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Surgical management and excision margins in melanoma

TL;DR — Seven randomised trials in 4,579 patients have compared narrow (1–2 cm) with wide (3–5 cm) excision margins and found no significant difference in locoregional recurrence (RR 1.09, 95% CI 0.98–1.22), local recurrence (RR 1.20, 0.66–2.21), distant metastasis (RR 0.95, 0.72–1.24), death (RR 1.00, 0.93–1.07) or melanoma death (RR 1.11, 0.96–1.28) (Hanna 2021, PMID 33722422). The two most informative trials disagree at the extremes: 2 cm was as safe as 4 cm for melanoma >2 mm at a median 19.6 years' follow-up (melanoma-specific HR 0.95, 0.78–1.16, P = .61; 936 patients) (Utjés 2019, PMID 31280965), whereas 1 cm was inferior to 3 cm for melanoma >2 mm on trunk and limbs (melanoma-specific HR 1.24, 1.01–1.53, P = .041; 900 patients) (Hayes 2016, PMID 26790922). The open question — whether 1 cm suffices for pT2–pT4 disease — is being tested in MelMarT-II (NCT03860883, 2,998 planned, recruiting, primary completion 2029), after the MelMarT feasibility study randomised 400 patients and showed that 2 cm margins doubled reconstruction requirements (34.9% vs 13.6%, P < .0001) (Moncrieff 2018, PMID 29850955; NCT02385214). For lentigo maligna and head-and-neck melanoma, margin-controlled techniques outperform standard wide excision on local recurrence (0.61% for Mohs vs 7.8% for wide local excision) though not on survival (Bittar 2021, PMID 33961921).

The randomised margin trials

Trial Population Comparison Result
Swedish/Danish/Estonian/Norwegian (Gillgren 2011, PMID 22027547; long-term Utjés 2019, PMID 31280965) 936 patients ≤75 years, localised melanoma >2 mm, trunk/extremities, 53 hospitals, enrolled 1992–2004 2 cm vs 4 cm At median 6.7 years: 181 vs 177 deaths, HR 1.05 (0.85–1.29), P = .64; 5-year OS 65% both arms. At median 19.6 years (IQR 200–260 months): 621 deaths, HR 0.98 (0.83–1.14), P = .75; 397 melanoma deaths, HR 0.95 (0.78–1.16), P = .61
UK/Poland/South Africa (Hayes 2016, PMID 26790922) 900 patients, primary localised melanoma >2 mm, trunk or limbs, 59 hospitals, enrolled 1992–2001 1 cm vs 3 cm At median 8.8 years: 359 melanoma deaths, 194 (1 cm) vs 165 (3 cm), HR 1.24 (1.01–1.53), P = .041. All-cause 253 vs 241, HR 1.14 (0.96–1.36), P = .14. Surgical complications 8% vs 15%
MelMarT feasibility (Moncrieff 2018, PMID 29850955; NCT02385214) 400 randomised, 377 analysable, 17 centres in 5 countries, melanoma >1 mm 1 cm vs 2 cm with sentinel node biopsy Reconstruction required 13.6% vs 34.9% (P < .0001); wound necrosis 0.5% vs 3.6%. Feasibility endpoint, not efficacy
MelMarT-II (NCT03860883) 2,998 planned, AJCC stage II primary cutaneous melanoma, started December 2019, primary completion December 2029 1 cm vs 2 cm Recruiting; verified live 2026-09-01

Meta-analytic summary. Across seven RCTs and 4,579 patients, narrow versus wide margins gave RR 1.09 (0.98–1.22) for locoregional recurrence, 1.20 (0.66–2.21) local recurrence, 1.30 (0.86–1.97) in-transit metastasis, 1.04 (0.91–1.18) regional nodal metastasis, 0.95 (0.72–1.24) distant metastasis, 1.00 (0.93–1.07) death, 1.11 (0.96–1.28) melanoma death, 1.22 (0.68–2.17) wound infection and 0.96 (0.54–1.71) wound dehiscence — none significant (Hanna 2021, PMID 33722422). The earlier Cochrane review of five trials (1,633 narrow, 1,664 wide, median follow-up 5–16 years) found the summary overall-survival estimate favouring wide excision by a small degree (HR 1.04, 0.95–1.15, P = .40), explicitly compatible with both a 5% relative mortality reduction favouring narrow excision and a 15% relative reduction favouring wide (Sladden 2009, PMID 19821334).

How to read this. The individual trials are underpowered for melanoma-specific survival and the meta-analyses pool comparisons that are not the same comparison — 1 vs 3 cm is not 2 vs 4 cm. The single significant result in the whole literature is Hayes's 1-vs-3 cm melanoma-specific survival difference, and it comes from the only trial testing a 1 cm margin in melanoma >2 mm (PMID 26790922). The literature therefore supports "2 cm is enough" and does not support "1 cm is enough" for thick melanoma. MelMarT-II is the trial designed to settle it, and it will not report until the 2030s.

Margin recommendations rest on inference, not on direct trial evidence

No completed randomised margin trial has reported specifically for T1 melanoma or melanoma in situ. That gap is now narrower: NORMA 2 is recruiting 1,749 patients with pT1b–pT4b superficial-spreading or nodular melanoma to re-excision with 1–2 cm margins versus no re-excision after a diagnostic excision clear by at least 1 mm (NCT07530887). No randomised melanoma-in-situ-specific margin trial was found in the ClinicalTrials.gov search on 2026-09-01. Society recommendations for these categories still rest on extrapolation pending those results. The American guideline of care for primary cutaneous melanoma sets out the recommended margins by thickness category (Swetter 2019, PMID 30392755), and the European guideline covers the surgical section of its treatment update (Garbe 2025, PMID 39709737) — synthesis in guidelines.

Lentigo maligna and melanoma in situ

The subvertical growth of lentigo maligna and its typical location on chronically sun-damaged head and neck skin make standard margins both cosmetically costly and frequently inadequate.

Technique Local recurrence rate Source
Mohs micrographic surgery 0.61% (95% CI 0.1–1.4) Bittar 2021, PMID 33961921
Staged excision 1.8% (1.0–2.9) PMID 33961921
Wide local excision 7.8% (6.4–9.3) PMID 33961921

Meta-analysis across 100 manuscripts and 13,998 head-and-neck cutaneous melanomas (51.0% wide local excision, 34.5% Mohs, 14.5% staged excision) (PMID 33961921). Adding intraoperative immunohistochemistry to margin-controlled surgery lowers local recurrence further: across 57 studies, 12,043 patients and 12,590 tumours, invasive melanoma local recurrence was 0.3% (0–0.6) with immunohistochemistry versus 1.8% (0.8–2.8) with haematoxylin and eosin alone (P < .001), with no significant difference in nodal recurrence, distant recurrence or disease-specific mortality (O'Hern 2024, PMID 38530980).

That last clause is the interpretive crux: margin-controlled techniques reliably reduce local recurrence and have never been shown to change survival. The quality of this literature has been formally criticised — a critical review found substantial limitations in reporting and data quality across the Mohs and staged-excision melanoma literature (Adalsteinsson 2023, PMID 33872715), and technical variation between centres is itself large (Krausz 2021, PMID 34743123).

Non-surgical options for lentigo maligna. The Cochrane review of interventions for melanoma in situ including lentigo maligna identified only one eligible randomised trial: 90 participants with 91 histologically proven lentigo maligna lesions randomised to imiquimod 5% plus tazarotene 0.1% versus imiquimod alone for 3 months, with staged excision at 2 mm margins two months after topical treatment; histological or clinical complete response was 66% (29/44) in the combination arm, and the study was open-label with non-intention-to-treat analysis and high risk of incomplete outcome data (Tzellos 2014, PMID 25526608). The evidence base for non-surgical management of lentigo maligna is one small trial.

Other operative questions

  • Upstaging on Mohs. Upstaging of melanoma in situ and lentigo maligna treated with Mohs rarely results in additional surgical management (Levoska 2020, PMID 32002653), which bears on whether staged margin control forfeits staging information.
  • Head-and-neck in situ margins. Retrospective single-centre review of margins for melanoma in situ on the head and neck treated with Mohs over ten years quantifies what margin is actually required (Tate 2024, PMID 38253130); a separate systematic review addresses safety margins for non-lentigo-maligna melanoma in situ (Dessinioti 2025, PMID 40231559).
  • Does primary-tumour excision margin affect survival at all? A large analysis revisited the role of primary excision margins on survival, concluding differently from the trial literature and illustrating why observational margin studies are confounded by thickness and site (Mocellin 2011, PMID 21173691).
  • Thick melanoma specifically. A recent systematic review and meta-analysis addresses margins for Breslow thickness >2 mm (Floriano 2026, PMID 40108923).
  • Metastasectomy. Resection of distant metastases was analysed within MSLT-I data, providing one of the few controlled contexts for surgical management of stage IV disease (Howard 2012, PMID 22648554).

In-transit metastasis: the locoregional problem surgery cannot solve

In-transit metastases sit between the primary and the nodal basin and are classified N1c/N2c/N3c in AJCC 8 by the number of involved nodes (Gershenwald 2017, PMID 29028110). The Ontario Health clinical practice guideline stratifies management by burden: "minimal" in-transit metastasis is generally 1–4 superficial, clustered, resectable lesions; "moderate" is more than 5 lesions over a wider area or rapid development of new lesions within weeks; "maximal" is large-volume disease (Wright 2020, PMID 32669939).

Modality Evidence
Surgical excision First-line for minimal disease; no randomised comparison against alternatives (PMID 32669939)
Isolated limb perfusion / infusion In 364 patients treated 2002–2023 across multiple institutions, complete and overall response rates did not differ between acral (n = 84) and non-acral (n = 280) melanoma on multivariable analysis, but median progression-free survival was shorter for acral (5.6 vs 7.7 months, P = .02), as were out-of-field PFS (9.6 vs 15.3 months, P = .02) and disease-specific survival (3.5 vs 7.8 years, P = .008) (Dugan 2025, PMID 40413325)
Talimogene laherparepvec (oncolytic HSV-1) OPTiM final analysis, 436 patients randomised 2:1, median follow-up 49 months: median OS 23.3 months (95% CI 19.5–29.6) vs 18.9 (16.0–23.7) for GM-CSF, unstratified HR 0.79 (0.62–1.00), P = .0494 descriptive; durable response rate 19.0% vs 1.4%, unadjusted OR 16.6 (4.0–69.2), P < .0001 (Andtbacka 2019, PMID 31171039)
Everything else A systematic review of 57 articles across eight modalities — amputation, hyperthermic isolated limb perfusion, isolated limb infusion, CO₂ laser, intralesional PV-10, intralesional IL-2, imiquimod, diphenylcyclopropenone — found that only amputation and topical imiquimod had data adequate for formal meta-analysis (Read 2019, PMID 30734295)

The in-transit literature is the weakest surgical evidence base in melanoma: eight competing modalities, one positive randomised trial with a descriptive primary analysis, and a guideline that stratifies by burden because the comparative evidence does not exist.

Surgery for distant metastasis

Metastasectomy in stage IV melanoma has never been randomised, and its role has changed with effective systemic therapy.

Study Finding
MSLT-I analysis (Howard 2012, PMID 22648554) Of 291 patients with complete stage IV recurrence data, 161 (55%) underwent surgery with or without systemic therapy. Median survival 15.8 vs 6.9 months and 4-year survival 20.8% vs 7.0% for surgery ± systemic therapy versus systemic therapy alone (P < .0001; HR 0.406), with advantages in M1a (median >60 vs 12.4 months; 4-year 69.3% vs 0%, P = .0106), M1b and M1c. Treatment was clinician-selected, so this is confounded by selection
Matched-pair analysis by era (Nelson 2019, PMID 31183639) 2,353 stage IV patients characterised by treatment era (1965–2007 vs 2008–2015) and by agent, with BRAF/MEK and checkpoint inhibitors counted as modern; 1,065 (45.2%) had surgical treatment. Selection factors for metastasectomy in the early era were female sex, no prior stage III disease, single-organ involvement and M1a versus M1c disease (all P < .007); the surgically treated proportion increased modestly in the modern era
Pulmonary metastasectomy (Deboever 2022, PMID 35489217) 377 procedures in 347 patients: mean 17 resections per year, rising from 6 in 1998 to a peak of 39 in 2008 then declining. Diagnostic resection fell from 22% (1998–99) to 5% (2008–09) to zero (2018–19), P = .02, while curative resection rose from 44% to 73% (P < .001) and remained the dominant indication

The indication changed rather than the operation. Diagnostic metastasectomy has essentially disappeared as imaging and systemic options improved, while curative-intent resection persists in selected oligometastatic disease — a role defined entirely by non-randomised, selection-confounded data.

Interaction with modern systemic therapy

Surgery is no longer the only local-control option in resectable stage III disease. Neoadjuvant immunotherapy achieves major pathological responses that raise the question of de-escalating the operation itself, and NADINA's design already omits therapeutic lymph-node dissection in major pathological responders (Blank 2024, PMID 38828984) — see neoadjuvant therapy. The margin trials all predate this era, and none was conducted in patients receiving effective systemic therapy.

How melanoma surgery reached its current shape

The trajectory of melanoma surgery is one of progressive de-escalation, and each step was decided by a trial rather than by preference.

Step What was abandoned Evidence
Wide margins 3–5 cm margins Seven RCTs, 4,579 patients, no significant difference on any endpoint (PMID 33722422); 2 cm safe at 19.6 years (PMID 31280965)
Elective lymph node dissection Routine dissection of clinically negative nodes A century of controversy resolved by a series of trials evaluating elective dissection and then sentinel node biopsy, producing increasingly selective surgical intervention (Faries 2022, PMID 34897707); the theoretical and empirical arguments were rehearsed in the 1990s (PMID 9267247) and the controversies reviewed as they narrowed (PMID 22393199; PMID 16297015)
Completion lymph node dissection Dissection after a positive sentinel node MSLT-II and DeCOG-SLT, no survival benefit, 24.1% lymphoedema (PMID 28591523; PMID 31557067); the shift to selective indication has been reviewed (PMID 41011113)
Diagnostic metastasectomy Surgery to establish a stage IV diagnosis Fell from 22% of pulmonary metastasectomies in 1998–99 to zero in 2018–19 (PMID 35489217)
Therapeutic lymph-node dissection after neoadjuvant response Under active test NCT06754904, recruiting, n = 213

Each de-escalation was justified by a negative trial, and the field's next de-escalation — omitting therapeutic dissection after a major pathological response — is being tested prospectively rather than adopted on inference (PMID 35661157).

Interpretation rules for this page

  • 1 vs 3 cm and 2 vs 4 cm are different comparisons and should not be pooled without saying so (PMID 26790922; PMID 31280965).
  • Absence of a significant difference in an underpowered trial is not equivalence. Cochrane's confidence interval spans a 5% benefit for narrow and a 15% benefit for wide margins (PMID 19821334).
  • Local recurrence and survival are different endpoints. Margin-controlled surgery improves the first with no demonstrated effect on the second (PMID 33961921; PMID 38530980).
  • Margins for T1 melanoma and melanoma in situ have never been randomised. Recommendations there are extrapolation (PMID 30392755).
  • Morbidity scales with margin. MelMarT: 2 cm required reconstruction in 34.9% vs 13.6% for 1 cm (PMID 29850955); Hayes: complications 15% vs 8% for 3 cm vs 1 cm (PMID 26790922).
  • All margin trials predate effective adjuvant and neoadjuvant systemic therapy (PMID 38828984).

Open questions

  • Is a 1 cm margin adequate for AJCC stage II melanoma? MelMarT-II (NCT03860883) is powered for it and reports in the 2030s.
  • What margin does melanoma in situ require, and does it differ by site and by lentigo maligna versus non-lentigo-maligna subtype (PMID 40231559; PMID 38253130)?
  • Does margin-controlled surgery improve any outcome beyond local recurrence (PMID 33961921; PMID 38530980)?
  • Should surgical extent be de-escalated after a major pathological response to neoadjuvant therapy (PMID 38828984)?
  • Is there a non-surgical management pathway for lentigo maligna supported by more than a single 90-patient trial (PMID 25526608)?

References

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