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Melanoma staging (AJCC 8th edition)

TL;DR — The AJCC 8th edition was built from >46,000 patients with stage I–III melanoma from 10 centres worldwide diagnosed since 1998, plus the 7th-edition stage IV database and contemporary trial data. Its eight substantive changes include recording thickness to 0.1 mm, redefining T1a/T1b around a 0.8 mm cut-point, removing mitotic rate as a T1 criterion, replacing "microscopic/macroscopic" nodal descriptors with "clinically occult/clinically apparent", expanding stage III from three to four subgroups (IIIA–IIID), adding LDH descriptors to every M1 subcategory without letting LDH upstage to M1c, and creating M1d for CNS metastases (Gershenwald 2017, PMID 29028110). Validation shows the changes are concentrated in stage III: 44.1% of Ontario stage III patients and 57% of Swedish stage III patients were reclassified, against minimal reclassification in stage II (Hynes 2022, PMID 35778691; Isaksson 2019, PMID 31111349). The predictive gain is real but modest — variance in melanoma-specific survival explained rose from 18.9% to 19.7% (PMID 35778691), and independent validation found improved discrimination for stage III (concordance index 0.65 → 0.70, P = .01) but a non-significant loss for stage I after removing mitotic rate (Bajaj 2020, PMID 31977051). The persistent anomaly is that stage IIC does worse than stage IIIA, which the staging system's own architecture cannot express.

What the 8th edition changed

# Change Consequence
1 Thickness recorded to nearest 0.1 mm, not 0.01 mm Reduces false precision; shifts borderline cases
2 T1a = <0.8 mm without ulceration; T1b = 0.8–1.0 mm ± ulceration, or <0.8 mm with ulceration Replaces the 1.0 mm/mitosis-based split
3 Mitotic rate removed as a T-category criterion Simplifies T1 but discards a validated variable
4 Pathological stage IA now includes T1b N0 M0 (formerly IB) Downstages a group
5 Nodal descriptors "microscopic/macroscopic" → "clinically occult/clinically apparent" Terminology aligned with detection method
6 Stage III prognostic groups expanded from 3 to 4 (IIIA–IIID), based on N and T criteria The largest single change
7 Microsatellites, satellites and in-transit metastases classified as N1c/N2c/N3c by number of involved nodes Unifies non-nodal regional disease
8 LDH descriptor added to each M1 subcategory; LDH no longer upstages to M1c. New M1d for CNS metastasis CNS disease gets its own designation

Source: PMID 29028110.

Stage migration in validation cohorts

Cohort Reclassification Key survival findings
Ontario Cancer Registry, 6,414 patients, 2007–2012 21.3% reclassified overall; stage II reclassification uncommon; 44.1% of stage III moved to a higher subgroup TNM8 5-year MSS: stage I 98.4%, II 82.5%, III 66.4%, IV 14.4%; within stage III, IIIA 91.7% and IIID 23.5%. Variance in MSS explained 18.9% (TNM7) → 19.7% (TNM8) (Hynes 2022, PMID 35778691)
Swedish Melanoma Registry, 2,067 stage III patients, 2005–2017 57% changed stage III subgroup Whole-cohort 5- and 10-year MSS 59% and 51%; MSS improved for IIIA, IIIB and IIIC on reclassification; new IIID had 10-year MSS 16% (Isaksson 2019, PMID 31111349)
German centre, 1,948 patients stage II–IV 23.5% assigned a different subgroup; stage IIIC rose from 24.8% to 50.8%, IIIA fell 28.7% → 16.2%, IIIB 46.5% → 28.3% Discrimination essentially unchanged (integrated time-dependent AUC 0.75 vs 0.74). 5-year MSS: IIB 80%, IIC 67%, IIIA 89% (Kanaki 2019, PMID 31401470)
SEER-18, 126,408 individuals, 2010–2015 — AJCC-7 3-year OS: IA 97%, IB 95%, IIA 87%, IIB 76%, IIC 57%, IIIA 86%, IIIB 69%, IIIC 50%, IV 24%. AJCC-8 similar but IIIC 56% and IIID 30%. Elevated LDH in stage IV predicted worse OS and CSS at every time point to 60 months (Tjokrowidjaja 2022, PMID 34811927)
Japanese Melanoma Study Group, 3,097 patients — 5-year DSS, 7th/8th edition: IA 98.5/97.9, IB 95.4/96.2, IIA 94.2/94.1, IIB 84.6/84.4, IIC 72.2/72.2, IIIA 76.2/87.5, IIIB 60.7/72.6, IIIC 42.0/55.3, IIID —/26.0 (Fujisawa 2019, PMID 31023613)
Melanoma Institute of Australia-style prospective cohort, 1,315 patients — Stage III RFS concordance index 0.65 (0.60–0.70) → 0.70 (0.66–0.75), P = .01. Stage I RFS c-index fell 0.63 (0.56–0.69) → 0.56 (0.49–0.63), P = .07 after mitotic-rate removal (Bajaj 2020, PMID 31977051)

Three consistent conclusions across five independent validations. (i) Stage III reclassification is large — 44% to 57% of stage III patients move subgroup. (ii) The improvement in prognostic discrimination is real but small, and concentrated in stage III. (iii) Reclassification improves the apparent survival of every stage III subgroup because the sickest patients are moved out and into IIID, which is a stage-migration artefact and not a change in patient outcome.

The stage IIC / stage IIIA inversion

Series Stage IIB Stage IIC Stage IIIA
German centre, 5-year MSS 80% 67% 89%
Japanese group, 5-year DSS (AJCC 8) 84.4% 72.2% 87.5%
Prospective US cohort, 5-year RFS (AJCC 8) — 26.5% (12.8–55.1) 56.0% (37.0–84.7), P = .002

Sources: PMID 31401470; PMID 31023613; PMID 31977051. Node-negative stage IIC melanoma has worse survival than node-positive stage IIIA melanoma in every one of these datasets. This is not a validation failure — thickness and ulceration carry more prognostic weight than a low-burden positive sentinel node — but it inverts the intuition that a higher stage number means worse disease, and it is the direct argument for extending adjuvant therapy into stage IIB/IIC (see adjuvant therapy). The German authors state the implication explicitly: stage IIB/IIC patients should be considered for adjuvant treatment while the indication in stage IIIA is questionable (PMID 31401470). Retrospective multicentre data in 628 stage IIIA patients across 34 centres bear on the second half of that claim: 2-year recurrence-free survival was 79.3% (95% CI 74.1–84.8) with anti-PD-1, 98.6% (96.0–100) with dabrafenib–trametinib and 84.3% with observation, with poor-prognostic variables significantly more frequent in the anti-PD-1 group (Grover 2025, PMID 40204154).

What the stage does not capture

  • Sentinel-node tumour burden. In 736 sentinel-node-positive patients, maximum deposit diameter was an independent predictor of melanoma-specific survival within existing AJCC stage III subgroups, at cut-offs of ≤0.5 mm (AUC 0.617) and ≤1 mm (0.599) (Satzger 2019, PMID 31677550). Lymph node ratio also adds information beyond N stage with standardised surgery (Spillane 2011, PMID 21119509).
  • Histotype. Acral lentiginous histology carries an independently worse disease-free survival after adjustment for thickness, ulceration and sentinel-node status (adjusted HR 1.25, 1.02–1.52) (Mandalà 2022, PMID 35421840). Stage does not record it.
  • Desmoplastic subtype. Pure versus mixed desmoplastic melanoma differ in sentinel-node positivity (6% vs 15%) independently of Breslow depth and ulceration (Yee 2026, PMID 41870859).
  • Mitotic rate, now excluded from T but still used in sentinel-node decision nomograms for T1 disease (Maurichi 2020, PMID 32167862).
  • Biomarkers in stage IV. In 200 patients on anti-PD-1, multivariable analysis identified M1c (vs M1a, P = .005), M1d (P = .001), pT4b primary category (P = .036) and elevated baseline S100B as independent predictors, alongside LDH (Janka 2023, PMID 37664072). AJCC 8 records LDH as an M1 descriptor but not S100B.
  • Gene expression. The 31-gene profile independently predicted recurrence-free and distant metastasis-free survival alongside thickness and sentinel-node status, and flagged 70% of stage I–II patients who later developed distant metastasis (Zager 2018, PMID 29402264).

Melanoma is staged by three different systems, not one

The AJCC cutaneous scheme above does not apply to the non-cutaneous subtypes, each of which has its own staging tradition and its own validation problems.

Subtype System Validation status
Cutaneous AJCC/UICC TNM 8th edition Validated in ≥5 independent population and centre cohorts (PMID 35778691; PMID 31111349; PMID 31401470; PMID 34811927; PMID 31023613)
Uveal AJCC 7th/8th edition ophthalmic classification, by tumour size category plus ciliary-body involvement and extrascleral extension Internationally validated in 3,809 patients from 10 ocular oncology centres on 4 continents, diagnosed 2001–2011 (AJCC Ophthalmic Oncology Task Force 2015, PMID 25555246). A competing-risk reanalysis of 6,528 consecutively registered patients from 3 centres over 1981–2022 proposes volume-based size categories and 7 stages instead (Stålhammar 2024, PMID 38071620)
Mucosal, head and neck Mucosal-melanoma TNM (mmTNM) — deliberately starts at T3 because even small mucosal melanomas behave aggressively — with Ballantyne/Prasad and squamous-cell TNM as competitors Contested. In 96 consecutive head-and-neck mucosal melanomas both mmTNM and sccTNM correlated with OS, PFS and DMFS (Moya-Plana 2019, PMID 31421470); in 35 sinonasal cases only the squamous-carcinoma TNM correlated with overall (P = .012) and disease-free survival (P = .041) (Michel 2014, PMID 23729399)

A "stage III melanoma" therefore means three different things depending on primary site, and survival figures are not comparable across them — see uveal melanoma and acral and mucosal melanoma.

Predicting distant metastasis beyond the stage

A systematic review and meta-analysis of 142 studies assessed clinical, dermatoscopic, histological and molecular predictors of distant metastasis and distant-metastasis-free survival in primary cutaneous melanoma, with subgroup analysis by AJCC stage (Lallas 2024, PMID 39074631). At the other end of the disease, initial metastatic kinetics outperformed the staged variables: in 126 stage IV patients, kinetic index of progression ranged from 0 to 24,839 mm³/day and median overall survival was 459, 388 and 183 days across ascending terciles; in multivariable analysis kinetic index predicted overall survival better than LDH or tumour load (Gaudy-Marqueste 2014, PMID 24440089). Rate of change is not a staging variable in any melanoma system.

Staging investigations

The European guideline ties imaging intensity to stage: no further imaging for melanomas up to 0.8 mm, lymph-node sonography from stage IB without further imaging, and whole-body CT or PET-CT plus brain MRI from stage IIB/C, with BRAF V600 mutation testing recommended from stage IIB/C (Garbe 2025, PMID 39700658). The evidence base for FDG-PET in melanoma remains old: a 2001 review reported pooled sensitivity 0.79 (95% CI 0.66–0.93), specificity 0.86 (0.78–0.95) and diagnostic odds ratio 33.1 across six poolable studies (Mijnhout 2001, PMID 11301402). A 2010 meta-analysis expanded this to 24 studies and found FDG-PET unsuitable for microscopic regional disease but potentially useful for distant metastases; scan-level specificity was 0.86 (0.77–0.92), positive likelihood ratio 5.86 (3.64–9.43) and diagnostic odds ratio 37.89 (15.80–90.86), with heterogeneity in other estimates (Jiménez-Requena 2010, PMID 19727717). Neither analysis evaluates contemporary PET-CT technology, so current recommendations still rest substantially on stage-specific pre-test probability rather than modern accuracy data.

Two further stage-migration mechanisms

The 7th-to-8th edition reclassification is not the only source of stage drift in current practice.

Mechanism Evidence
Omitting completion dissection Among 68,933 clinically node-negative ≥T1b patients in the National Cancer Database 2012–2018, 60,536 underwent sentinel node biopsy with 9,031 (14.9%) positive; completion dissection was performed in 3,776 (41.8%). Patients undergoing biopsy plus dissection were more likely to have N classification >N1a (36.8%) than biopsy alone (19.3%), P < .0001 (Senders 2023, PMID 36934378). Abandoning completion dissection therefore downstages the same disease, and stage III cohorts from before and after that practice change are not comparable
Pathological upstaging between biopsy and excision In 4,391 invasive melanomas from a statewide SEER-affiliated registry 2014–2018, 9.4% were upstaged between biopsy and definitive excision. Risk factors on multivariable analysis were head/neck location and higher pathological T stage; univariably also older age, male sex, non-White race, larger clinical size, incisional or punch biopsy, and longer biopsy-to-excision interval. Upstaging changed clinical management in over half of cases (Rosenthal 2025, PMID 39579989)
Understaging of clinical stage II disease Among 198 patients with clinical stage IB/II melanoma undergoing sentinel node biopsy, 41 (20.7%) had a positive node and 6 of 39 with recorded metastasis size (15.4%) had a macrometastasis ≥10 mm, five of them clinically stage II — raising the question of whether ultrasound staging should precede treatment decisions now that neoadjuvant therapy exists for macroscopic disease (McCahill 2026, PMID 42581274)

Clinical and pathological stage are formally distinct in AJCC 8 — the 8th edition revised pathological but not clinical stage IA (PMID 29028110) — and these three mechanisms are why a stage label without its derivation is uninterpretable.

Stage IV outcomes have moved, so historical stage IV survival is not transportable

Endpoint Historical Contemporary Source
US 5-year relative survival, metastatic melanoma 16% (mid-1990s) 35% (2015–2021) Siegel 2026, PMID 41528114
1-year net survival, distant stage ~43% (2001–2010) 58.9% (56.6–61.2) in 2013 Di Carlo 2020, PMID 33409455
5-year MSS, TNM8 stage IV, Ontario 2007–2012 14.4% — Hynes 2022, PMID 35778691
3-year OS, SEER stage IV 2010–2015 24% — Tjokrowidjaja 2022, PMID 34811927

Registry stage IV survival figures lag the trial and modern-cohort figures by years because they include pre-immunotherapy diagnosis cohorts. A stage IV survival number is uninterpretable without its diagnosis-year window — see immunotherapy in advanced disease.

Interpretation rules for this page

  • State the edition and the diagnosis years. 21–57% of patients change subgroup between editions depending on cohort and stage (PMID 35778691; PMID 31111349).
  • Never compare stage III survival across editions. Improvement in IIIA–IIIC survival from AJCC 7 to AJCC 8 is stage migration, not treatment effect (PMID 31111349).
  • Higher stage number does not mean worse prognosis — IIC is worse than IIIA in every validation cohort here (PMID 31401470; PMID 31023613; PMID 31977051).
  • The staging system explains under one fifth of the variance in melanoma-specific survival (19.7% for TNM8) (PMID 35778691). Most prognostic information is outside the stage.
  • Clinical and pathological stage are different quantities; the 8th edition revised pathological but not clinical stage IA (PMID 29028110).
  • Elevated LDH is prognostic in stage IV but no longer upstages (PMID 29028110; PMID 34811927).

Open questions

  • Should sentinel-node tumour burden be an N-category variable, and at what cut-off (PMID 31677550)?
  • Should mitotic rate return to the T category with a defined section count (PMID 31977051; PMID 25239732)?
  • Should acral lentiginous histotype be a stage modifier given its independent adverse effect (PMID 35421840)?
  • Does the IIC/IIIA inversion warrant restructuring the stage groups, or is it correctly informative as it stands (PMID 31401470)?
  • What is the diagnostic accuracy of modern PET-CT in melanoma staging? The two melanoma-specific meta-analyses searched literature only through 1999 and 2006 (PMID 11301402; PMID 19727717).
  • Can a staging system that explains under 20% of survival variance be improved by incorporating molecular assays (PMID 35778691; PMID 29402264)?

References

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