Revised U.K. guidelines for the management of cutaneous melanoma 2010

Abstract

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 (i.e. not tumour or of AJCC staging also requires that must be which has not been this may be subject to Microsatellites are of lymph node this is by naevus The presence of melanocytic naevus should be level of invasion This is a less of prognosis than thickness and is subject to observer It is not used to melanomas in the AJCC staging except that levels IV or may be used for melanoma in rare when count be in a melanoma. These are given in Table It may not be possible to distinguish a melanoma and a melanocytic Such patients must be referred to the SSMDT for clinical and pathological review. A to as a melanoma should be made by the SSMDT in with the Thickness should be measured as for melanoma. This needs to be in a so that are (Level III, Grade B). The should be either by or multiple although the is A minimum of should be but a higher of is by with at each The clinical relevance of the by these is of and and is and A are most but a such as is also appropriate. This gives prognostic The following are the of the from the of the sentinel lymph node the according to its either or measuring the of the of melanoma The pathological examination of following should include an to all lymph at at and count the number The presence of and of should be recorded with the size of the The of such as or A are not for patients with primary melanoma. are is not recommended for patients with and melanoma as this has a very of and high of Patients with particularly high-risk primary melanoma may staging if deemed appropriate by the SSMDT and/or as a to trial There is no for with other including and is not in detecting sentinel lymph and/or distant in patients with primary (Level Grade as has high and for lymph node and is the best but quoted from to with the higher achieved by sentinel node and of the sentinel node in all cases of staging by following a sentinel lymph and to has a very this should be after with an patient and the SSMDT (Level Grade D). In and IV melanoma, will be by the SSMDT. of the and will adequately exclude and is most relevant in melanoma planning lymph node and If patients are entry to an adjuvant following the of should be by the SSMDT to avoid When IV is suspected of the and whole body should be will be by clinical trial and for or of previous the of is to be clinically relevant in IV melanoma (Level III, Grade D). Where is may be useful in that make surgery should be measured in all patients with suspected IV melanoma. There is no for a in staging except where to possible disease. Staging are summarized in Table Surgery is the treatment for melanoma. excision for diagnosis and for of Breslow a and margin is to complete removal of the primary lesion, and to The of the excision has been to the or and there is no evidence to support this surgical excision for invasive melanoma on Breslow thickness and are based on trials including about patients, and a National of Health However, of these studies is adequately and two provide for detecting or due to exclude melanoma on the and and/or A recent review in favour of wide excision although the was not a but in wide and excision be trial evidence is to excision for primary cutaneous The recommended surgical are those measured clinically at the time of surgery, but of excision should be confirmed by review of re-excision an for of The about the size of the margin should be made by the after with the The should be made with of and of the margin All patients with primary melanoma and higher should be referred treatment to an SSMDT when this provides an When the SSMDT does not provide all primary melanomas or should be There are no data for margin size for LM or other in situ melanoma. LM and other in situ melanomas have no potential for and the should be to excise the lesion with a clear histological although margin size remains treatment is then LM is best by complete excision because of the risk of This may be on incisional biopsy due to sampling The risk of to invasive melanoma is poorly and in the very may be within their for some clinical treatment by other such as or may be There is evidence to support the of and this treatment may make subsequent to treatment with is as of value so should be used in the of a clinical If the patient with LM is by then the reason for this should be and clearly by the Local of LM in about of patients by 2 Excision with of surgical should be although histological is often to situ melanoma on acral and skin is also associated with a higher risk of local but this is less in other of in situ melanoma. In in situ melanoma should not but cases This may be due to histological regression a more advanced tumour, or after removal of in situ disease. There have been three of patients with melanomas in this thickness The recommended surgical are based on the Health Melanoma Group This trial 1 and cm for melanomas up to 2 mm local and were in patients with melanomas 1 mm in with either excision However, this was based on of data from The and studies 2 cm with 5 cm and the included patients with melanomas mm or more in thickness in this A 1 cm margin is deemed for this (Level Grade A). There have been studies that have included patients in this The a small of local as site of in the 1 cm There was no in 1 and cm but the was to The Melanoma 2 cm of excision for lesions of mm in was the two groups in either local or other studies have included patients with melanomas up to 2 also with either 2 or 5 cm There was no in the The 1 2 cm and 2 5 cm studies be but no using 2 cm as has shown of than However, trials of have either not been performed 1 2 cm or have been and not a that a 1 cm margin is Evidence to that a minimum margin of 1 cm is although 2 cm are appropriate. The will be by MDT and after with an patient (Level Grade A). The Melanoma no in of local patients with 2 and those with cm However, follow up in the 2 cm although this