Melanoma

Quick Answer

Melanoma is highly FDG-avid, so FDG-PET/CT is central to staging and restaging stage III–IV disease — detecting nodal, in-transit, and distant metastases (including unusual sites) and monitoring response to immunotherapy/targeted therapy. In early clinically node-negative disease, nodal staging is done by sentinel-lymph-node biopsy guided by lymphoscintigraphy, not by PET (which misses microscopic nodal disease). Brain metastases need MRI.

Definition

Melanoma is a malignant neoplasm of melanocytes, most often cutaneous but also arising in mucosal, acral, and uveal (ocular) sites. It is among the most immunogenic solid tumors and one of the most reliably FDG-avid.

Synonyms

Malignant melanoma; cutaneous melanoma; subtypes — superficial spreading, nodular, lentigo maligna, acral lentiginous, and (distinct biology) mucosal and uveal melanoma.

Epidemiology

Incidence has risen substantially in fair-skinned populations. Risk associates with ultraviolet exposure (especially intermittent intense sunburn), fair skin/light eyes, numerous or dysplastic nevi, family history, prior melanoma, and immunosuppression. Acral and mucosal melanomas are UV-independent and relatively more common in darker-skinned populations.

Etiology & Risk Factors

• UV radiation (sunburn history, tanning beds) — the dominant modifiable cause for cutaneous disease.
• Phenotype: fair skin, red/blond hair, freckling, many/atypical nevi.
• Genetic: family history, CDKN2A and other susceptibility genes; BAP1 (uveal/mesothelioma spectrum).
• Immunosuppression and prior melanoma.

Pathophysiology

Most cutaneous melanomas activate the MAPK pathway (BRAF or NRAS). Growth progresses from a radial (in-situ/microinvasive) to a vertical growth phase, when metastatic potential rises; Breslow thickness and ulceration are the key prognostic descriptors. Spread is via lymphatics (regional nodes, in-transit/satellite deposits) and hematogenously to lung, liver, brain, bone, and characteristically unusual sites (bowel, subcutaneous tissue, myocardium, spleen). Uveal melanoma has distinct biology (GNAQ/GNA11; hepatotropic metastasis).

Genetics & Molecular Biology

• BRAF V600 (~40–50% of cutaneous melanoma) — targetable with BRAF + MEK inhibitors.
• NRAS, NF1 — alternative MAPK drivers.
• KIT — enriched in acral/mucosal melanoma.
• Uveal: GNAQ/GNA11, and BAP1 loss (poor prognosis); distinct from cutaneous therapy (e.g. tebentafusp in HLA-A*02:01).
• High tumor mutational burden (UV-driven) underlies checkpoint-immunotherapy sensitivity.

Histopathology

Diagnosis rests on cytologic atypia, architectural disorder, dermal invasion, and mitoses. Subtypes (superficial spreading, nodular, lentigo maligna, acral lentiginous) differ in growth pattern. Breslow thickness (mm), ulceration, and mitotic activity drive staging; immunohistochemistry (S100, SOX10, HMB-45, Melan-A) confirms melanocytic lineage.

Clinical Presentation

A changing pigmented lesion (ABCDE: asymmetry, border, color, diameter, evolution). Regional disease presents as nodal, satellite, or in-transit metastases. Distant disease is protean given melanoma's wide metastatic range — including GI bleeding (bowel deposits), subcutaneous nodules, and neurologic symptoms (brain). Uveal melanoma presents with visual symptoms and hepatic metastasis.

Laboratory Findings

LDH is incorporated into M1 substaging and is prognostic in metastatic disease. S100B is used in some centers. Tissue BRAF/KIT/NRAS testing directs targeted therapy.

Imaging Findings by Modality

• Dermoscopy / excisional biopsy: diagnosis and Breslow measurement.
• Ultrasound: regional nodal assessment and biopsy guidance.
• FDG-PET/CT: stage III–IV whole-body staging, surgical planning, and response — melanoma's high avidity makes PET particularly powerful, including for unusual sites.
• MRI brain: dedicated detection of cerebral metastases (PET insensitive due to cortical FDG).
• CT: anatomic staging and where PET is unavailable; liver MRI for uveal melanoma.

Radiopharmaceutical Uptake Mechanisms

FDG reflects the high glucose metabolism of melanoma (typically strongly avid, aiding detection of small deposits). On checkpoint immunotherapy, FDG also lights up immune-related inflammation (sarcoid-like nodes, colitis, thyroiditis, hypophysitis) — an interpretive challenge. Sentinel-node radiocolloids map lymphatic drainage physically (particle trapping in the first-draining node).

Typical PET Tracers

Typical SPECT Tracers

• Sentinel-node lymphoscintigraphy (Tc-99m-sulfur colloid / tilmanocept ± SPECT/CT) — the early-stage nodal stager, essential for head-and-neck and aberrant drainage.

Therapy Indications

• Localized: wide local excision; sentinel-node biopsy for staging (per Breslow/ulceration).
• Regional/advanced (resectable): completion strategies and (neo)adjuvant systemic therapy.
• Advanced/metastatic: immune-checkpoint inhibitors (anti-PD-1 ± anti-CTLA-4), BRAF + MEK inhibitors (BRAF-mutant), and intralesional T-VEC; uveal melanoma uses distinct agents (tebentafusp).

Theranostics

There is no established radioligand therapy for cutaneous melanoma — melanin- and other target-directed radioligands remain investigational. The nuclear-medicine contribution is therefore diagnostic and response-defining, with the important caveat that immunotherapy inflammation complicates FDG response reads.

Differential Diagnosis (of FDG findings)

• Immune-related adverse events on checkpoint therapy (sarcoid-like mediastinal/hilar nodes, thyroiditis, hypophysitis, colitis) — inflammation mimicking or coexisting with progression.
• Brown fat, muscle, and physiologic bowel uptake obscuring small in-transit/nodal deposits.
• Benign nevi/inflammation and post-surgical change at the primary site.

Reporting Checklist

• Review the whole body carefully for melanoma's unusual metastatic sites (bowel, subcutaneous, myocardium, spleen).
• Recommend brain MRI for stage III–IV staging (PET insensitive for brain).
• On immunotherapy, distinguish irAE inflammation from progression; avoid calling failure on equivocal single-site change (consider pseudoprogression).
• Report nodal basins, in-transit/satellite deposits, and LDH context.

Prognosis

Prognosis is governed by Breslow thickness, ulceration, mitotic rate, nodal status, and LDH (AJCC 8th edition). Thin, non-ulcerated, node-negative disease has excellent survival; nodal and distant disease worsen it, though immunotherapy and BRAF/MEK targeted therapy have transformed advanced-stage outcomes. Uveal melanoma has a distinct, often hepatotropic course.

Board Pearls

Stage-based tool split (memorize):

Nuclear medicine splits melanoma by stage: sentinel-lymph-node biopsy (lymphoscintigraphy) stages the early, clinically node-negative patient — FDG-PET has low yield for microscopic nodal disease and must not be used to "clear" the nodes — while FDG-PET/CT is the stage III–IV tool for whole-body staging, surgical planning, and detecting distant/unusual metastases.

Melanoma seeds unusual sites (bowel, subcutaneous, myocardium, spleen) — review the whole-body study deliberately — and brain metastases require MRI.

On checkpoint immunotherapy, immune-related adverse events (sarcoid-like nodes, thyroiditis, hypophysitis, colitis) produce FDG-avid inflammation that mimics or coexists with progression, and pseudoprogression occurs — confirm equivocal change rather than calling failure prematurely. There is no established radioligand therapy in melanoma (a contrast to prostate/NET disease).

Related Pages

• Tracer: FDG (uptake, preparation, immunotherapy effects).
• Related studies: Lymphoscintigraphy & sentinel node (early-stage nodal mapping).
• Pitfalls: Pearls, pitfalls & normal variants, Incidental findings on FDG-PET.

Figure / Diagram Suggestions

• A stage-based tool split: sentinel node (early) vs FDG-PET (stage III–IV).
• Unusual metastatic sites whole-body plate (bowel, subcutaneous, myocardium, spleen).
• An immunotherapy response vs irAE comparison (true progression vs sarcoid-like nodal inflammation).

Common Pitfalls

• On lymphoscintigraphy, intense injection-site "shine-through" can obscure an adjacent sentinel node (especially head/neck and axillary primaries near the drainage basin) — use SPECT/CT and source shielding.
• Small in-transit, subcutaneous, or micrometastatic nodal deposits fall below PET spatial resolution, so a negative PET does not exclude low-volume disease (reinforcing why PET cannot clear cN0 nodes).
• Reactive draining nodes after recent excisional biopsy of the primary can be FDG-avid and mimic nodal metastasis — correlate with the biopsy timing and site.
• Dermal radiotracer contamination during lymphoscintigraphy injection can create a spurious focus mistaken for a node.

Self-Check (Board-Style)