What investigations should be performed when stage IV melanoma is diagnosed?

From Cancer Guidelines Wiki


A diagnosis of stage IV (M1) melanoma can occur in differing clinical scenarios. Principally these are:

  1. presentation with symptoms/signs of metastatic (stage IV) disease in a patient with no prior history of primary melanoma
  2. presentation with symptoms/signs of metastatic disease (stage IV) in a patient with a prior history of a primary melanoma
  3. discovery of asymptomatic metastatic disease (stage IV) in a patient being followed up following a prior diagnosis of ‘high risk’ stage II or stage III melanoma
  4. discovery of asymptomatic metastatic disease (stage IV) as an incidental finding during investigation of an unrelated condition.

In (1) by definition, a histological diagnosis will have been obtained. In (2) histological confirmation that the metastatic malignancy is melanoma is essential to rule out alternative primary sites and to obtain tissue for molecular analysis. For patients in scenarios (3) and (4) where stage IV disease is found on imaging, histological confirmation is required particularly for patients with a long interval from the previous melanoma diagnosis, where the imaging appearance is atypical for melanoma metastases (e.g. a speculated lung lesion with intra-thoracic nodes), and where the stage IV lesion is solitary. The biopsy technique chosen (FNA, core biopsy, excision) should be performed to obtain enough tissue for molecular studies.

Appropriate investigations for individual patients with stage IV melanoma will be related to that patient’s symptoms, findings on physical examination, medical history and co-morbidities. Other baseline investigations may be necessary for specific treatment options (e.g. endocrine tests for patients having immunotherapy). The recommendations in this chapter are however applicable to all patients with stage IV melanoma.

Systematic review evidence

A systematic review was undertaken to identify relevant evidence regarding investigations for stage IV melanoma. Several diagnostic accuracy studies were identified examining different types of investigations.


Under the AJCC Staging Manual 8th Edition, stage IV melanoma is subdivided into:

  • Stage M1a – skin, soft tissue including muscle and/or non-regional lymph nodes
  • Stage M1b – lung metastases with or without M1a sites of disease
  • Stage M1c – metastases to other non-central nervous system visceral sites with or without M1a or M1b sites of disease
  • M1d – metastases to CNS with or without M1a, M1b, or M1c disease.

Additionally, each subdivision above is further divided by the LDH level, with (0) denoting LDH not elevated and (1) denoting LDH elevated. Sub-staging is essential to provide a more accurate prognosis and to determine treatment options. Serum LDH level is required for sub-staging and is an essential test when stage IV melanoma is first diagnosed.

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Serum LDH level should be measured at the time of diagnosis of stage IV melanoma.

Imaging – PET, PET/CT

Imaging for patients with stage IV melanoma requires, at minimum, a contrast enhanced CT of chest/abdomen/pelvis and/or a whole body PET scan with concurrent low-dose CT or combined PET/contrast enhanced CT scan. Comparative studies of these imaging modalities are based on both stage III and stage IV patients.[1][2] Systematic reviews show PET and PET/CT are superior in detecting sites of metastatic disease[3][4], and will therefore be preferred in most patients. However there are no randomised trials and in the absence of these, it must be realised the endpoint of diagnostic accuracy does not necessarily lead directly to better patient outcomes. Studies have described potentially beneficial outcomes based on changes to management plans, particularly where the proposed treatment is surgical[1][2] Where CT scanning has shown widespread metastatic disease and findings on PET will not change the planned management approach, metabolic imaging can be omitted.

Evidence summary Level References
Systematic reviews show superior diagnostic accuracy of whole body PET scanning and PET/CT scanning over CT scanning in stage IV melanoma. II, III-2 [3], [4]
Whole body PET scanning or PET/CT can lead to beneficial changes to patient management. II, IV [1], [2]
Evidence-based recommendationQuestion mark transparent.png Grade
Whole body PET scanning or PET/CT is required in patients diagnosed with stage IV melanoma if the result will change management.

Imaging – MRI

Staging of melanoma with whole body MRI was been reported to have higher diagnostic accuracy than CT scanning in study of test accuracy[5] and comparable to PET or PET/CT in another study of test accuracy[6] but this is unlikely to be widely utilised. MRI scanning may be helpful in clarifying otherwise indeterminate liver lesions.[7]

Imaging – brain metastases

Neither whole body PET or PET/CT can reliably detect brain metastases. Because melanoma has a high rate of brain metastases developing during the course of stage IV disease, some guidelines have recommended routine brain imaging with contrast enhanced CT or MRI at initial presentation in all stage IV melanoma patients who do not have neurological symptoms or signs.[8] This also reflects the approach taken in most Phase III trials evaluating targeted or immune-based treatments for stage IV melanoma. Only one recent comparative study (697 patients) has reported the incidence of asymptomatic brain metastases in stage IV patients – 12% using contrast enhanced CT scanning.[9] Although a higher number would likely have been detected using MRI, the clinical utility of detecting small brain metastases detectable only by MRI is unclear particularly with the increasing use of active systemic treatments as initial treatment of brain metastases from melanoma rather than brain directed RT.

Evidence summary Level References
One comparative study reported asymptomatic brain metastases on contrast enhanced CT in 12% of patients at diagnosis of stage IV melanoma. III-2 [9]
Evidence-based recommendationQuestion mark transparent.png Grade
Brain imaging with contrast enhanced CT or MRI is appropriate in asymptomatic patients diagnosed with stage IV melanoma.

Molecular analysis

All patients with stage IV melanoma must have documentation of the presence or absence of activating V600 BRAF mutations prior to commencing systemic treatment because of the availability of targeted treatments for patients with these mutations. Analysis of BRAF mutation status can be performed on FFPE tumour tissue using a variety of techniques either as a single BRAF analysis or as part of multi-gene mutation panel assessment in accredited molecular pathology laboratories. The most recently obtained tumour biopsy should be used for analysis, preferably a direct biopsy from a site of stage IV disease or prior stage III disease. Use of a primary melanoma for analysis is not recommended, especially if there is a long time interval between the primary and the diagnosis of stage IV melanoma.

The most common activating V600 mutation, V600E, can be detected in tumour tissue using immunohistochemistry, but this method will miss other potentially targeted inhibitor-sensitive mutations so is of value only if positive.

BRAF gene mutations can be detected in tumour DNA from peripheral blood samples, but at present this technique has a high false-negative rate and is not recommended for routine use.

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Documentation of the presence/absence of activating V600 BRAF mutations in tumour tissue is required before commencing systemic therapy for stage IV melanoma.

How should patients at each stage of melanoma be followed after initial definitive treatment

How should patients at each stage of melanoma be followed after initial definitive treatment?

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  1. 1.0 1.1 1.2 Schüle SC, Eigentler TK, Garbe C, la Fougère C, Nikolaou K, Pfannenberg C. Influence of (18)F-FDG PET/CT on therapy management in patients with stage III/IV malignant melanoma. Eur J Nucl Med Mol Imaging 2016 Mar;43(3):482-8 Available from:
  2. 2.0 2.1 2.2 Singnurkar A, Wang J, Joshua AM, Langer DL, Metser U. 18F-FDG-PET/CT in the Staging and Management of Melanoma: A Prospective Multicenter Ontario PET Registry Study. Clin Nucl Med 2016 Mar;41(3):189-93 Available from:
  3. 3.0 3.1 Schröer-Günther MA, Wolff RF, Westwood ME, Scheibler FJ, Schürmann C, Baumert BG, et al. F-18-fluoro-2-deoxyglucose positron emission tomography (PET) and PET/computed tomography imaging in primary staging of patients with malignant melanoma: a systematic review. Syst Rev 2012 Dec 13;1:62 Available from:
  4. 4.0 4.1 Xing Y, Bronstein Y, Ross MI, Askew RL, Lee JE, Gershenwald JE, et al. Contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst 2011 Jan 19;103(2):129-42 Available from:
  5. Mosavi F, Ullenhag G, Ahlström H. Whole-body MRI including diffusion-weighted imaging compared to CT for staging of malignant melanoma. Ups J Med Sci 2013 May;118(2):91-7 Available from:
  6. Jouvet JC, Thomas L, Thomson V, Yanes M, Journe C, Morelec I, et al. Whole-body MRI with diffusion-weighted sequences compared with 18 FDG PET-CT, CT and superficial lymph node ultrasonography in the staging of advanced cutaneous melanoma: a prospective study. J Eur Acad Dermatol Venereol 2014 Feb;28(2):176-85 Available from:
  7. Sofue K, Tateishi U, Tsurusaki M, Arai Y, Yamazaki N, Sugimura K. MR imaging of hepatic metastasis in patients with malignant melanoma: evaluation of suspected lesions screened at contrast-enhanced CT. Eur J Radiol 2012 Apr;81(4):714-8 Available from:
  8. National Comprehensive Cancer Network. NCCN Guidelines for Melanoma. Fort Washington, PA: National Comprehensive Cancer Network; 2016.
  9. 9.0 9.1 Zukauskaite R, Schmidt H, Asmussen JT, Hansen O, Bastholt L. Asymptomatic brain metastases in patients with cutaneous metastatic malignant melanoma. Melanoma Res 2013 Feb;23(1):21-6 Available from: