT/CT and metastatic node detection and disease-free survival in melanoma. JAMA. 2012;308(10):1007-14.
9. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
10. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211-22.
11. Leiter U, Stadler R, Mauch C, et al. Final analysis of DeCOG-SLT trial: no survival benefit for complete lymph node dissection in patients with melanoma with positive sentinel node. J Clin Oncol. 2019;37(32):3000-8.
12. Xing Y, Bronstein Y, Ross MI, et al. Contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst. 2011;103(2):129-42.
13. Wagner JD, Schauwecker D, Davidson D, et al. Inefficacy of F-18 fluorodeoxy-D-glucose-positron emission tomography scans for initial evaluation in early-stage cutaneous melanoma. Cancer. 2005;104(3):570-9.
14. Aukema TS, Valdés Olmos RA, Wouters MW, et al. Utility of preoperative 18F-FDG PET/CT and brain MRI in melanoma patients with palpable lymph node metastases. Ann Surg Oncol. 2010;17(10):2773-8.
15. Lopci E, Hicks RJ, Dimitrakopoulou-Strauss A, et al. Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0. Eur J Nucl Med Mol Imaging. 2022;49(7):2323-41.
16. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S-50S.
17. Anwar H, Sachpekidis C, Winkler J, et al. Absolute number of new lesions on 18F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab. Eur J Nucl Med Mol Imaging. 2018;45(3):376-83.
18. Ito K, Teng R, Schöder H, et al. 18F-FDG PET/CT for monitoring of ipilimumab therapy in patients with metastatic melanoma. J Nucl Med. 2019;60(3):335-41.
19. Goldfarb L, Duchemann B, Chouahnia K, et al. Monitoring anti-PD-1-based immunotherapy in non-small cell lung cancer with FDG PET: introduction of iPERCIST. EJNMMI Res. 2019;9(1):8.
20. Tan AC, Emmett L, Lo S, et al. FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma. Ann Oncol. 2018;29(10):2115-20.
21. Dimitriou F, Lo SN, Tan AC, et al. FDG-PET to predict long-term outcome from anti-PD-1 therapy in metastatic melanoma. Ann Oncol. 2022;33(1):99-106.
22. Iravani A, Osman MM, Weppler AM, et al. FDG PET/CT for tumoral and systemic immune response monitoring of advanced melanoma during first-line combination ipilimumab and nivolumab treatment. Eur J Nucl Med Mol Imaging. 2020;47(12):2776-86.
23. Lin Z, Tang C, Liu T, et al. Comparison of [18F]PFPN and [18F]FDG PET in mucosal melanoma: diagnostic performance, staging impact, and correlation with molecular markers. Clin Cancer Res. 2026;32(10):2036-46.
24. Bensch F, van der Veen EL, Lub-de Hooge MN, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24(12):1852-8.
25. Farwell MD, Gamache RF, Babazada H, et al. CD8-targeted PET imaging of tumor-infiltrating T cells in patients with cancer: a phase I first-in-humans study of 89Zr-Df-IAB22M2C, a radiolabeled anti-CD8 minibody. J Nucl Med. 2022;63(5):720-6.