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Melanoma of unknown primary

March 28, 2023 - read ≈ 8 min



Sola Adeleke

Department of Oncology, University College London Hospitals, London, WC1E 6AG, UK | School of Cancer & Pharmaceutical Sciences, King’s College London, Strand, London, WC2R 2LS, UK


Joao R Galante

Department of Oncology, University College London Hospitals, London, WC1E 6AG, UK

Stergios Boussios

Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, ME7 5NY, Gillingham, Kent, UK | King’s College London, Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, SE1 9RT, London, UK | AELIA Organization, 9th Km Thessaloniki – Thermi, 57001, Thessaloniki, Greece*

* Correspondence to: Prof. Stergios Boussios MD, M.Sc., Ph.D., FRCP Consultant Medical Oncologist King’s College London, Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, London, UK, Medway NHS Foundation Trust, Kent, UK E-mails: [email protected] [email protected] [email protected]



Melanoma of unknown primary (MUP) accounts for 3-4% of melanoma cases and consists of pathologically confirmed melanoma metastases involving the lymph nodes, subcutaneous tissues and/or visceral without an identifiable primary after adequate workup [1].

Though the first definition of MUP goes back to 1963, the mechanisms underlying the development and progression of MUP have not been fully elucidated [2]. One hypothesis suggests that the interplay between the melanoma primary site and microenvironment leads to a regression of the stationary cells at the primary site while the motile cells undergo metastatic dissemination [2,3].

Another hypothesis is that ectopic non-cutaneous melanocytes already pre-existing within the lymphatic system undergo a malignant transformation which eventually leads to metastatic melanoma in the absence of a primary site of disease [2,3].

The lack of well-established pathogenesis for MUP raises questions about the accuracy of the diagnostic workup performed at each encounter and ultimately whether MUP exists as a distinct entity. Nonetheless, the clinical reality supports the existence of MUP with a natural history different from that of melanoma of known primary. MUP shares many similarities with cutaneous melanomas however, there are some distinct clinical, pathological and genomic differences between them [4–6].

For instance, melanoma primaries occur in chronically sun-damaged skin, acral skin and mucosal sites present melanoma primary and harbor KIT mutations in about 20% of cases whereas MUP tends to occur in non-cutaneous or non-mucosal primary sites and rarely present KIT mutations. TERT-promoter mutations were more frequent in MUP than in mucosal melanoma (66% vs 13.2%).

The clinical manifestations and an approach to the diagnosis and treatment of MUP will be reviewed here.

Clinical presentation

The median age at presentation ranges between 40-50 years and a male-to-female ratio of 2:1 [3,7]. Patients with MUP typically present with visible lumps and bumps resulting from axillary, cervical and inguinal lymphadenopathies in half the cases [3,8,9].

They can also present with various symptoms referable to metastases depending on organ involvement or paraneoplastic syndromes such as systemic vasculitis, inflammatory demyelinating polyneuropathy and diffuse vitiligo-like depigmentation [10–17].

Diagnostic workup

The initial diagnosis of MUP is confirmed by a biopsy of a metastatic lesion without an identifiable primary. The diagnostic workup includes the following (Figure 1):

  • Thorough history examination including any history of skin lesions that required excision. History of moles, freckles or birthmarks that have changed in size, color, edges or symmetry are considered essential to rule out melanoma of known primary.
  • Exhaustive physical examination including head and neck, anal and pelvic examination. Dermoscopy is useful, especially for the optimal selection of pigmented lesions [18]. If a cutaneous lesion is identified either in the setting of MKP, skin secondaries or direct infiltration from involved lymph nodes or if unclear, Clarke’s level assessment and Breslow’s thickness measurement are important.
  • Blood tests: complete blood counts, serum chemistries, liver function tests
  • Computed tomography (CT) scans of the chest, abdomen, and pelvis or positron emission tomography (PET)/CT scans could reveal deep-seated primaries in the abdomen or pelvis.
  • Focused evaluation of specific signs/symptoms such as endoscopies for patients with gastrointestinal manifestations. If there is any suspicious lymph node identified, a lymph node ultrasound and then a sentinel lymph node biopsy of any accessible, superficial lymph node could provide any early diagnostic information about the disease.

Thereafter a multi-disciplinary discussion between dermatologists, pathologists, oncologists and surgeons can retain or exclude the diagnosis of  MUP mainly according to Das Gupta’s exclusion criteria [2]:

  • Evidence of previous orbital exenteration or enucleation
  • Evidence of previous skin excision, electrodessication, cauterization
    or other surgical manipulation of a mole, freckle, birthmark, paronychia, or skin blemish
  • Evidence of metastatic melanoma in a draining lymph node with a scar in the area of skin supplying that lymph node basin.
  • Lack of a non-thorough physical examination, including the absence of an ophthalmologic, anal, and genital exam

Figure 1. Diagnostic workup in patients with melanoma of unknown primary

CT: computed tomography scan; ENT: ear, nose and throat; MUP: melanoma of unknown primary; PET: positron emission tomography


There are no specific guidelines for the treatment of patients with MUP but traditionally experts follow the standard guidelines for melanoma of known primary of the equivalent stage given that the corresponding pivotal clinical have included patients with melanoma of known primary and MUP. Overall, the staging of MUP according to the eighth edition of the American Joint Committee on Cancer (AJCC) classification of melanoma is as follows [22]:

  • Stage IIIB: patients with no sign of the primary tumor (T0) and limited spread to only one lymph node (N1b) without distant spread (M0).
  • Stage IIIC: patients with T0 and either spread to 2 or more involved lymph nodes, with at least one visible or palpable (N2b or N3b) or clumped together lymph nodes (N3b or N3c), while still M0.
  • Stage IV: patients with organ or multisite lymph node metastases (M1); MUP is classified as stage IV. Of note, M1 is sub-categorized into M1a (non-visceral distant cutaneous, subcutaneous, or nodal metastases), M1b (lung metastases), M1c (non-central nervous system (CNS) visceral metastases) and M1d (CNS metastases), with increasingly poorer prognosis [22].

Further specific details on the treatment of melanoma can be accessible through the following links to related guidelines:


Unites states:

United Kingdom:


  1. Boussios S, Rassy E, Samartzis E, Moschetta M, Sheriff M, Pérez-Fidalgo JA, et al. Melanoma of unknown primary: New perspectives for an old story. Crit Rev Oncol Hematol. 2021;158:103208.
  2. Dasgupta T, Bowden L, Berg JW. Malignant melanoma of unknown primary origin. Surg Gynecol Obstet. 1963;117:341‑5.
  3. Kamposioras K, Pentheroudakis G, Pectasides D, Pavlidis N. Malignant melanoma of unknown primary site. To make the long story short. A systematic review of the literature. Crit Rev Oncol Hematol. 2011;78(2):112‑26.
  4. Egberts F, Bergner I, Krüger S, Haag J, Behrens HM, Hauschild A, et al. Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas. Ann Oncol Off J Eur Soc Med Oncol. 2014;25(1):246‑50.
  5. Gos A, Jurkowska M, van Akkooi A, Robert C, Kosela-Paterczyk H, Koljenović S, et al. Molecular characterization and patient outcome of melanoma nodal metastases and an unknown primary site. Ann Surg Oncol. 2014;21(13):4317‑23.
  6. Rassy E, Boussios S, Chebly A, Farra C, Kattan J, Pavlidis N. Comparative genomic characterization of melanoma of known and unknown primary. Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex. 2021;23(11):2302‑8.
  7. Olsen CM, Thompson JF, Pandeya N, Whiteman DC. Evaluation of Sex-Specific Incidence of Melanoma. JAMA Dermatol. 2020;156(5):553‑60.
  8. Savoia P, Fava P, Osella-Abate S, Nardò T, Comessatti A, Quaglino P, et al. Melanoma of unknown primary site: a 33-year experience at the Turin Melanoma Centre. Melanoma Res. 2010;20(3):227‑32.
  9. Scott JF, Gerstenblith MR. Melanoma of Unknown Primary. In: Scott JF, Gerstenblith MR, editors. Noncutaneous Melanoma [Internet]. Brisbane (AU): Codon Publications; 2018 Mar. Chapter 7.
  10. Stagnitti F, Orsini S, Martellucci A, Tudisco A, Avallone M, Aiuti F, et al. Small bowel intussussception due to metastatic melanoma of unknown primary site. Case report. Il G Chir. 2014;35(9‑10):246‑9.
  11. Shan GD, Xu GQ, Chen LH, Wang ZM, Jin EY, Hu FL, et al. Diffuse liver infiltration by melanoma of unknown primary origin: one case report and literature review. Intern Med Tokyo Jpn. 2009;48(24):2093‑6.
  12. Suzuki T, Kusumoto S, Iida S, Tada T, Mori F. Amelanotic malignant melanoma of unknown primary origin metastasizing to the bone marrow: a case report and review of the literature. Intern Med Tokyo Jpn. 2014;53(4):325‑8.
  13. Primka EJ, King C, O’Keefe EJ. Malignant melanoma of unknown origin presenting as a systemic vasculitis. Arch Dermatol. 1993;129(9):1205‑7.
  14. Skarbez K, Fanciullo L. Metastatic melanoma from unknown primary presenting as dorsal midbrain syndrome. Optom Vis Sci Off Publ Am Acad Optom. 2012;89(12):e112-117.
  15. Kiratli H, Thirkill CE, Bilgiç S, Eldem B, Keçeci A. Paraneoplastic retinopathy associated with metastatic cutaneous melanoma of unknown primary site. Eye Lond Engl. 1997;11 ( Pt 6):889‑92.
  16. Palma JA, Martín-Algarra S. Chronic inflammatory demyelinating polyneuropathy associated with metastatic malignant melanoma of unknown primary origin. J Neurooncol. 2009;94(2):279‑81.
  17. Manganoni AM, Farfaglia R, Sereni E, Farisoglio C, Pavoni L, Calzavara-Pinton PG. Melanoma of unknown primary with nodal metastases, presenting with vitiligo-like depigmentation. G Ital Dermatol E Venereol Organo Uff Soc Ital Dermatol E Sifilogr. 2012;147(2):210‑1.
  18. Stante M, de Giorgi V, Carli P. Possible role of dermoscopy in the detection of a primary cutaneous melanoma of unknown origin. J Eur Acad Dermatol Venereol JEADV. 2006;20(3):299‑302.
  19. Michielin O, van Akkooi A, Lorigan P, Ascierto PA, Dummer R, Robert C, et al. ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(11):1449‑61.
  20. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, et al. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(11):1435‑48.
  21. Utter K, Goldman C, Weiss SA, Shapiro RL, Berman RS, Wilson MA, et al. Treatment Outcomes for Metastatic Melanoma of Unknown Primary in the New Era: A Single-Institution Study and Review of the Literature. Oncology. 2017;93(4):249‑58.
  22. Keung EZ, Gershenwald JE. The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert Rev Anticancer Ther. 2018;18(8):775‑84.
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