Revised U.K. guidelines for the management of cutaneous melanoma 2010
Authors: J.R. Marsden, J.A. Newton-Bishop, L. Burrows, M. Cook, P.G. Corrie, N.H. Cox, M.E. Gore, P. Lorigan, R. MacKie, P. Nathan, H. Peach, B. Powell, C. Walker
Journal: British Journal of Dermatology (2010)

NHS Evidence has accredited the process used by the British Association of Dermatologists to produce guidelines. Accreditation is valid for three years from May 2010 and is applicable to guidance produced using the processes described in the British Association of Dermatologists' guidelines development manual (Bell & Ormerod, 2009). More information on accreditation can be viewed at http://www.evidence.nhs.uk.Disclaimer These guidelines reflect the best published data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations in this report. It may be necessary or even desirable to depart from the guidelines in the interests of specific patients and special circumstances. Just as adherence to the guidelines may not constitute defence against a claim of negligence, so deviation from them should not necessarily be deemed negligent. These guidelines are published simultaneously in the British Journal of Dermatology (DOI 10.1111/j.1365-2133.2010.09883.x) and the Journal of Plastic, Reconstructive & Aesthetic Surgery (DOI 10.1016/j.bjps.2010.07.006). These guidelines for the management of cutaneous melanoma present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiology, diagnosis, investigation and follow up. Contribution to these guidelines has been made by a large number of clinicians. They have also been endorsed by, or have had input from, representatives of the following groups or organizations: the U.K. Melanoma Study Group, the British Association of Dermatologists, the British Association of Plastic, Reconstructive and Aesthetic Surgeons, the Royal College of Physicians, London, the Association of Cancer Physicians, the Royal College of Radiologists, London, the Royal College of Surgeons of England, the Royal College of Pathologists (pathology section only), the Royal College of General Practitioners, London, and the Department of Health. These consensus guidelines have been drawn up by a multidisciplinary working party with membership drawn from a variety of groups and coordinated by the U.K. Melanoma Study Group and the British Association of Dermatologists. The guidelines deal with aspects of the management of melanoma from its prevention, through the stages of diagnosis and initial treatment to palliation of advanced disease. PubMed literature searches for this guidelines revision were carried out to identify publications from 2000 to April 2010, with search terms including: melanoma genetics, epidemiology, early diagnosis, risk factors, clinical features, pathology, surgery, chemotherapy and clinical trials. Relevant materials were also isolated from reviews and other publications identified from the PubMed searches, independent searches carried out by the authors, as well as materials collected by the authors as part of their ongoing professional interest in the latest developments in this clinical area. Levels of evidence to support the guidelines are quoted according to the criteria stated in Appendix 1. The consultation process for British Association of Dermatologists guidelines and their compliance with guideline recommendations have been published elsewhere.1, 2 There are arguments in favour of newer guideline grading methods, such as those of GRADE,3 but the authors believe that the system used here allows greater potential for consensus in areas of conflicting evidence or where evidence sources are not directly comparable. In some instances, this is not due to an absence of high quality (Level Ib) trials but because different entry criteria or endpoints preclude direct comparison of results; in other cases interpretation of the clinical significance of results has been challenged. To assist production of unified guidelines taking account of these issues, the ‘quality of evidence’ grading used in these guidelines differs slightly from that used in other British Association of Dermatologists current guidelines; the ‘strength of recommendations’ grading is the same as used in many other publications. Where no level is quoted the evidence is to be regarded as representing Level IV (i.e. a consensus statement). The intention of the working party was to agree best practice for the management of melanoma in the belief that this will promote good standards of care across the whole country. However, they are guidelines only. Care should be individualized wherever appropriate. These guidelines will be revised as necessary to reflect changes in practice in light of new evidence. Multidisciplinary care of the patient is held to be the most desirable model, as recommended in the Calman/Hine report.4 This has been defined by the National Institute for Health and Clinical Excellence (NICE) Improving Outcomes for People with Skin Tumours including Melanoma.5 Core services will be provided within each Cancer Network by Local Skin Cancer Multidisciplinary Teams (LSMDTs). Specialist services will be provided by Specialist Skin Cancer Multidisciplinary Teams (SSMDTs). For melanoma there is a clear demarcation of care such that more advanced primary melanoma, rare subtypes of melanoma, melanoma in children, and patients eligible for trial entry or sentinel lymph node biopsy (SLNB) should be promptly referred for investigation and treatment from an LSMDT to an SSMDT (Table 1). Individuals, and particularly children, should not get sunburnt (Level I).6-9 Meta-analysis of case–control studies provides good evidence that melanoma is caused predominantly by intermittent intense sun exposure; fair-skinned individuals should therefore limit their recreational exposure through life (Level I).10 People with freckles, red or blond hair, skin which burns in the sun, increased numbers of naevi, and those with a family history of melanoma are at increased risk and should heed this advice. Adequate sun exposure to allow vitamin D synthesis, or sufficient dietary intake of vitamin D3, is essential to human health; insufficiency of vitamin D is now recognized to be common.11 It would therefore be inappropriate to greatly limit sun exposure in people without the risk factors listed above. Recent studies have shown that in the U.K. vitamin D levels are often suboptimal in melanoma patients, and are lower in fair-skinned people.12, 13 Fair-skinned people who avoid the sun rigorously to reduce the risk of melanoma should consider supplementing their intake of vitamin D3 in the absence of medical contraindications. There is evidence from a recent meta-analysis that sunbed usage does increase the risk of melanoma, particularly under the age of 35 years, and therefore it is recommended that this should be avoided (Level Ia).14 Melanoma remains relatively uncommon and therefore the opportunity to develop diagnostic skills is limited in primary care. All lesions suspicious of melanoma should be referred urgently under the 2-week rule to local screening services usually run by dermatologists. In England and Wales, this would be to an LSMDT. In Scotland, referral should be made to a local Rapid Access Cancer Clinic according to Scottish Cancer Referral Guidelines. The seven-point checklist or the ABCD rule may be helpful in the identification of melanomas although they are more sensitive than specific.15-18 Urgent referral to the LSMDT is indicated where there is: • A new mole appearing after the onset of puberty which is changing in shape, colour or size • A long-standing mole which is changing in shape, colour or size • Any mole which has three or more colours or has lost its symmetry • A mole which is itching or bleeding • Any new persistent skin lesion especially if growing, if pigmented or vascular in appearance, and if the diagnosis is not clear • A new pigmented line in a nail especially where there is associated damage to the nail • A lesion growing under a nail Lesions which are suspicious for melanoma should not be removed in primary care. This is because clinicopathological correlation is vital for diagnostic accuracy, which in turn determines prognosis and defines adjuvant treatment options, and because diagnostic surgery requires specialist training. Early recognition of melanoma presents the best opportunity for cure15, 19-22 (Level III, Grade A). All patients presenting with an atypical melanocytic lesion or a large number of moles should have a complete skin examination and assessment of risk factors. The dermoscope is a useful tool for the trained clinician screening pigmented lesions, as it can increase diagnostic accuracy.23 It is also useful for monitoring multiple pigmented lesions where photography of dermoscopic images provides a record of change (Level Ia, Grade A). Recommendations for LSMDT record keeping of clinical features are provided in Table 2. There are some individuals at higher risk of melanoma who should be considered for referral to specialist clinics. These individuals can be divided broadly into two groups based upon the degree of risk: 1 Individuals at moderately increased risk (approximately 8–10 times that of the general population) should be counselled about this risk and taught how to self-examine for changing naevi, but long-term follow up is not usual. Such patients are those with either a previous primary melanoma or large numbers of moles, some of which may be clinically atypical (Level Ia, Grade B).24-28 Organ transplant recipients are also at this level of increased risk (Level III, Grade B).29, 30 2 Those at greatly increased risk of melanoma (more than 10 times that of the general population). Patients with a giant congenital pigmented hairy naevus (definitions include ‘20 cm or more in diameter’ and ‘5% of body surface area’) should be monitored by an expert for their life time because of the risk of malignant change, which is significant but poorly quantified (Level III, Grade B).31, 32 Excision biopsy of suspicious areas in large congenital naevi may be necessary but requires expert histopathological review. Patients with a strong family history of melanoma are also at greatly increased risk. In some families, most clearly in mainland Europe and North America, families at risk of melanoma are also at increased risk of pancreatic cancer.33 Those with three or more cases of melanoma or pancreatic cancer in the family should be referred to appropriate clinics managing inherited predisposition to cancer (involving dermatologists and/or clinical geneticists) for counselling. It is the consensus of the Melanoma Genetics Consortium (http://www.genomel.org) that it is premature to suggest gene testing routinely but this may change as more is known of the genes predisposing to melanoma.34 The risk to families associated with the presence of two family members affected with melanoma is lower. In these families, if affected individuals also have the atypical mole syndrome, or if there is a history of multiple primary melanomas in an individual or pancreatic cancer, then referral should also be made for counselling; otherwise family members should probably be considered at moderately increased risk. All of the above individuals at increased risk of melanoma should be advised on the specific changes that suggest melanoma and encouraged to undertake monthly skin self-examination (Level III, Grade B). Close-up and distant photography may be a useful adjunct to detecting early melanoma in either of these high-risk groups (Level III). They should be given written information and access to images of moles and melanomas. Such images are available at: http://www.genomel.org or http://www.rcplondon.ac.uk/pubs/contents/f36b1656-cc74-4867-8498-cc94b378312a.pdf. Recommendations for screening and surveillance of high-risk individuals are summarized in Table 3. A lesion suspected to be melanoma, or where melanoma needs to be excluded, should be photographed, and then excised completely. The axis of excision should be orientated to facilitate possible subsequent wide local excision; generally on the limb this will be along the long axis. If uncertain, direct referral to the multidisciplinary team (MDT) will allow appropriate planning for future surgery. The excision biopsy should include the whole tumour with a clinical margin of 2 mm of normal skin, and a cuff of fat. This allows confirmation of the diagnosis by examination of the entire lesion, such that subsequent definitive treatment can be based on Breslow thickness.35-37 Diagnostic shave biopsies should not be performed as they may lead to incorrect diagnosis due to sampling error, and make accurate pathological staging of the lesion impossible (Level III). For the same reasons partial removal of naevi for diagnosis must be avoided and partial removal of a melanocytic naevus may result in a clinical and pathological picture very like melanoma (pseudomelanoma). This gives rise to needless anxiety and is avoidable. Incisional or punch biopsy is occasionally acceptable, for example in the differential diagnosis of lentigo maligna (LM) on the face or of acral melanoma, but there is no place for either incisional or punch biopsy outside the skin cancer MDT (Level III). It is acceptable in certain circumstances to excise the lesion entirely but without repair, and to dress the wound while awaiting definitive pathology. Biopsies of possible subungual melanomas should be carried out by surgeons regularly doing so. The nail should be removed sufficiently for the nail matrix to be adequately sampled: clinically obvious tumour should be biopsied if present. Prophylactic excision of naevi, or of small (< 5 cm diameter) congenital naevi in the absence of suspicious features is not recommended (Level III, Grade D). Full clinical details should be supplied on the histopathology form, including history of the lesion, relevant previous history, site and differential diagnosis. All melanocytic lesions excised for whatever reason must be sent for histopathological review to the pathologist associated with the LSMDT or SSMDT. The diagnosis of melanoma, both in situ and invasive, should be given or supervised by doctors who have received advanced communication skills training, following local policies for breaking bad news. A skin cancer trained nurse should be present to provide continuing support. The Royal College of Pathologists has produced a minimum dataset which should be included in the histopathology report.38 Double reporting is recommended for all melanomas and all naevi showing severe dysplasia if resources allow this to be achieved within 14 days.5 The report should include the following: • Site of the tumour • Type of surgical procedure: excision or re-excision, incision biopsy, punch biopsy • Any other relevant clinical information Contour, colour and size of the tumour and the excised skin specimen in millimetres. Presence or absence of ulceration Ulceration has prognostic value, and its presence should be confirmed microscopically as full-thickness loss of epidermis with reactive changes which include a fibrinous exudate and attenuation or acanthosis of the adjacent epidermis. These distinguish true ulceration from artefact.39 Thickness The tumour should be measured from the granular layer of the overlying epidermis to the deepest cells in the dermis judged to be malignant, to the nearest 0·1 mm. Ulcerated tumours should be measured from the base of the ulcer. Tumour forming a sheath around appendages should be excluded when measuring thickness except when the melanoma extends out into the adjacent reticular dermis when it should be measured in the conventional manner. In the presence of histological regression thickness measurements should be of the residual melanoma. Microsatellites should not be included in thickness measurements (Level III, Grade B). Mitotic count The number of mitoses has prognostic value and is now included in the American Joint Committee on Cancer (AJCC) staging system for melanomas ≤ 1·0 mm.40, 41 It should be recorded as number of mitoses mm−2 in the area of greatest number of mitoses in the vertical growth phase (VGP). It has prognostic value at all thicknesses. Histological subtypes Desmoplastic melanoma with or without neurotropism should be recorded because of its different biological behaviour and clinical outcome.42 The subtypes superficial spreading, nodular, LM and acral lentiginous melanomas have good clinicopathological correlation, but their prognostic value has not been established. Margins of excision This indicates whether excision is complete and the minimum margin of excision to peripheral and deep aspects measured in millimetres. If the excision or re-excision is not complete, whether the tumour is in situ or invasive at the resection margin should be indicated. When possible a statement should be made of whether the lesion is primary or secondary melanoma. Pathological staging Staging using TNM and AJCC (Table 4), and coding, e.g. SNOMED, should be given.41 Growth phase Invasive melanoma without a VGP is termed microinvasion.43 The assessment of microstaging criteria should be applied to the VGP only. Regression The presence or absence of tumour regression has not been shown consistently to affect long-term outcome. Until its relevance is clear it should be reported as segmental replacement of melanoma by fibrosis, as this is subject to less observer variation.44 Tumour-infiltrating lymphocytes It remains unclear whether tumour-infiltrating lymphocytes have prognostic value.40 The categories absent, non-brisk and brisk are subject to wide observer variation. ‘Absent’ indicates no lymphocytes infiltrating among the tumour cells, but does not exclude lymphocytes in the surrounding dermis. ‘Non-brisk’ is a patchy or discontinuous infiltrate either among the peripheral cells or in the centre of the tumour, whereas ‘brisk’ is a continuous infiltrate but may be confined to peripheral cells. These are qualified as mild, moderate or severe in intensity. Lymphatic or vascular invasion Vascular or lymphatic infiltration has prognostic value, and its presence should be recorded even though it is infrequently observed.45 Perineural infiltration Perineural infiltration occurring beyond the main bulk of the tumour correlates with increased local recurrence. It is most commonly associated with desmoplastic melanoma.46 Microsatellites These are defined as islands of tumour > 0·05 mm in the tissue beneath the main invasive mass of melanoma, but separated from it by 0·3 mm of normal collagen (i.e. not tumour stroma or sclerosis of regression).47 Current AJCC staging also requires that satellites must be intralymphatic, which has not previously been required; this may be subject to revision. Microsatellites are predictive of regional lymph node metastases; this is reflected by stage N2c. Precursor naevus The presence of contiguous melanocytic naevus should be recorded. Clark level of dermal invasion This is a less reliable indicator of prognosis than thickness and is subject to poor observer agreement. It is not used to define T1 melanomas in the 2009 AJCC staging system, except that Clark levels IV or V may be used for defining T1b melanoma in rare instances when mitotic count cannot be determined in a nonulcerated T1 melanoma. These are given in Table 5. It may not be possible to distinguish pathologically between a melanoma and a benign melanocytic lesion. Such patients must be referred to the SSMDT for clinical and pathological review. A decision to treat as a melanoma should be made by the SSMDT in discussion with the patient. Thickness should be measured as for melanoma. This needs to be done in a standardized way so that findings between centres are comparable (Level III, Grade B). The dissection should be either by bivalving or multiple slicing, although the former is recommended.48-50 A minimum of six serial sections should be taken, but a higher incidence of metastases is detected by extended step sectioning with immunohistochemistry at each level. The clinical relevance of the smaller metastases detected by these extended procedures is still unclear. Use of haematoxylin and eosin and immunohistochemistry is essential. S100 and Melan A are most favoured immunohistochemical stains but a composite method such as PanMel is also appropriate. This gives additional prognostic information. The following are recommended: Assessing the depth of the metastasis from the inner aspect of the sentinel lymph node capsule; categorizing the metastasis according to its site, either subcapsular or parenchymal; measuring the maximum dimension of the largest confluent group of melanoma cells.50-52 The pathological examination of regional nodes dissected following positive SLNB should include an attempt to examine all lymph nodes at least at one level, and count the number involved. The presence of extracapsular spread and involvement of perinodal fat should be recorded together with the size of the tumour-free margin. The use of immunohistochemistry such as S100 or Melan A facilitates this. Routine investigations are not required for asymptomatic patients with primary melanoma. Blood tests are unhelpful. Routine computed tomography (CT) is not recommended for patients with stage I and II melanoma as this has a very low incidence of true-positive and high incidence of false-positive findings. Patients with particularly high-risk primary melanoma may undergo staging investigations if deemed appropriate by the SSMDT and/or as a prerequisite to trial entry. There is no indication for routine imaging with any other modality including plain X-ray, positron emission tomography (PET)/CT and magnetic resonance imaging (MRI). PET/CT is not effective in detecting positive sentinel lymph nodes and/or distant metastases in patients with primary melanoma53-58 (Level IIa, Grade E). SLNB, as discussed later, has high sensitivity and specificity for diagnosing subclinical regional lymph node involvement. Ultrasound and fine needle aspiration cytology (FNAC) is the next best method but quoted sensitivities range from 4·7% to 80%, with the higher sensitivities being achieved only by sentinel node mapping and FNAC of the sentinel node in all cases regardless of morphological appearance.59-62 Further staging by CT imaging following a positive sentinel lymph node, and prior to completion lymphadenectomy, has a very low yield.63-65 Consequently this should be done only after discussion with an informed patient and the SSMDT (Level IIa, Grade D). In stage III and IV melanoma, imaging strategies will be planned by the SSMDT. CT scanning of the head, chest, abdomen and pelvis will normally adequately exclude metastases, and is most relevant in stage III melanoma before planning regional lymph node dissection (LND) and regional chemotherapy. If patients are considering entry to an adjuvant study following lymphadenectomy, the timing of scans should be determined by the SSMDT to avoid duplication. When stage IV disease is suspected clinically, CT scanning of the head and whole body should be considered. Further imaging will be determined by symptoms, clinical trial protocols, and for clarification or reassessment of previous imaging findings. Generally, the added yield of PET/CT is unlikely to be clinically relevant in established stage IV melanoma (Level III, Grade D). Where metastasectomy is planned, PET/CT may be useful in excluding disease that might make surgery inappropriate. Serum lactate dehydrogenase (LDH) should be measured in all patients with suspected stage IV melanoma. There is no indication for a bone scan in staging except where symptoms point to possible bone disease. Staging investigations are summarized in Table 6. Surgery is the only curative treatment for melanoma. Following excision for diagnosis and for measurement of microscopic Breslow thickness, a wider and deeper margin is taken to ensure complete removal of the primary lesion, and to remove any micrometastases. The depth of the therapeutic excision has conventionally been to the muscle fascia or deeper, and there is no evidence to support altering this approach. Lateral surgical excision margins for invasive melanoma depend on Breslow thickness and are based on five randomized controlled trials (RCTs) including about 3300 patients, and a National Institutes of Health Consensus Panel.66-73 However, only one of these studies is adequately powered, and two provide little scope for detecting reduced disease-free or overall survival due to narrow margins.68, 69, 71 Most exclude melanoma on the head and neck and/or extremities.74 A recent systematic review estimated overall survival in favour of wide excision (hazard ratio 1·04; 95% confidence interval 0·95–1·15; P = 0·40), although the difference was not significant. Therefore a small, but potentially important, difference in overall survival between wide and narrow excision margins cannot be confidently ruled out. Current randomized trial evidence is insufficient to address optimal excision margins for primary cutaneous melanoma.75 The recommended surgical margins are those measured clinically at the time of surgery, but adequacy of excision should be subsequently confirmed by review of re-excision histology, making an adjustment for average shrinkage of 20%.76 The final decision about the size of the margin should be made by the MDT, after discussion with the patient. The recommendation should be made with consideration of functional and cosmetic implications of the margin chosen. All patients with primary melanoma stage IB and higher should be referred before treatment to an SSMDT when this provides an SLNB service. When the SSMDT does not provide this, all primary melanomas stage IIB or IIC should be referred. There are no RCT data for margin size for LM or other in situ melanoma. LM and other in situ melanomas have no potential for metastatic spread and the aim should be to excise the lesion completely with a clear histological margin, although margin size remains undefined. No further treatment is then required. LM is best treated by complete excision because of the risk of subclinical microinvasion. This may be missed on incisional biopsy due to sampling error.73 The risk of progression to invasive melanoma is poorly quantified, and in the very elderly may be unlikely within their lifespan. Therefore, for some particular clinical situations, treatment by other methods such as radiotherapy, or observation only may be appropriate.77-81 There is little evidence to support the use of cryotherapy, and this treatment may make subsequent progression difficult to detect. Topical treatment with imiquimod is as yet of unproven value so should be used only in the context of a clinical trial.82 If the patient with LM is treated by nonsurgical means then the reason for this choice should be discussed and clearly documented by the MDT. Local recurrence of LM occurs in about 5% of patients by 2 years.77 Excision with micrographic control of surgical margins should be considered, although histological clearance is often difficult to define.83In situ melanoma on acral and genital skin is also associated with a higher risk of local recurrence, but this is less common in other types of in situ melanoma. In theory, in situ melanoma should not metastasize, but occasional cases do recur. This may be due to histological regression obscuring a more advanced tumour, missed microinvasion, or progression after incomplete removal of in situ disease. There have been three RCTs of patients with melanomas in this thickness band.66, 68, 69, 73 The recommended surgical margins are based on the World Health Organization (WHO) Melanoma Co-operative Group Trial 10.66, 73 This randomized trial compared 1 and 3 cm margins for melanomas up to 2 mm thick. No local metastases, and similar overall survival, were seen in patients with melanomas < 1 mm in depth with either excision margin. However, this was based on analysis of data from only 359 patients. The French and Swedish studies compared 2 cm with 5 cm margins, and the latter included only patients with melanomas 0·8 mm or more in thickness in this group.68, 69 A 1 cm margin is deemed safe for this group (Level Ib, Grade A). There have been four randomized studies that have included patients in this category. The WHO study showed a small excess of local metastasis as first site of relapse in the 1 cm margins group.66, 73 There was no difference in overall survival between 1 and 3 cm margins but the study was inadequately powered to detect this. The Intergroup Melanoma Trial compared 2 vs. 4 cm margins of excision for lesions of 1–4 mm in thickness.67, 70 No difference was seen between the two groups in either local recurrence or survival. Two other studies have included patients with melanomas up to 2 mm, also treated with either 2 or 5 cm margins.68, 69 There was no difference in outcome between the groups. The 1 vs. 3 cm, 2 vs. 4 cm and 2 vs. 5 cm studies cannot be compared directly, but no study using 2 cm margins as one comparator has shown any advantage of wider margins than this. However, trials of narrower margins have either not been performed (e.g. 1 vs. 2 cm margins) or have been underpowered, and do not permit a definite conclusion that a 1 cm margin is adequate. Evidence to date shows that a minimum margin of 1 cm is required, although 2 cm margins are equally appropriate. The final decision will be determined by anatomical site, MDT review, and after discussion with an informed patient (Level Ib, Grade A). The Intergroup Melanoma Trial showed no difference in rates of local metastasis between patients treated with 2 cm, and those treated with 4 cm margins.67 However, longer follow up showed reduced overall survival in the 2 cm margins group, although this