Nodal diseaseWorkflowAJCC 8 T0ICD-10 C77.x · C80.0
Cutaneous cancer of unknown primary
Melanoma CUP · cSCC nodal CUP · occult primary skin cancer
Cutaneous cancer of unknown primary (CUP) describes nodal disease histologically compatible with a cutaneous melanoma or cSCC where no current or past primary cutaneous tumour can be identified despite systematic workup. AJCC 8 introduces a T0 designation for melanoma with histologically confirmed regional or distant metastasis from a clinically occult primary. Prognosis in melanoma CUP is broadly similar to, and possibly better than, stage-matched known-primary melanoma. Management follows the regional or systemic pathway appropriate for the AJCC 8 stage.
CurrentLast reviewed 16 May 2026
Definition and incidence
- Histologically confirmed nodal or in-transit metastasis of cutaneous tumour without an identifiable primary skin site.
- Accounts for ~3-5% of melanomas with regional nodal disease and a small proportion of nodal cSCC.
- Mechanisms: complete spontaneous regression of primary; tumour previously excised but mis-diagnosed (e.g. as a "naevus"); occult / very early primary not yet visible; nodal primary from ectopic melanocytes or epithelial inclusions.
Workup
- Total skin examination — and complete mucosal / scalp / nail-bed / ano-genital review. Document any regressed pale macule / halo lesion / depigmented patch.
- Review of previous skin histopathology — request slide review for any prior excised "naevus" or "atypical lesion".
- Ophthalmologic review if melanoma — exclude uveal primary.
- Nodal core / FNA with IHC: melanoma markers (S100, SOX10, Melan-A, HMB-45); cSCC markers (CK5/6, p63, p40). PRAME may help in occult melanoma.
- Whole-body imaging: CT chest / abdomen / pelvis; PET-CT in melanoma; brain MRI in stage III-IV melanoma.
- Molecular profiling: BRAF V600 testing in melanoma; HPV status in head & neck cSCC (also informs aggressive head & neck SCC CUP differential).
- ENT / dental review where head & neck nodal disease.
AJCC 8 staging
- Melanoma CUP: AJCC 8 introduced T0 for melanoma with no identifiable primary. Stage assignment is by N and M status — e.g. T0N1bM0 = stage IIIB; T0N2bM0 = stage IIIC; T0N3M0 = stage IIIC.
- cSCC nodal CUP: AJCC 8 uses a separate head & neck SCC nodal staging framework (cN1-N3); BWH staging does not apply when no primary is identifiable.
Management
- Therapeutic lymph-node dissection historically standard; in melanoma CUP, completion lymph-node dissection has fallen out of favour in line with MSLT-II / DeCOG-SLT — discuss at MDT.
- Adjuvant systemic therapy: stage III melanoma CUP candidates for anti-PD-1 (nivolumab, pembrolizumab) or BRAF/MEK if BRAF-mutated, per existing stage-III pathway.
- Stage IV CUP: standard advanced-melanoma combination ICI or BRAF / MEK.
- cSCC nodal CUP: surgical clearance + adjuvant radiotherapy ± concurrent cisplatin; cemiplimab / pembrolizumab in recurrent / metastatic disease.
- Multidisciplinary discussion essential — melanoma MDT for melanoma CUP, head & neck MDT for cSCC CUP.
Prognosis
- Several large retrospective series show melanoma CUP has similar or better stage-matched survival compared to known-primary melanoma — possibly reflecting strong immunologic regression as a biological signature.
- cSCC nodal CUP prognosis depends on N-stage and ECE; broadly comparable to known-primary cSCC stage-matched.
- Long-term skin surveillance remains essential — a delayed primary may emerge.
References
- Egger ME et al. Melanoma of unknown primary: a comparison with melanoma of known primary in the era of effective adjuvant therapy. Ann Surg Oncol. 2020;27:5275-5283.
- Boussios S et al. Melanoma of unknown primary: a multicenter analysis. Cancers (Basel). 2022;14:5475.
- Gershenwald JE et al. Melanoma staging: evidence-based changes in the AJCC 8th-edition cancer staging manual. CA Cancer J Clin. 2017;67:472-492.
- Faries MB et al. Completion dissection or observation for sentinel-node metastasis in melanoma (MSLT-II). N Engl J Med. 2017;376:2211-2222.
- NICE NG14 — Melanoma: assessment and management. London: NICE; 2022.
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