Melanoma: assessment and management

Immunohistochemistry

The 2015 guideline recommended genetic testing for stage IIC and above melanoma. The 2022 committee extended this by recommending that BRAF analysis be considered for stage IIA or IIB melanoma, and carried out for stage IIC to IV melanoma. The committee agreed, based on their experience and in view of advances in targeted treatments since 2015, that early determination of BRAF status has practical utility. They noted that disease relapse occurs in a significant proportion of people with stage IIA to IIC melanoma (up to 50% at 5 years in people with stage IIC melanoma). Knowing BRAF status can speed up decisions about treatment for relapsed melanoma and optimise the use of these newer treatments.

The committee also noted that BRAF analysis of melanoma tissue samples should be arranged by the local skin cancer multidisciplinary team to provide a more coordinated process. The pathology report on the primary lesion should also include the relevant tissue block suitable for molecular genetic testing, as specified by the dermatopathologist within the local skin cancer multidisciplinary team.

The 2015 guideline did not specify the type of genetic test. The 2022 committee looked at specific types of test. They concluded that immunohistochemistry using BRAF V600E analysis is the most rapid method and enables treatment to be started sooner than is the case with other types of genetic testing. They also noted evidence that showed BRAF V600E immunohistochemistry rarely produces false positive results. However, some false negative results do occur so the committee agreed that a different BRAF genetic test should be used to double-check a negative or inconclusive result.

The committee agreed to retain the 2015 recommendation that genetic testing should not be offered to people with stages IA to IB melanoma.

Genetic testing for people with melanoma who are potential candidates for clinical trials will streamline enrolment into clinical trials and identify more candidates for trials.

Biomarkers

Biomarkers are of increasing relevance in the diagnosis and monitoring of various cancers, but their utility in the context of melanoma is still unclear. The committee made recommendations for research on monitoring and response biomarkers, and safety, prognostic and predictive biomarkers.

Sentinel lymph node biopsy

Evidence showed that sentinel lymph node biopsy (SLNB) should be done (or ruled out) before imaging for most people because imaging does not accurately detect lymph node metastases during staging. The committee agreed that imaging should only be offered before SLNB if lymph node or distant metastases are suspected.

Specific risk factors were shown by the evidence to be strongly associated with a positive sentinel lymph node and the committee recommended that SLNB be considered for people with any of these risk factors. They agreed that SLNB is not cost effective if the risk of sentinel node metastases is low. The committee noted that the existing economic evidence was highly contradictory. They also noted that the model previously developed for the 2015 guideline and 1 study showed that SLNB was not cost effective.

The committee noted that women who are pregnant may have concerns about having SLNB because it needs to be done under a general anaesthetic and uses a radioactive tracer and an unlicensed drug. The committee agreed that, in their experience, there is no harm associated with delaying SLNB until after pregnancy. They noted that the decision should be made within the specialist skin cancer multidisciplinary team on a case-by-case basis after discussion with the person.

Imaging

Most of the evidence concerned imaging during follow-up. There was less evidence on imaging during staging, but the committee agreed that the imaging used for staging should be consistent with the imaging that will be used during follow-up, and made recommendations to reflect this (see the recommendations on imaging in the section on follow-up after treatment for melanoma).

The committee agreed that MRI has utility during staging, due to the increased sensitivity for detecting brain metastases compared with CE-CT. They recommended considering brain MRI instead of CE-CT when staging people with stage IIIC to IV melanoma because of their higher risk of developing brain metastases. The committee noted that many clinical factors are also associated with an increased risk of developing brain metastases and included the main risk factors in the recommendations.

The evidence showed a high rate of recurrence in the interim period between surgery and starting adjuvant therapy. The committee agreed that for people starting adjuvant therapy, imaging should be repeated to exclude recurrence if recent imaging is not available. They agreed to define this as imaging done within the past 8 weeks, based on their experience and noting that 1 study had used a definition of 7.4 weeks.

Completion lymph node dissection

Evidence suggested that completion lymph node dissection for people with stage III melanoma does not improve survival or melanoma-specific survival when compared with routine surveillance, and that it is associated with an increased risk of lymphoedema. The committee concluded that the overall risks of completion lymph node dissection outweigh the benefits for most people, and agreed to amend the 2015 recommendation to reflect this. However, there is evidence of less nodal basin disease control in people who had SLNB and surveillance compared with people who had completion lymph node dissection. The committee acknowledged that certain factors can make it difficult to manage recurrent nodal disease. They therefore agreed that completion lymph node dissection may be considered for people with these factors.

SLNB (no recommendations)

There was no evidence on the benefit of SLNB for people with stage III melanoma and microsatellite lesions. The committee discussed the potential benefits and harms in the absence of evidence. They agreed that the presence of microsatellite lesions indicates that the melanoma has progressed beyond the lymph nodes and so would automatically become stage IIIB or IIIC disease without the need for SLNB.

The committee agreed that SLNB may sometimes be thought useful as a way of finding out whether the melanoma has spread to the lymph nodes. However, its prognostic utility in this context is unclear. The committee also agreed that most centres in the UK do not currently offer SLNB to people with stage III disease. Therefore they agreed not to make recommendations in this area.

Information and support for people who have had melanoma

The committee agreed, based on their experience, that the information given to people after treatment for melanoma varies, and that it is particularly important to give people details of a specialist skin cancer service that they can contact if they have questions or concerns after treatment. The committee agreed to retain the 2015 recommendation to provide psychosocial support and to include provision of advice in local follow-up policies. The committee noted the lack of evidence on the views of people who have had melanoma and made a recommendation for research on survivorship.

Exceptions to routine follow-up

Based on their experience, the committee agreed that people who have completed treatment for stage 0 melanoma can be discharged after a clinic visit for advice. They also identified groups who should be offered personalised follow-up, including people with unresectable melanoma and those at increased risk of further primary melanomas.

The committee also identified groups for whom MRI should be considered, as a substitute for CE-CT. See the rationale section on imaging during follow-up.

Frequency of follow-up

The committee sought to find a frequency of clinical follow-up that would balance the need for prompt identification of recurrence or progression with the need to reduce the burden of follow-up appointments for people with melanoma and avoid the costs of unnecessary follow-up.

Evidence showed that for stage IB to IIC disease, a lower frequency of follow-up visits did not increase mortality or cancer recurrence, or worsen quality of life. The committee therefore agreed to reduce the frequency of follow-up visits. They agreed to retain 4 visits per year for the first 2 years after stages IIB to IIC melanoma to coincide with their recommended imaging frequency, but to reduce this to 2 visits in year 3. Recommendations for clinic visits after resected stage III to IV disease were made to allow for a clinic visit after each imaging scan.

Imaging during follow-up

The committee agreed that CT scanning during follow-up after all stages of melanoma should include the head because of the frequency of brain metastases developing during follow-up. The committee considered that the radiation risk from exposure to ionising radiation during CE-CT scans was not serious. However, the committee agreed that brain MRI could be considered instead of CE-CT, if it is more suitable (for example, when there are high-risk factors associated with brain metastases or when MRI has been used in staging). This will reduce radiation exposure and potentially increase accuracy of assessing brain metastases. They noted that this should be after a discussion with the specialist skin cancer multidisciplinary team. The committee acknowledged the logistical difficulties and increased burden on MRI capacity of arranging separate CE-CT and MRI scans.

Evidence on stage III melanoma suggested that while PET-CT is more sensitive for detecting metastases compared with CE-CT it was not cost effective. The committee agreed that frequent imaging with CE-CT, particularly in the first 2 to 3 years when rates of recurrence are highest, will ensure timely identification of recurrences. The committee therefore agreed to recommend twice yearly imaging with CE-CT in the first 3 years, then once yearly in years 4 and 5. There was no evidence on CE-CT after stages IIB and IIC melanoma, but there was evidence suggesting a high risk of recurrence, particularly in stage IIC melanoma, that was worse than the risk of recurrence after stage IIIA disease. Based on this, the committee agreed that CE-CT imaging should be considered after stage IIB, and offered after stage IIC, at the same frequency as stage III.

The committee agreed that MRI should be offered for children and young adults having follow-up because of the cumulative risk of radiation associated with CE-CT scanning, and during pregnancy when CE-CT is undesirable.

Ultrasound scanning was shown by the evidence to be more sensitive than clinical examination and alternative imaging modalities (particularly CE-CT) for detecting local lymph node metastases. The committee agreed, based on their experience, that CE-CT alone can miss or delay detection of lymph node recurrences. However, there was no good quality evidence to show that ultrasound reduces mortality or time to recurrence in people with positive sentinel lymph nodes. Moreover, in current practice people with positive sentinel lymph nodes are offered frequent cross-sectional imaging and it is unclear whether ultrasound offers practical benefit above and beyond this imaging. This guideline does not recommend routine completion lymph node dissection, based on evidence comparing it with ultrasound scanning. However, there is no randomised controlled trial evidence comparing completion lymph node dissection with surveillance alone (with no ultrasound scanning). In addition, evidence suggested that most nodal recurrences develop within the first few years of diagnosis. The committee noted that nodal status is unknown in people who have not had an SNLB, and thus their staging is incomplete. Based on this, the committee agreed to recommend ultrasound surveillance for 3 years for people with a positive sentinel lymph node and those who were considered for but did not have an SLNB.

The committee acknowledged the practical implications of ultrasound imaging during follow-up, such as the capacity to provide increased numbers of scans and the variable experience of healthcare professionals involved in follow-up. They noted the need for more evidence to inform future guidance on follow-up after melanoma and made a recommendation for research on surveillance strategies.