A national clinical guideline by kuyu3000123



Scottish Intercollegiate Guidelines Network

 72         Cutaneous Melanoma
            A national clinical guideline

                            1    Introduction                                       1
                            2    Prevention, surveillance and genetics              3
                            3    Diagnosis and prognostic indicators                7
                            4    Surgical management and staging                    16
                            5    Further investigations and non-surgical staging    21
                            6    Adjuvant treatment of stage II and III disease     22
                            7    Patient follow up in stage I, II and III disease   23
                            8    Management of stage IV disease                     27
                            9    Melanoma in women                                  31
                            10   Information for patients                           32
                            11   Implementation and audit                           39
                            12   Development of the guideline                       42
                                 References                                         45

                                                                            July 2003


1++      High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs),
         or RCTs with a very low risk of bias
1+       Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low
         risk of bias
1-       Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2   ++
         High quality systematic reviews of case control or cohort studies
         High quality case control or cohort studies with a very low risk of confounding or bias
         and a high probability that the relationship is causal
2+       Well conducted case control or cohort studies with a low risk of confounding or bias
         and a moderate probability that the relationship is causal
2-       Case control or cohort studies with a high risk of confounding or bias
         and a significant risk that the relationship is not causal
3        Non-analytic studies, e.g. case reports, case series
4        Expert opinion


Note: The grade of recommendation relates to the strength of the evidence on which the
recommendation is based. It does not reflect the clinical importance of the recommendation.

    A    At least one meta-analysis, systematic review of RCTs, or RCT rated as 1++
         and directly applicable to the target population; or
         A body of evidence consisting principally of studies rated as 1+, directly applicable to
         the target population, and demonstrating overall consistency of results

    B    A body of evidence including studies rated as 2++, directly applicable to the target
         population, and demonstrating overall consistency of results; or
         Extrapolated evidence from studies rated as 1++ or 1+

    C    A body of evidence including studies rated as 2+, directly applicable to the target
         population and demonstrating overall consistency of results; or
         Extrapolated evidence from studies rated as 2++

    D    Evidence level 3 or 4; or
         Extrapolated evidence from studies rated as 2+


    þ    Recommended best practice based on the clinical experience of the guideline
         development group

© Scottish Intercollegiate Guidelines Network
ISBN 1 899893 88 1
First published 2003
SIGN consents to the photocopying of this guideline for the
purpose of implementation in NHSScotland
Scottish Intercollegiate Guidelines Network
Royal College of Physicians
9 Queen Street
Edinburgh EH2 1JQ

                     http://chn-health.com                                                         1 INTRODUCTION

1     Introduction
      Cutaneous melanoma, previously referred to as cutaneous malignant melanoma, is a malignant
      tumour of cutaneous melanocytes. The incidence of melanoma has been increasing rapidly for
      the last few decades in most parts of the world. The reasons for this are not clear although the
      role of sunlight exposure is widely accepted.
      The epidemiology of cutaneous melanoma in Scotland has been described in detail elsewhere.1
      Currently, over 600 cases of invasive disease are diagnosed in Scotland every year. Between 1979
      and 1998, age-standardised incidence rates increased from 3.5 to 10.6 per 100,000 in males, and
      from 7.0 to 13.1 in females. After 1995, the rate of increase levelled out in females younger than
      65 years at diagnosis. Between the years of diagnosis 1979 and 1993, five year survival increased
      from 58% to 80% in males, and from 74% to 85% in females. Most of this improvement in
      prognosis was attributable to a higher proportion of thinner tumours.
      Although melanoma is the major cause of skin cancer mortality, it is usually curable, if recognised
      and treated at an early stage. The visibility of the vast majority of melanomas makes them
      accessible tumours. There is variation in approaches to all stages of melanoma management in
      Scotland. Surgical management of the primary lesion has changed considerably over time.
      Melanoma in its later stages remains relatively resistant to currently available treatments.
      Considerable efforts have been made to encourage increased public and professional awareness
      of melanoma in recent years.

      Many specialties and professions are involved in the management of patients with melanoma.
      This guideline provides advice at all stages of the patient’s pathway of care, from primary prevention
      to early recognition, treatment and follow up. The guideline covers both established management
      techniques and newer approaches such as sentinel node biopsy. It does not address melanomas
      of non-cutaneous origin such as melanomas arising from mucosae, ocular melanomas and other
      rare non-cutaneous sites.
      The guideline should be of interest and relevance to primary care providers, dermatologists,
      surgeons, pathologists, medical and clinical oncologists, public health physicians, nurses, health
      promotion professionals and epidemiologists.


      i      Effective communication and appropriate information giving are integral components of
             high quality patient care. The guideline highlights the points throughout the journey of
             care when patients should routinely be given information about their care and the services
             available to them.

      This guideline is not intended to be construed or to serve as a standard of medical care. Standards
      of care are determined on the basis of all clinical data available for an individual case and are
      subject to change as scientific knowledge and technology advance and patterns of care evolve.
      These parameters of practice should be considered guidelines only. Adherence to them will not
      ensure a successful outcome in every case, nor should they be construed as including all proper
      methods of care or excluding other acceptable methods of care aimed at the same results. The
      ultimate judgement regarding a particular clinical procedure or treatment plan must be made by
      the doctor, following discussion of the options with the patient, in light of the diagnostic and
      treatment choices available. It is advised however that significant departures from the national
      guideline or any local guidelines derived from it should be fully documented in the patient’s
      case notes at the time the relevant decision is taken.

CUTANEOUS MELANOMA   http://chn-health.com

        This guideline was issued in 2003 and will be considered for review as new evidence becomes
        available. Any updates to the guideline will be noted on the SIGN website: www.sign.ac.uk

                                   2 PREVENTION, SURVEILLANCE AND GENETICS

2     Prevention, surveillance and genetics
      Melanoma, especially when diagnosed at an advanced stage, can cause serious morbidity and
      may be fatal despite treatment. Prevention of the disease, or failing that, minimising its
      consequences by early detection, are key goals.

      A comprehensive review of evidence by the International Agency for Research on Cancer (IARC)
      has concluded that solar radiation is a cause of melanoma.2
      Two more recent systematic reviews focussed on the relationship between patterns of sun exposure
      and risk of melanoma. The first was a high quality review of case control studies which concluded
      that intermittent unaccustomed exposure was more important than age at sunburn.3 The second
      study was a review of ecological and case control studies and concluded that exposure to high          2++
      levels of sunlight in childhood is a strong determinant of risk, but that exposure in adulthood
      also plays a part.4
      The contribution of specific wavelength bands and the action spectrum for melanoma induction
      are unknown.3 Sunburn is mainly due to UVB (280 to 320 nm) radiation, implicating UVB as a
      contributing factor to the pathogenesis of melanoma. There is accumulating evidence for the role
      of UVA (and sunbeds) in the pathogenesis of melanoma.5

      Primary prevention is defined as prevention targeted towards the general population.
      There is indirect evidence that sun avoidance and other sun-protective measures (eg clothing,
      hats and opaque sunscreens) are likely to reduce the risk of melanoma. Sunscreen effectiveness is
      difficult to demonstrate for a number of reasons. High risk individuals are more likely to use
      sunscreen, although sunscreen use may be associated with greater sun exposure.6,7 It may be that
      sunscreens offer a false sense of security and lead to increased time spent in the sun. 6,7 Most
      sunscreens offer greater protection from UVB, reducing the risk of sunburn, but not of exposure        2++
      to UVA. 6,7 Some ingredients found in sunscreens may be carcinogenic.6,7 Case control studies and
      clinical trials have shown no reduction or increase in melanoma incidence with broad spectrum
      sunscreen use. Little is known about the potential long term effects of sunscreen use.6,7 Given
      these potentially adverse effects of sunscreens in relation to risk of melanoma, physical protection
      measures should be regarded as more important than sunscreen use.6,7
      There may be theoretical risks associated with sun avoidance,8 eg a lack of vitamin D, but the
      balance of evidence in terms of risks and benefits favours a cautious approach to sun exposure. In
      the absence of evidence to support recommendations about specific aspects of protection measures       4
      in Scotland, the advice below is based on the Australian guidelines on melanoma, interpreted in
      the light of the Scottish climate.9
      Table 1 : Prevention of Melanoma
      n  Use clothing as the primary means of protecting against the sun
      n  People of fair complexion should be especially careful about sun exposure
      n  Avoid using sunbeds, tanning booths, and tanning lamps as an increased risk has been reported
         in some studies5
      n  Use broad spectrum sunscreens with a minimum sun protection factor (SPF) of 15 as an
         adjunct to sun avoidance and other sun protective measures, providing this does not lead to
         increased time spent in the sun
      n  Avoid exposure to direct, intense sunlight, especially around midday (eg seek out shade)
      n  Provide children with appropriate sun protection for outdoor activities.

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         As melanoma is potentially preventable, educating the general public might be an important
         preventive measure. Six randomised controlled trials (RCTs) of interventions aimed at a variety of
         target groups including the general public, employees and school children were identified.10-
            All interventions were in some part reliant on brochures and leaflets to deliver preventive             1+
         information. Leaflets significantly increased short term user-knowledge of sun awareness measures,
         and assisted in the early detection of melanoma (see also section 2.4.4). The tone of a leaflet or
         educational brochure is important when delivering health promotion messages relating to sun
         awareness and should be non-alarmist.11
         Two observational studies suggest that interactive computer-based educational packages may
         result in higher short term knowledge gain (sun awareness) when compared to non-interactive
         packages.16,17 A retrospective cohort study of French primary school children found that health            2+
         education programmes could improve the knowledge, attitude and behaviour of young children.
         Children with a fair complexion (the target of this campaign) showed the best improvement in
         their responses.18
         Leaflets, brochures and educational packages can significantly influence increased short term
         user-knowledge of sun awareness measures, and can assist in the early detection of melanoma
         (see also section 2.4.4). Insufficient evidence was identified to enable recommendations to be
         made about the style or content of leaflets and brochures.

          D     Brochures and leaflets should be used to deliver preventive information on melanoma to
                the general public.

          þ     Leaflets and brochures used in melanoma prevention work should be non-alarmist.

          þ     If computer-based learning programmes are used they should be interactive in nature.


         A review of the literature on the reliability and usefulness of risk-assessment tools suggests that
         patients can count the number of moles 5 mm or larger in reasonable agreement with physicians,             2++
         but that they cannot accurately distinguish atypical moles from others.19 No longitudinal studies
         of the use of risk-assessment tools in primary care were identified.
         A cross-sectional study that sent postal questionnaires to a random sample of households from a
         general practice population found that self assessment of risk was generally poor compared with            3
         the assessment of a dermatologist, suggesting that it might be very difficult to identify systematically
         a high risk population suitable for screening. 20
         An RCT carried out in 11 communities in Western Australia showed that targeted advertising can
         increase the yield of individuals with a higher prevalence of risk factors.21 This may not be              1+
         immediately transferable to Scotland, where disease prevalence is lower and baseline awareness
         may be lower.

         Risk factors for melanoma have been identified mainly from case control studies (see Table 2).
         The strength of a risk factor is usually expressed in terms of an “odds ratio” (OR). In the context
         of this guideline, the OR is the ratio of the odds in favour of exposure to a risk factor in people
         with melanoma to the odds in favour of exposure to the same risk factor among people who have
         not developed melanoma. For relatively rare diseases such as melanoma, the OR can be thought
         of as being equivalent to the relative risk, that is, the ratio of the incidence rate of melanoma
         among exposed individuals to the incidence rate among unexposed individuals. The higher the
         OR (or relative risk), the stronger the association between the risk factor and melanoma. This is
         important from the perspective of an individual, but from a public health perspective a lower OR
         for a commonly occurring risk factor may be more important than a higher OR for a risk factor
         which occurs rarely in the population.

                            2 PREVENTION, SURVEILLANCE AND GENETICS

Table 2: Established risk factors for cutaneous melanoma

Risk factor                           OR*          Information

11-50 common moles >2mm               1.7-1.9      The risk of melanoma rises with the
                                                   number of common moles.19
51-100 common moles >2mm              3.2-3.7
>100 common moles >2mm                7.6-7.7
Family history of melanoma            1.8          Melanoma in a first degree family
                                                   member (parent, sibling or child of the
                                                   patient; see section 2.5).19
Previous history of melanoma                       Standardised incidence ratio range
                                                   4.5 - 25.622 (see section 7.8).
The presence of 1-4 atypical moles.   1.6-7.3      Atypical moles: ill-defined or irregular
                                                   border; irregular pigmentation; diameter
                                                   >5 mm; erythaema (blanchable in lesion or
                                                   at edge); accentuated skin markings.19
Red or light-coloured hair19          1.4-3.5
Presence of actinic lentigines   19
                                      1.9-3.5      Actinic lentigines: flat, brown skin lesions
                                                   associated with acute and chronic sun
                                                   exposure. No direct malignant potential.
Giant congenital melanocytic                       Relative risk range 239-1,224 for
naevi ≥ 20 cm in diameter                          extracutaneous as well as cutaneous
                                                   melanoma. 23,24
Unusually high sun exposure19         2.6
Reported growth of a mole   19
Skin that does not tan easily19       1.98
Light coloured eyes 19
Light coloured skin19                 1.40-1.42
Affluence                                          Relative risk approximately 3.0 for people
                                                   residing in areas defined as Carstairs
                                                   deprivation category 1 (least deprived)
                                                   compared to Carstairs category 7 (most
Female sex                                         Female:male ratio of age-standardised
                                                   incidence rates is approximately 1.3:1.0.25
Age                                                Melanoma is rare in absolute terms in
                                                   childhood and adolescence but risk begins
                                                   to increase with age during adolescence, the
                                                   elderly being at highest risk.25 The validity of
                                                   some risk factors, such as hair colour and sun
                                                   exposure, is lower in the elderly.19
*OR = odds ratio. In some cases the range of ORs from more than a single study are given.
eg A person with skin that does not tan easily has an approximately twofold (1.98 times) risk of
developing melanoma compared to someone with skin that tans (after allowing for other risk
factors). This is modest in comparison, for example, to the approximately 10-fold or greater risk
of developing lung cancer in someone who smokes cigarettes compared to a person who has
never smoked.27

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         Results from a Scottish cohort study suggest that surveillance of individuals at higher risk, once
         identified, can lead to early diagnosis of thin lesions. The cost effectiveness of this approach is   2+

         A study in the west of Scotland suggested that a public education campaign and rapid referral
         system to encourage earlier detection of melanoma could result in sustained decreases in the rate
         of diagnosis of thick melanomas (>3.5mm) and mortality in females, but not in males.29 This           3
         contrasts with the results of the Cancer Research Campaign Mole Watcher Study that did not
         find lower cumulative mortality from melanoma in regions exposed to a health education
         intervention compared to non-intervention regions.30
         The available evidence is insufficient to recommend for or against the routine screening of
         individuals at higher risk of melanoma. Interventions to promote the awareness of risk factors
         and skin self awareness are probably warranted.

          B     Healthcare professionals and members of the public should be aware of the risk factors
                for melanoma.

          C     Individuals identified as being at higher risk should be
                n  advised about appropriate methods of sun protection
                n  educated about the diagnostic features of cutaneous melanoma
                n  encouraged to perform self examination of the skin.

         No randomised controlled trials on mass screening were identified. Two American systematic
         reviews of screening for melanoma (and other skin cancers) have identified observational data to      2++
         suggest that screening in high risk groups might be effective. 19,31

          þ     A formal programme of mass screening for melanoma in Scotland is not recommended.

 2.5     GENETICS
         A recent consensus document estimated that one to two percent of melanomas were attributable
         to the inheritance of melanoma susceptibility genes.32 The document also estimates that a similar
         percentage of melanoma patients come from “melanoma prone” families with three or more first
         degree relatives with melanoma.
         Members of such families are at significantly increased risk of developing melanomas. Many
         more melanoma patients have only one relative who also has melanoma.33 An intensive search
         for putative melanoma susceptibility genes has identified mutations in the CDKN2A gene in 20-         4
         30% of melanoma prone families in Scotland, reflecting rates reported in other parts of the
         world.34 -37 This mutation is less frequently found in families with only two affected members.
         Mutations in the CDK4 gene have been found in only three families and it is likely that there are
         as yet unidentified melanoma susceptibility genes. Current expert consensus recommends that
         genetic testing in familial or sporadic melanoma is not appropriate in a routine clinical setting
         and should only be undertaken in the context of appropriate research studies and when appropriate
         counselling services are available.38

          D     Genetic testing in familial or sporadic melanoma is not appropriate in a routine clinical
                setting and should only be undertaken in the context of appropriate research studies.

                                     3 DIAGNOSIS AND PROGNOSTIC INDICATORS

3       Diagnosis and Prognostic Indicators
        The vast majority of melanomas are visible, if not to the patient, then at least to friends, family
        or health professionals. Members of the general public and health professionals should be aware
        of the signs suggestive of melanoma. In Scotland, melanomas occur more commonly in women
        than men. The most frequent site is the leg for women and the trunk in men. A small number of
        patients have occult primary lesions and present with metastatic disease. Up to ten percent of
        melanomas can be amelanotic (non-pigmented), increasing diagnostic difficulty.

        Melanomas are subdivided into types on the basis of clinical features and pathology.

        This is the most frequently encountered type of melanoma; characteristically an asymmetrical
        pigmented lesion with irregular borders, irregular pigmentation and sometimes an irregular outline.
        Patients may have noted growth, a change in sensation and/or colour, crusting, bleeding or
        inflammation of the lesion. The duration of the symptoms varies from a few months to several

        The second most common type is nodular melanoma. This usually has a shorter presentation and
        a greater tendency to bleed and/or ulcerate.

        The next in frequency is the type that occurs most often in sun damaged skin on the head and
        neck of older patients. This is the only variety that has a clearly recognised and often lengthy pre-
        invasive (in situ) lesion termed Lentigo Maligna (LM) before progressing in some instances to an
        invasive melanoma (LMM).

        The least common type of melanoma in Scotland is the acral lentiginous melanoma. This occurs
        on sites including the palms, soles and beneath the nails.

        Suspicious pigmented lesions are best examined in a good light with or without magnification
        and should be assessed using the 7 point checklist or ABCDE systems given below.39,40 The
        presence of any major feature in the 7 point checklist, or any of the features in the ABCDE             4
        system, is an indication for referral. The presence of minor features should increase suspicion. It
        is accepted that some melanomas will have no major features.
        Table 3: The 7 point checklist lesion system
        Major features                             Minor features
        n   change in size of lesion               n   inflammation
        n   irregular pigmentation                 n   itch/altered sensation
        n   irregular border                       n   lesion larger than others
                                                   n   oozing/crusting of lesion

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         Table 4: The ABCDE lesion system

         A                                                     Geometrical Asymmetry in two axes
         B                                                     Irregular Border
         C                                                     At least two different Colours in lesion
         D                                                     Maximum Diameter >6 mm
         E                                                     Elevation of lesion

         Clinical diagnosis of melanoma is difficult and the accuracy of diagnosis may vary according to
         a clinician’s level of experience, with reports of considerable variation in sensitivity from 50 to      3
         86% and an inverse relationship between sensitivity and experience. 41-43
         High magnification dermatoscopy is more sensitive than non-dermatoscopic diagnosis when
         used by clinicians with experience of the technique.44 High magnification requires more                  1+
         sophisticated equipment than the current widely-used hand held dermatoscopy.
         Training clinicians to be ‘experts’ in hand held dermatoscopy improves diagnostic accuracy but
         it may diminish the sensitivity of the diagnosis of ‘non-expert’ or untrained dermatologists.45-47
         Observational studies have compared excision and pathological assessment to using other                  1+
         preoperative assessment methods of diagnosis including magnetic resonance imaging (MRI),                 3
         high resolution ultrasound (US) and digital imaging of possible melanomas.48-51 These studies
         failed to show significant benefit and require specialist equipment that is unlikely to be widely

             D   Clinicians should be familiar with the 7 point or the ABCDE checklist for assessing

             D   Clinicians using hand held dermatoscopy should be appropriately trained.

         A flow chart showing the suggested management of cutaneous melanoma is given at the end of
         this chapter.

         When melanoma presents as a metastasis and no primary melanoma site can be identified the
         patient should be referred to the appropriate regional specialist (see section 8).

         Nine observational studies exploring delay were identified.41,52-59 Significant delays (>three months)
         in diagnosis of invasive melanoma are usually patient- rather than physician-related.41,52-59 Delay      3
         was defined differently in each study, with some including both patient and physician components.
         All of the studies identified show inconsistency between Breslow thickness (see section 3.8.4)
         and delay, although melanomas diagnosed incidentally by health professionals were consistently
         thinner than those noted by patients themselves.55
         Several studies showed longer delays in older patients,42,57 in men, in rural versus urban dwellers      2+
         and in plantar melanomas.58,42
         There is inconsistency in findings regarding patients’ knowledge of melanoma and delay. Two
         observational studies found that delay in presentation was shorter if the patient was aware of
         possibility of malignancy.55,59 Conversely, another study found that delays were longer in those
         with greater knowledge, perhaps due to false reassurance caused by greater knowledge42 (see
         section 2.4.1).
         Physician delay accounts for a very small part of the total delay in diagnosis.41 Medical delays
         were shorter and the Breslow thickness was less when patients were seen by dermatologists as             3
         opposed to general practitioners.41

                                   3 DIAGNOSIS AND PROGNOSTIC INDICATORS

      No studies were identified exploring the consequences of delays in diagnosis on patient outcomes.

       D     Health professionals should be encouraged to examine patients’ skin during other clinical

       þ     Patients with suspicious pigmented lesions should be seen at a specialist clinic in a time
             commensurate with the level of concern indicated by the GP referral letter.

       þ     Emphasis should be given to the recognition of early melanoma by both patients and
             health professionals.

      An Australian RCT demonstrated a decrease in the number of benign lesions excised by GPs after
      being given algorithms and cameras as aids to diagnosis.60 In an American RCT, the use of a            1+
      booklet, magnifying and measuring tools and feedback sessions improved the ability of primary          1-
      care residents to triage suspicious lesions. 61

       þ     Targeted education can enhance health professionals’ ability to diagnose melanoma.

      Biopsy of highly suspicious lesions should be by fast-track referral to the appropriate specialty
      according to local circumstances.
      The optimal specimen for full histological evaluation of a suspected melanoma is a complete
      excision with a 2 mm surround of normal skin and a cuff of fat.62 This enables assessment of the
      entire lesion and allows direct wound closure with a relatively short scar that will not compromise
      subsequent wider surgery (see section 4.1). Elliptical excisions should be performed along the
      long axis in the line of a natural skin crease or longitudinally in limbs and transversely over        2+
      joints. The exact surgical margins of excision should be recorded on the operation note.
      Non-excisional biopsy may lead to inadequate histology.63-67 The least useful type of biopsy is
      the superficial shave variety. Two large studies demonstrate that non-excisional biopsy of the
      primary lesion has no effect on prognosis.64,68

       D     A suspected melanoma should be excised with a 2 mm margin and a cuff of fat.

       C     If complete excision cannot be performed as a primary procedure a full thickness incisional
             or punch biopsy of the most suspicious area is advised.

       C     A superficial shave biopsy is inappropriate for suspicious pigmented lesions.

       þ     GPs should refer urgently all patients in whom melanoma is a strong possibility rather
             than carry out a biopsy in primary care.

       þ     The local availability of fast-track services for patients in whom melanoma is suspected
             should be advertised widely to general practitioners.

      i      Newly diagnosed patients should receive both verbal and written information about
             melanoma including the treatment options and support services available to them.

      Biopsy of in situ lentigo maligna melanoma (LMM) and of invasive LMM should be approached
      differently. The frequently facial site and large diameter of such lesions may render full excision
      difficult or excessively destructive. In these instances incisional biopsy(s) of the most clinically   2+
      suspicious areas are appropriate. Lentigo maligna melanoma ideally should be surgically removed
      as in other invasive types.69 Where the size, site or patient comorbidity prevents this, other

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         techniques can be considered. Cryotherapy and topical-5-fluorouracil have been used but there is
         a risk of local recurrence and no reduction in the risk of developing invasive disease. 70 The
         patient should be fully appraised of these risks. Several small studies also report the use of        2+
         radiotherapy in pre-malignant LM and LMM with good recurrence-free intervals and excellent


         The volume of evidence addressing the handling of suspected melanomas is small.
         Recommendations on how to describe and select tissue blocks from a suspected melanoma are
         available from standard surgical pathology textbooks.74
         Accepted practice has been supplemented by best practice guidelines published in 2000.62              4
         Appropriate treatment, follow up and prognostication for patients with melanoma are entirely
         dependent on accurate pathological diagnosis and microscopic staging. The macroscopic
         description of the specimen, together with adequate and appropriate methods of block selection,
         is central to this process.

          D     The macroscopic description of a suspected melanoma should:
                n  state the biopsy type, whether excision, incision, or punch
                n  describe and measure the biopsy (in mm)
                n  state the size of the lesion in mm and describe the lesion in detail (shape, pattern of
                   pigment distribution, presence or absence of a nodular component and presence or
                   absence of ulceration)
                n  state the clearance of the lesion (in mm) from the nearest lateral margin and the deep

          D     Selection of tissue blocks:
                n  the entire lesion should be submitted for histopathological examination
                n  the lesion should be sectioned transversely at 3 mm intervals and the blocks loaded
                   into labelled cassettes
                n  cruciate blocks should not be selected (they limit the assessment of low power
                   architectural features such as symmetry).
         Note: a photograph of the macroscopic specimen may be of great value, especially if the precise
         origins of labelled blocks are drawn onto the photograph to permit exact orientation.


         Superficial spreading melanomas are less prone to recurrence when compared to nodular
         melanomas, however both groups have similar survival figures when matched for tumour
         thickness.75 Cochran’s prognostic model (see section 3.8.11) uses an assessment of the histogenetic   2++
         type (SSM versus all others) to calculate the risk of tumour recurrence but this variable is not      2+
         required for the calculation to derive the probability of survival.75 Classifying melanomas into      4
         different subtypes is reported to be of no prognostic relevance. Both desmoplastic and neurotropic
         melanomas (long regarded as being particularly aggressive) have similar survival rates to other
         subtypes although lesions with a neurotropic component are associated with a higher rate of
         local recurrence.62,76-78
         Although the majority of studies do not demonstrate a significant association between histogenetic
         subtype and patient outcome, histogenetic type does appear to play a role in determining the          2++
         likelihood of recurrence. Histogenetic type also defines a group of well recognised
         clinicopathological entities.

                                     3 DIAGNOSIS AND PROGNOSTIC INDICATORS

         B     The histogenetic type should be included in the pathology report.

        The relationship between cell type and outcome is unclear. Studies that examine melanomas of
        all thicknesses tend to find either no evidence of a relationship or a weak association that is lost
        on multivariate analysis.75,76,79-81,90,258 The effect of cell type on prognosis may only become apparent   2-
        in the specific subgroup of patients with thick tumours exhibiting paradoxical behaviour. Here,
        the presence of a spindle cell or Spitz-like phenotype may confer a modest survival advantage.81

         þ     The predominant cell type in the vertical growth phase should be stated, especially for
               thick tumours.

        Tumour growth phase correlates strongly with clinical outcome.76,82 A study of 501 patients with
        primary melanomas identified a subgroup of 122 as being in radial growth phase only. No
        patients in this subgroup showed evidence of metastatic disease during a minimum follow up
        period of 100 months. The OR for a patient with radial growth phase melanoma surviving for
        eight years was given as 1.0.76 A second study evaluated 624 patients, of whom 161 had melanoma
        displaying radial growth phase characteristics only. None of the patients developed metastatic
        disease at long term follow up (median 13.7 years). 82

         B     The growth phase characteristics should be stated in the pathology report of all melanomas
               except nodular melanomas which, by the time of diagnosis, show only vertical growth
               phase characteristics.

        A strong association between tumour thickness and prognosis was originally demonstrated by
        Breslow83 and has since been verified in many large scale studies of melanoma.75,76,84 ,85,110 Breslow      2++
        thickness is the single most important prognostic variable in primary cutaneous melanoma.

         B     An accurate (to within 0.1 mm) measurement of the Breslow thickness should be included
               in the pathology report for any melanoma that has an invasive component.

        In a study of 5,093 patients (minimum follow up seven years) the Clark level of invasion yielded
        additional prognostic information in patients with a Breslow thickness of <1mm.86 This observation
        has also been confirmed by the large study (based on 17,600 patients) used to derive the new                2++
        American Joint Committee on Cancer (AJCC) staging system (see section 4.1).110 A small study                2+
        of patients with metastasising lesions <1.5 mm noted significantly higher metastases of level IV            1+
        lesions compared to control groups.87 A detailed systematic review of the staging of melanoma
        reports similar results.88

         B     The Clark level of invasion should be provided when the lesion has a Breslow
               thickness <1 mm.

        A small study of 177 subjects with intermediate thickness melanomas (1.51 to 3.99 mm) identified
        epidermal ulceration as one (of four) variables that predicted visceral and bony metastases.89
        Ulceration has been shown to act as a prognostic variable after adjustment for other variables.76,84
        A study of 1,042 patients identified epidermal ulceration as a significant prognostic variable and          2+
        this was incorporated into a mathematical model for predicting recurrence and survival at three,
        five and ten years.75 Ulceration was confirmed as a strong prognostic variable in the recent large
        scale study that validates the AJCC guidelines.110 Some studies also show that increasing breadth
        of epidermal ulceration is associated with an increasingly unfavourable prognosis (see section

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           B     The presence or absence of histological evidence of epidermal ulceration should be noted
                 in the pathology report.

           þ     When Cochran’s model is used to calculate the likelihood of recurrence or
                 death the breadth of ulceration should be stated in mm.

 3.8.7    MITOTIC RATE
          Although some studies have identified mitotic rate as a significant prognostic variable,76,90 with
          survival probability decreasing in a linear relationship with increasing mitotic rate, the exact
          strength of this parameter remains unclear. Mitotic rate appears to be a less useful predictor of
          survival than variables such as tumour thickness and epidermal ulceration and it is not used as a        2++
          staging parameter in the revised AJCC guidelines.110 In some studies the prognostic significance
          of mitotic index is either greatly weakened or entirely subsumed after multivariate analysis assesses
          other histological and clinical variables.75,90

           þ     It is desirable to comment on the mitotic rate, expressed in terms of mitoses per
                 mm2, in the vertical growth phase component.

          The association between survival advantage and the presence of tumour infiltrating lymphocytes
          (TILs) within the vertical growth phase component is unclear. Although one study demonstrated
          a strong correlation,76 the presence of an inflammatory response loses independent prognostic
          strength on multivariate modelling.75

           þ     It is desirable to comment on the host inflammatory response using Clark’s
                 classification system.76

 3.8.9    REGRESSION
          There is an adverse association between histological evidence of regression and outcome, but the
          strength of this relationship is disputed.75,76,87 One large study identified tumour regression in the
          radial growth phase as a variable that retained predictive strength after multivariate analysis. 76 In   2++
          a subsequent study of 1,042 patients the significance of tumour regression was subsumed by the           2+
          other clinical and histological features studied.75 Extensive late regression might indicate that the
          melanoma has, at some time, been significantly thicker than it now appears. Tumours with this
          feature are liable to be understaged.87

           C     If late regression is apparent it should be included in the pathology report.

          A systematic review found that the prognosis for patients with microsatellites is essentially
          identical to that for patients with macrosatellites.88 There was no demonstrable difference in           1+
          survival for patients with satellites compared to those with in-transit metastases.
          A prospective cohort study of 258 patients with clinical stage I melanoma found that 13 out of
          14 patients with histological evidence of lymphatic invasion developed in-transit metastases             2++
          after a median interval of 10 months and concluded that lymphatic invasion correlates strongly
          with early locoregional cutaneous relapse.91
          A study of 140 patients with thick (>3 mm) stage I melanomas reported that the identification of
          lymphatic invasion was associated with an increased risk of metastasis but not with overall
          survival.90 However, in a series of 17,600 patients the presence of microsatellites had a profound
          negative impact on prognosis and in the new AJCC staging system the presence of satellites               2+
          upstages the tumour from I or II to IIIb or IIIc.110
          Identifying lymphovascular invasion and/or microscopic satellites confers considerable prognostic
          value. The presence of lymphatic invasion accurately predicts early cutaneous relapse and should
          be included as a stratification criterion for the selection of patients for adjuvant therapy.

                                      3 DIAGNOSIS AND PROGNOSTIC INDICATORS

         The histological identification of microsatellites also defines a subset of patients at much greater
         risk of relapse. The presence of microsatellites correlates strongly with occult metastatic disease
         in regional lymph nodes.

          B     Identification of lymphatic space invasion and/or microscopic satellites should be included
                in the pathology report.

         Models attempting to predict accurate survival for patients with melanoma have become
         increasingly complex in order to accommodate both the clinical and histopathological data
         demonstrated to be of independent prognostic significance.75,76,92 The Cochran model predicts
         survival at three, five and ten years, based on simple clinical data (age, sex and anatomic site) in
         combination with the Breslow thickness and the breadth of epidermal ulceration.75 An                   2++
         individualised risk score is derived that predicts the likelihood of survival for any patient with
         invasive melanoma. The model can be modified to calculate risk of recurrence (at three, five and
         ten years) by inclusion of histogenetic subtype. (Worked examples of how to use Cochran’s
         model are available on the SIGN website at www.sign.ac.uk).

          B     If the likelihood of survival is calculated using the Cochran model, the breadth of any
                epidermal ulcer should be measured by micrometer and stated in the pathology report.

          þ     The way in which the prognostic index is discussed with a patient should be tailored to
                the needs of the individual patient.

         Significant discrepancy exists between general pathologists, dermatopathologists and between
         experts in pigmented lesion pathology, in the reporting of melanocytic tumours.93-95 Both under-       2++
         and over-diagnosis of malignancy is recognised and, for melanoma, there is poor agreement on
         the assessment of prognostic parameters.

          þ     Pathologists responsible for reporting melanocytic lesions must be aware of the diagnostic
                pitfalls in this area. Participation in appropriate continuing professional development
                (CPD) activity is advisable.

          þ     Cases where significant diagnostic doubt exists should be referred for specialist opinion,
                preferably to a panel of experts.

         The table below outlines the important features of a melanoma pathology report.
         Table 5: Features of a melanoma pathology report

         Essential features                                   Desirable features
         Breslow thickness                                    Histogenetic type
         Clark level (if Breslow thickness <1 mm)             Cell type
         Ulceration                                           Host inflammatory response
         Growth phase characteristics                         Mitotic rate
         Lymphovascular space invasion
         Microscopic satellites
         Microscopic clearance (mm)

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        Detailed protocols for dissection of therapeutic lymph node dissection specimens are available
        in standard textbooks of surgical pathology.74,96
        The surgical report should identify
        n   the exact number of lymph nodes within the resection specimen
        n   the total number of nodes containing metastatic disease
        n   extracapsular spread (attributed with a significant reduction in disease free survival although
            it does not impact on overall survival).97
        When macroscopic examination reveals tumour within a node, a single block of tissue is sufficient
        to confirm the observation. Nodes that appear tumour free should be serially sliced (if large) and
        all of the tissue processed. Small nodes may be processed intact and levelled to ensure thorough
        Sentinel lymph node biopsies (SNLB) are processed using either lymphoscintigraphy and/or blue
        dye to trace the afferent lymphatic channels and node. Protocols giving further details are available.
                 Nodes identified by lymphoscintigraphy (usually technetium99) should be fixed in formalin
        for 24 hours to allow for radioactive decay.
        When dye has been used, the sentinel node should be examined macroscopically to determine
        whether any staining has occurred. The node should then be bisected through its longest
        circumference and both halves processed for the removal of ten serial sections. Sections one,
        three, five and ten should be examined by routine haematoxylin and eosin staining. Sections two
        and four should be stained immunohistochemically for S-100 protein and HMB-45. Sections six
        and seven act as negative controls for immunohistochemistry (IHC) and sections eight and nine            4
        can be used for additional studies or to repeat any unsatisfactory stains.99 If the appearances in
        the first set of ten sections are deemed suspicious then additional sets of ten sections can be cut
        and stained.
        Although IHC facilitates the detection of melanoma in sentinel nodes, the possibility of false
        positive results, for example, the misinterpretation of capsular naevus cells, remains. This can be
        minimised by careful evaluation of the immunochemical preparations in the context of the
        corresponding haematoxylin and eosin stained section.
        Groups of sections at multiple levels throughout the sentinel node are sometimes examined, but
        there is no evidence that such rigorous sampling increases the diagnostic yield. Detecting melanoma
        cells in SNLB using polymerase chain reaction (PCR) techniques cannot be recommended at
        present due to concerns regarding both sensitivity and specificity.100

                                    3 DIAGNOSIS AND PROGNOSTIC INDICATORS

                Patient / relative / carer notes change /               Opportunistic detection by health professional.
          discharge / bleeding / altered sensation / new lesion          Irregular colour, margin, surface, asymmetry

                                                      Suspicious Pigmented

Feedback to GP                                                                                                Feedback to GP
                                                          Consult GP for

         ,      Benign - Reassure
                                                                                         Equivocal - Reassess +
                                                                                                                          ,   Benign -

                                                      ,     Suspicious
                                                                                          photo within 2 months               Reassure

                                                      Refer to appropriate

                                                    specialist for assessment
                Benign - Reassure

                                                                                                ,      Suspicious                 ”
         ,    Equivocal, arrange review ±
              photograph within 2 months

                                                                                               Local excision if practical

         ,      Benign - Reassure

                      ‘                               ,     Melanoma

                            Reassess for local lymph nodes and other suspicious pigmented lesions.
                          Arrange wide excision by locally appropriate specialty ± sentinel node biopsy

                                  FNAC or               Pathology negative
        Clinically suspicious                                                                      No involved nodes
                                                      Evidence of lymph node
           positive nodes

                      ‘                                Removal of draining
                                                         lymph nodes

                                                                                                        Follow up
                                                   Consider need for other treatment
                                                      according to clinical exam

    ,   Evidence of melanoma elsewhere

                                                                                                  No obvious residual

                                                                                                   metastatic disease
                Refer medical oncology for possible
                        clinical trial

                                                                                                 ,      Follow up

    ,     Refer medical oncology or other
          appropriate specialty
                                               Feedback to GP
                           ‘                                                                    ‘
    , = Opportunity to give verbal and / or written information to patients and carers

CUTANEOUS MELANOMA      http://chn-health.com

 4       Surgical management and staging
         Historically very wide margins of excision were advocated in the management of melanoma.
         Appreciation of Breslow thickness as a prognostic indicator (see section 3.8.4) supports the             3
         concept of a conservative approach to surgery, with narrowing of the margins of excision.101-104         1+
         The safety of these narrower margins has been demonstrated in a series of studies.105-108
         A comparison of 1 cm and 3 cm margins for tumours up to 2 mm thick found no overall survival
         difference between the two groups.105 A small number of patients with lesions thicker than 1mm           1+
         developed local recurrence.107-109 A 1cm margin should therefore be adequate for melanomas less          3
         than 1mm thick. For lesions between 1-2 mm thickness a width excision of 1-2 cm should be
         considered, in the context of a full clinical assessment.
         The following recommendations use the TNM staging classification recently updated by the
         American Joint Committee on Cancer (AJCC; see section 4.2).110

          D     In pTis (melanoma in situ) a surgical excision margin of 2 to 5 mm is
                recommended to achieve complete histological excision.

          B     In pT1 (melanoma 0 to 1 mm thickness) a surgical excision margin of 1 cm is

          B     In pT2 (melanoma 1 to 2 mm thickness) a surgical excision margin of 1 to 2 cm is

          B     In pT3 (melanoma 2 to 4 mm thickness) a surgical excision margin of 2 cm is

          D     In pT4 (melanoma > 4 mm thickness) a surgical excision margin of 2 cm is recommended.

         p = pathological         T = tumour
         The suggested width of excision at sites of aesthetic and functional importance requires clinical
         consideration. The deep excision margin should incorporate adipose tissue down to, but not
         including, the deep fascia.111,112 The majority of melanomas should be excised with direct wound
         closure (see section 3.5). No evidence was identified on the role of optimal timing of wide
         excision in melanoma.

          þ     Wider excision requires referral to a specialist centre to facilitate the use of reconstructive
                and staging techniques.

          þ     The deep excision margin should incorporate adipose tissue down to, but not including,
                the deep fascia.

         Guidelines recommend that the microscopic distance of the lesion from the lateral and deep
         margins should be measured in mm and the results stated in the pathology report,62                       4
         (see section 3.5).
         Measurement of surgical clearance is standard practice in reporting other tumours (eg breast and
         colorectal carcinoma) where the adequacy of surgical removal dictates the need for further
         treatment. This is directly comparable to the management of melanoma where the requirement
         for further surgical excision is dictated by a combination of the Breslow thickness and the distance
         of the lesion from the surgical margins defined at the time of initial surgery.

                                           4 SURGICAL MANAGEMENT AND STAGING

           D        The microscopic clearance of the tumour from the nearest lateral margin and from the
                    deep margin should be stated (in mm) for all excision biopsies.

           þ        Surgical excision margins should be recorded by the surgeon.

          Melanoma should be staged using the TNM staging classification described by the American
          Joint Committee on Cancer110 and outlined in Table 6.
          Table 6: AJCC Staging Classification

                                           Melanoma TNM Classification
 T classification
                                                                                                         5 year
               Breslow thickness                       Ulceration Status                   Stage
                                                                                                    survival rate (%)
                                            a: without ulceration and level II/III        IA       95.3
 T1        ≤1 mm
                                            b: with ulceration or level IV or V           IB       89-90.9
                                            a: without ulceration                         IB       89-90.9
 T2        1.01 – 2 mm
                                            b: with ulceration                            IIA      77.4-78.7
                                            a: without ulceration                         IIA      77.4-78.7
 T3        2.01 – 4 mm
                                            b: with ulceration                            IIB      63-67.4
                                            a: without ulceration                         IIB      63-67.4
 T4        > 4 mm
                                            b: with ulceration                            IIC      45.1
 N classification
            No. of Metastatic Nodes                Nodal Metastatic Mass

                                            a: micrometastasis*                           IIIA     69.5
 N1        1 node
                                            b: macrometastasis**                          IIIB     59
                                            a: micrometastasis*                           IIIA/B   63.3
 N2        2-3 nodes
                                            b: macrometastasis**                          IIIB/C   59
                                            c: in-transit met(s) / satellite(s) without
                                                                                          IIIB     No data available
                                            metastatic lymph nodes
 N3        4 or more metastatic nodes,                                                    IIIC     26.7
           or matted nodes, or
           in-transit combination of
           in-transit mets/satellites or
           ulcerated melanoma and
           metastatic lymph nodes
 M classification
                        Site                                  LDH

 M1a       Distant skin,
           subcutaneous, or nodal           Normal                                        IV       18.8 +/- 3

 M1b       Lung mets                        Normal                                        IV       6.7 +/- 2

           All other visceral mets          Normal                                        IV       9.5 +/- 1.1
           Any distant mets                 Raised

 Mets = metastases
 LDH = Lactate Dehydrogenase
 *Micrometastasis are diagnosed after elective or sentinel lymphadenectomy
 ** Macrometastasis are defined as clinically detectable nodal metastases confirmed by therapeutic
 lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

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         Examination of the regional lymph node basin is an essential component of the clinical evaluation
         of melanomas (see section 3.7.1). The presence or absence of nodal metastasis is the most              2++
         significant predictor of outcome in melanomas.113
         The risk of developing nodal metastases increases with the thickness of the primary melanoma.114,115
         Metastasis to lymph nodes is rare in melanomas less than 1 mm thick. At least 25% of melanomas
         between 1.5 and 4 mm will have microscopic lymph node metastasis at the time of primary
         diagnosis and this rises to over 60% incidence in melanomas more than 4 mm thick.116,117
         Regional lymph node metastasis is associated with poor prognosis, survival being less than half        2++
         that of patients without nodal involvement. 118-120

         Melanoma patients who have palpable lymph node(s) either at their first presentation or at a
         follow up visit should have a sample taken for fine needle aspiration cytology (FNAC). If the first    4
         sample is unsatisfactory or negative with persistent suspicion, it should be repeated. If doubt
         persists an open biopsy can be performed.9,121

          þ     Palpable regional lymphadenopathy must be fully investigated in patients with primary

          þ     If there is palpable lymphadenopathy FNAC should be used to obtain cytological
                confirmation of metastases.

          þ     If open biopsy is undertaken the incision must be placed in the same line as for a potential
                radical lymphadenectomy.

         Nodal involvement indicates an advanced stage of disease. Confirmation of metastatic melanoma
         in one node is an indication for radical dissection of that lymph node basin. The number of
         involved nodes is of prognostic significance. Ten year survival varies between 20 to 45% dependent
         on the extent of nodal involvement.9,113,118,120
         Therapeutic lymph node dissection is beneficial in controlling locoregional disease. The risk of
         recurrence in the dissected node field remains, particularly with head and neck melanomas.122,123
         Groin nodes include a superficial group of inguinal nodes below the inguinal ligament and the
         obturator and iliac group of nodes which lie deeper in the pelvis. Ilioinguinal dissection offers a    2++
         survival benefit in patients with palpable positive inguinal nodes compared with inguinal block
         dissection of the femoral triangle node.124 ,125
         Head and neck melanomas have the most variable pattern of lymph node metastasis and require
         a variety of types of neck dissection that may include the parotid or the posterior occipital chain

          B     Radical lymph node dissection requires complete and radical removal of all draining
                lymph nodes to allow full pathological examination.

          þ     Regional lymph node dissection carries a well defined and significant morbidity and
                should be undertaken only by surgeons with appropriate expertise.

         The high incidence of occult metastasis in clinically impalpable nodes has prompted surgeons to
         investigate regional lymph nodes. This is achieved either by elective lymph node dissection or by
         sentinel lymph node biopsy.

                                          4 SURGICAL MANAGEMENT AND STAGING

        Although retrospective series126-128 suggest that resection of clinically non-involved lymph nodes
        provides a survival advantage in melanomas of intermediate thickness, this has not been confirmed       2+
        in RCTs.129-131
        The Intergroup Surgical Melanoma Trial132 identified a small subgroup of patients with a possible
        survival advantage following elective lymph node dissection. This subgroup consisted of patients
        <60 years with non-ulcerated melanomas of 1 to 2 mm thickness situated on limbs. Sentinel               1+
        lymph node biopsy (see section 4.3.5) has replaced elective lymph node dissection as a method
        of staging the regional lymph node basin.

            B      Elective lymph node dissection should not be routinely performed in patients with primary

        The sentinel lymph node is defined as the first node in the lymphatic basin that drains the lesion
        and is the node at greatest risk for the development of metastasis.133 Biopsy of this node can assist
        in staging patients at risk of metastatic disease. Current practice is for patients with a positive
        sentinel node to proceed to radical node dissection.
        The standard for sentinel node biopsy is a triple diagnostic approach of lymphoscintography;
        blue dye dermal infiltration and localisation using a hand held gamma probe.133-138 Performing
        SLNB requires appropriate surgical expertise,133 specialist nuclear medicine services and the
        availability of serial sectioning and immunohistochemistry techniques (see section 3.5).
        Sentinel lymph node biopsy accurately determines the presence or absence of metastasis within
        the regional lymph node basin139-141 and it is a useful staging tool in melanomas >1 mm.110 In          2++
        thick melanomas (>4 mm) it can identify a subset of good prognosis melanomas which are node             4

            B      SLNB should be considered as a staging technique in patients with a primary melanoma
                   >1 mm thick or a primary melanoma <1 mm thick of Clark level 4 (see section 3.8.5).

        Isolated limb perfusion (ILP) is a surgical technique that allows localised delivery of a high dose
        of chemotherapy (usually melphalan). Minimal systemic leakage occurs confining toxicity to the
        limb. ILP has been used in two clinical situations:142,143
        n       adjuvant treatment for high risk primary melanoma
        n       therapeutic treatment for major limb recurrence of melanoma.
        Isolated limb perfusion is a significant surgical undertaking and should only be made available
        in centres where a significant number of such operations are performed each year. One centre
        can provide this service for a population of approximately five million people.

            þ      ILP should be performed in regional centres.

        A prospective multicentre RCT involving 832 patients showed that prophylactic ILP with melphalan
        cannot be recommended in high risk primary limb melanoma.144

            þ      ILP should not be used as an adjuvant treatment.

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         A multicentre RCT145 and reviews146,147 suggest that hyperthermic ILP with melphalan alone or
         melphalan plus Tissue Necrosis Factor-a can produce a complete though short lived response rate       1-
         ranging from 50 to 90% in patients with limb recurrence (in-transit metastases).

          þ    ILP is the treatment choice for bulky limb disease for patients fit to undergo the procedure.


         The carbon dioxide laser delivers short wave length energy in a focussed light beam to destroy
         tumour nodules. It can be applied under local anaesthetic, can be repeated and provides effective     4
         local disease control.148-150

          þ    Carbon dioxide laser ablation can be considered for multiple lesions of trunk or abdomen
               and for limb disease when ILP is not appropriate.

         Techniques such as cryotherapy, intralesional bacille Calmette-Guerin (BCG) and radiotherapy
         have been used in the past. Their use has not been based on published scientific evidence.

          þ    Patients with substantial cutaneous recurrence should be referred to an appropriate centre
               where a range of treatment options can be considered.

                                   5 FURTHER INVESTIGATIONS AND NON-SURGICAL STAGING

5       Further investigations and non-surgical staging
        Further investigation to determine precisely the extent of the disease is important in terms of
        prognosis, treatment, entry into clinical trials, research and audit.
        Following pathological microstaging of a patient’s melanoma (see section 3.7) the presence of
        metastatic spread can be determined using three techniques:
        n       Surgical: assessment of the impalpable node by sentinel node biopsy and of the palpable
                node (see section 4)
        n       Imaging: conventional radiography, ultrasound scanning (US), computerised tomography (CT),
                magnetic resonance imaging (MRI) and positron emission tomography (PET)
        n       Blood Tests: routine haematology, tumour markers, liver function tests and lactic
                dehydrogenase (LDH).


5.1.1   CHEST X-RAY
        One large retrospective study was identified that examined the role of chest X-ray (CXR) in
        staging melanoma in 876 asymptomatic patients with stage I or II melanoma.151 One hundred                 3
        and thirty patients (15%) had suspicious CXR findings necessitating further investigation but
        only one patient (0.1%) was found to have a true pulmonary metastasis.

        Two retrospective studies have examined the ability of lymph node ultrasound scanning (US) to
        stage melanoma. One study of 87 patients found the sensitivity of US to be 86% and the
        specificity 74%.152 Ultrasound examination of the regional lymph nodes is a less accurate means
        of determining nodal status than sentinel node biopsy.153

        Two relatively small retrospective studies have shown that computerised tomography (CT) scanning          3
        does not assist in staging and may be counterproductive by generating false positives.154,155

            C      Chest X-ray, ultrasound scanning and computerised tomography scanning are not indicated
                   in the initial assessment of primary melanoma unless indicated for investigation of clinical
                   symptoms and signs.

        Magnetic Resonance Imaging (MRI) is unable to image the lungs in sufficient detail to exclude
        parenchymal disease such as metastases, and is therefore unable to provide a comprehensive
        assessment of disease status in melanoma patients. No studies were found that examined the
        routine use of MRI to identify distant disease in stage I-III melanoma. There is insufficient
        evidence to make a recommendation on the role of MRI scanning and melanoma staging.

        Investigations such as full blood counts (FBC) and liver function tests (LFT) are not helpful in
        identifying asymptomatic patients with distant disease.156,157 Elevated lactate dehydrogenase (LDH)
        in the absence of clinical symptoms or signs is the first indicator of stage IV disease in 12.5% of
        patients. By the time other blood parameters are significantly deranged, the patient will have            3
        other manifestations of metastasis.156,157 For patients with advanced disease, LDH is now included
        in the AJCC classification system.110 The evidence and availability of tumour markers such as
        S100 protein, Melanoma Inhibitory Activity (MIA) protein and tyrosinase mRNA are limited.
        Investigating these markers is not routinely indicated.202

            D      Routine blood tests are not indicated in staging asymptomatic melanoma patients.

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 6       Adjuvant treatment of stage II and III disease
         Pathological features of primary melanoma, particularly thickness and ulceration, make it possible
         to identify patients with stage II disease who are at high risk of local or systemic recurrence (see
         section 3.7). Once patients have had melanoma recurrence in the local regional lymph nodes
         (stage III disease), over 50% will subsequently develop further metastatic spread. These observations
         support attempts to identify adjuvant treatment such as chemotherapy, immunotherapy and
         radiotherapy, given after complete clinical surgical clearance of melanoma.
         An RCT of adjuvant chemotherapy and immunotherapy including the use of BCG and DTIC (see
         section 8.2) reported negative results.158 A number of well designed trials of adjuvant therapy            1+
         open to new patients are ongoing.

         Three retrospective cohort studies,159-161 two studies using historical controls162,163 and an
         observational study were identified.164 Studies in small numbers of patients have shown that               3
         outcomes following lymph node dissection plus radiotherapy were not significantly different                1-
         from those following dissection alone.165

          D     The routine use of adjuvant radiotherapy is not recommended for patients who have had
                therapeutic lymph node dissections.


         The observation that a large number of primary melanomas undergo partial regression and a small
         number of melanoma patients experience total regression of the whole melanoma has led to the
         concept of using either specific or non-specific immune stimulation as therapy for melanoma.
         Adjuvant interferon α has been used in at least 10 large RCTs involving over 5,000 patients.166-175
         Interferon dosage, frequency and route of administration and total duration of therapy all varied,
         but no trial reported significant overall survival benefit for interferon-treated patients. Several of
         the larger studies do report longer disease-free intervals after surgery169-171 but there is no evidence
         of a dose or duration of treatment effect. Toxic effects of interferon include extreme lassitude,          1++
         muscle aches, headache, rigors, nausea, vomiting, and marrow toxicity, the latter being the
         cause of death in two patients in the first reported high dose study.
         Final results are not yet available for some of these trials, and until these are published it would
         be premature to offer interferon to patients with AJCC stage II or stage III melanoma.

          A     Adjuvant interferon should not be used for AJCC stage II and III melanoma patients other
                than in a trial setting.

          þ     Patients with AJCC stage II and III disease should be offered entry into RCTs to confirm
                whether or not interferon therapy extends the disease-free interval after surgery.

 6.2.2   VACCINES
         Melanoma vaccines are still in the research phase. There are some Phase I and II studies that do not
         have controls. The vaccinia melanoma oncolysate (VMO) RCT involved 217 patients but did not
         show an advantage for the vaccine.176 An RCT including 700 patients compared vaccinia melanoma
         cell lysates (VMCL) to no immunotherapy and found that VMCL did not significantly improve overall
         survival or relapse-free survival.177 An RCT comparing interferon alfa-2b with a GM2 ganglioside
         vaccine was closed early when the interferon showed evidence of increased relapse-free survival and
         overall survival.178 Melanoma vaccines are not currently available commercially.

          þ     Patients should be entered into vaccine clinical trials as appropriate.

                        http://chn-health.com I, II AND III DISEASE
                                    7 PATIENT FOLLOW UP IN STAGE

7     Patient follow up in stage I, II and III disease
      The purpose of the follow up clinic is to
      n       provide reassurance and psychological counselling
      n       provide comprehensive information about all aspects of the patient’s melanoma
      n       detect recurrent disease
      n       teach patients techniques of self examination for discovery of local and nodal recurrence
      n       detect new primary melanomas.

      i          Follow up is an opportunity to provide relevant information to patients, carers and family

      No RCTs on follow up methods were identified. Eight retrospective studies179-186 and one prospective
      cohort study187 were identified which highlight the following issues:
      n       who should be followed up?
      n       how frequently should patients be followed up?
      n       for how long should patients be followed up?
      n       how are recurrences detected?
      These questions are addressed in this section.

      Current practice is that all patients with an invasive melanoma who are at risk of recurrent
      disease have a period of follow up and all patients with stage III disease have a prolonged follow
      up, often for the rest of their life. Patients with melanoma in situ have no risk of recurrence.179
      Patients with a pure radial growth phase tumour have a very low chance of recurrence.82

          D      Patients who have had melanoma in situ do not require follow up.

          þ      Patients with an invasive melanoma should have a period of follow up; stage III patients
                 with lymph node metastases should have longer, possibly lifelong, follow up.

      Large retrospective studies show that between 60 and 80% of first recurrences are local and/or            4

      The timing and rate of recurrence of melanoma is well recognised (see Figure 1 & Table 7).185,188         3

      Table 7: Timing and rate of recurrence of melanoma

      Tumour thickness                          Recurrence rate                    Median recurrence time
      <1.5 mm                                   2-19%                              25-32 months
      >1.5 mm                                   47-66%                             12-16 months
      The annual risk of recurrence for tumours <1.5 mm thick remains <6% for the first five years
      dropping to under 1% for the next five years. Tumours >1.5 mm thick have a higher risk of
      recurrence in the first year, dropping to <2% after year five.179,184,185 Overall most studies indicate   3
      that about 80% of recurrences occur within the first three years179,188,189 but up to 16% of first
      recurrences have been reported to occur after five years185 and late recurrence (more than ten
      years) is well recognised.190-193

CUTANEOUS MELANOMA      http://chn-health.com

         Figure1: Breslow thickness plotted against recurrence rates, years 1 to 10 following surgery
         Graph compiled from data from McCarthy et al, 1988185

         Many follow up frequencies and durations have been suggested but there is no overall consistency
         in the recommendations made for either follow up frequency or duration. Examples of the variation
         in recommendations are given below.

         The variation in the management of tumours <0.75 thick mm is considerable. Three studies
         recommend follow up at yearly intervals for between 15 years and life. 184-186 Two studies advocated
         six-monthly reviews for five years or ten years,187,188 reducing to yearly for a further five years187 or   4
         for life;188 and another suggested that tumours less than 0.6 mm needed no follow up but those
         over 0.6 mm needed three-monthly reviews for eight years.181 Another study recommended three-
         monthly follow up for three years only.179

         For thick tumours > 4 mm the recommendations are equally varied. Five papers propose an initial
         three-monthly follow up for three,179,188 four,117 five187 or eight years.181 Two papers suggest one-
         monthly follow up for the first two years.185,186 One advocated six-monthly visits for the third
         year and then yearly for life,185 whilst the other recommended two-monthly visits for the third             4
         year, six-monthly visits for the fourth year and then yearly visits until year 15.186
         A further study recommended two-monthly follow up for the first year, three-monthly for year
         two, four-monthly for year three, five-monthly for year four, six-monthly for year five to ten and
         then yearly for life.194

         One aspect of follow up recommended by both Australian and North American authors is lifelong
         surveillance of all patients with the aim of detecting late recurrences and picking up second
         primaries.184,185 Similar follow up practice has been advocated by Italian authors.188 The risk of          4
         recurrence after eight years was considered to be too low for French authors to recommend
         follow up after this time.181 British authors, while acknowledging the benefits of a lifelong

                        http://chn-health.com I, II AND III DISEASE
                                    7 PATIENT FOLLOW UP IN STAGE

        follow up, suggest limiting the follow up period to five years due to limited resources.179 Another
        UK group suggests follow up for 15 years but accept that a five year period may be more

            þ   The specific frequency and duration of follow up should be determined from the timing
                and rate of recurrence of the individual patient’s melanoma.

        None of the studies identified explored patients’ psychological and emotional needs when
        determining the frequency or length of follow up.

            þ   Follow up frequency and duration should take account of patients’ psychological and
                emotional needs.

        Three retrospective studies found second primaries in 1.2%, 2% and 7% of their patients.179,185,195
        The timing of discovery ranged from synchronous with the initial melanoma to more than 10
        years later. The second primaries were usually thinner. One paper estimated that the Scottish                 4
        melanoma patients in their study had a 200-fold increase in risk of developing a second melanoma
        compared to the general population,195 (see Table 2, section 2.4.2).

        Large retrospective studies have shown that 90% of recurrent disease in patients with stage I and
        II is detected solely by signs or symptoms noted either by the patient or the physician, with
        imaging techniques (usually chest X-ray) detecting the remainder.180,181,183,196,199 Patients’ own
        detection rates in between clinic visits are generally in the range of 33 - 72% 179,181,183,186,199,197 but   3
        in one study where patients with stage I-III melanoma were meticulously educated in self
        examination techniques the rate of self detection rose to 100%. 198 The rate of self detection in
        one prospective trial was much lower at 17%.187 Three retrospective studies indicate that the
        overall survival time is the same for patient-detected recurrences as for those detected in the

        Routine laboratory tests (full blood count and liver function tests) do not detect asymptomatic
        recurrent disease in stages I-III.156,180,181,182,198
        Lactate dehydrogenase (LDH) is a marker of liver metastases and tumour burden in patients with
        stage IV disease that indicates a poor prognosis with a median survival of six months.199-201 Two             3
        studies have looked at LDH as a first indicator of metastases. In stage III disease an elevated LDH
        was the first indicator in 12.5% of patients (with a sensitivity of 73%) when tested for every
        three months.157 In a prospective cohort study of stages I-IV disease an elevated LDH was the first
        indicator in 2% of recurrences when patients were tested every 12 months (stages I and II
        melanoma) or every six months (stages III and IV melanoma).187

        A variety of new tumour marker blood tests have been developed:
        n   S100B protein
        n   Melanoma Inhibitory Activity (MIA) protein                                                                1+
        n   Tyrosinase mRNA.
        None of these tests is currently sensitive or specific enough to be used in clinical practice.202

CUTANEOUS MELANOMA          http://chn-health.com

 7.9.3   IMAGING
         n       Chest X-ray
         In stages I and II, four retrospective18,183,198,203 and one prospective study187 have reported the
         percentage of metastases detected by routine chest X-ray to be 0%198,203 (frequency of examination
         six-monthly203 or 12-monthly198), 4.5%187 (frequency of examination 12-monthly), 5%181 (frequency
         of examination six-monthly) and 11%183 (frequency of examination three-monthly in year one,
         four-monthly in year two, six-monthly in years three to five and yearly thereafter). There is
         evidence that the identification by chest X-ray of treatable asymptomatic pulmonary metastases
         gives no overall survival advantage when compared to symptomatic pulmonary disease.134 In
         stage II and III melanoma, one retrospective study detected 6% of recurrences by chest X-ray
         (frequency of examination two-monthly for year one, four-monthly for year two, six-monthly for
         year three and yearly thereafter).180 In stage III melanoma, one prospective study detected 4.4% of
         recurrences by chest X-ray (frequency of examination six-monthly).187
         n       Ultrasound (US)
         In stage I and II melanoma, two retrospective studies were identified which used abdominal US
         routinely during follow up in asymptomatic patients. One study found that 5% of metastases
         were detected (frequency of examination six-monthly)181 and the other found that none were
         detected using this modality (frequency of examination six-monthly).203 A single prospective trial           3
         found a detection rate of 1.5% (frequency of examination 12-monthly).187
         In stage III melanoma a single prospective trial found a detection rate of 4.4% of all detected
         metastases using abdominal ultrasound (frequency of examination six-monthly).187 In this study
         21% of all metastases in stages I and II; and 9.5% in stage III were detected by using ultrasound
         to examine regional nodes.
         n       Computed tomography (CT)
         In stage I and II melanoma, two retrospective studies were identified that used CT routinely for
         examination of brain, chest and abdomen during follow up in asymptomatic patients. 181,203 The
         first study detected less than 1% of metastases using CT, the second reported a detection rate of
         21% (frequency of examination in both studies six-monthly). In stage III, four retrospective
         studies were identified which looked at the usefulness of CT as a staging exercise upon a patient
         being diagnosed as stage III. One study found that CT offered a 2% chance of finding further
         metastases.183 The other three studies found a true positive rate of detecting further metastatic
         disease of 4% (false positive rate of 8%),204 7% (false positive rate of 22%)155 and 16% (false
         positive rate of 12%).205

             D      Routine full blood counts, liver function tests, tumour markers, chest X-rays, ultrasound
                    scans, computed tomography and lactate dehydrogenase are not recommended as part of
                    a follow up schedule in the asymptomatic patient.

             þ      n   Patients should be educated in self assessment techniques to detect local and nodal
                        recurrent disease and secondary lesions and appraised of the possibility of late recurrence
                    n   There should be an easy route into the clinic if problems occur between clinic visits or
                        after discharge.

                       http://chn-health.com OF STAGE IV DISEASE
                                        8 MANAGEMENT

8       Management of stage IV disease
        The outlook for patients with distant and visceral metastatic melanoma is poor with survival
        time ranging from six to nine months. Survival appears to be increased in women and in those
        patients who have undergone surgery for metastases.206 Poorer survival is associated with initial      3
        metastases to the skin and brain; poor Karnovsky status; involvement of more than two primary
        sites;206 short durations of remission; visceral compared to non-visceral metastases;207 an ECOG
        status of one or less, and metastases to the lungs, gastrointestinal tract or liver.208

8.1     SURGERY
        Metastasectomy may be an option for patients with distant skin, node and visceral metastases. In
        subcutaneous metastases prevention of ulceration of superficial lesions is best ensured by resection
        when they are at a size where skin closure is possible. Surgery of single or localised metastases
        has been shown to improve survival.208 The proportion of patients suitable for metastasectomy
        ranges from 10 to 25%.206,209,210 Five year survival of 14-33% was described in one retrospective
        review for those with distant subcutaneous and lung metastases respectively. This study showed
        prognostic significance for Breslow thickness, number of metastases and prior disease-free
        interval. 206

         þ     Metastasectomy should be considered in patients with stage IV disease.

        No RCTs were identified comparing systemic therapy with placebo or best-supportive care in
        metastatic cutaneous melanoma.211 The most commonly used agent is DTIC (dacarbazine), a
        single agent with an overall response rate activity of approximately 20%.211

        A meta-analysis comparing the ‘gold standard’ DTIC with combination chemotherapy, with or
        without immunotherapy, found a response rate to treatment of 16.9% for single agent DTIC; no
        statistically significant benefit for multiple drug regimens with or without DTIC compared to
        single agent DTIC was identified.212 Interferon α (IFN) combined with DTIC produced a 53%
        greater response rate than DTIC alone though there was no increase in survival.
        One of the most popular combination regimens, the Dartmouth regimen (DTIC, cisplatin,
        carmustine and tamoxifen), was compared with single agent DTIC in a randomized Phase III
        study.213 There was more toxicity with the combination regimen in that 21% versus 2% were
        taken off treatment due to unacceptable side effects. The response rate was higher with the
        combination therapy (18.5% versus 10.2%) but there were no complete responses and no survival
        difference between the two treatments.
        The oral preparation of DTIC, temozolamide, has been shown to have equivalent efficacy and
        better CNS penetration.214
        Most published studies are Phase II non-randomised studies incorporating fewer than fifty patients.
        One review of seven Phase II and nine RCTs concluded that tamoxifen does not improve patient
        outcome.215 Two RCTs published since the review also conclude against any benefit for addition
        of tamoxifen.216,217
        Interferon a                                                                                           1+
        An overview of trials including six published and five unpublished melanoma trials of 1,164
        patients evaluated regimens with or without IFN.218 The overall response rates for IFN containing
        regimens was 24% compared with 17% without IFN. Analysis of five trials where the survival
        data were reported demonstrated a pooled odds ratio for improved survival of 0.69 but heterogeneity
        of patient groups may have led to the non-significant result.218

CUTANEOUS MELANOMA       http://chn-health.com

         Multiple drug regimens and DTIC-based chemoimmunotherapy combinations increase response               1+
         rates but improved rates do not correlate with better survival
         Interleukin 2
         Interleukin 2 (IL2) has been given intravenously or subcutaneously as a single agent or in
         combination with IFN and chemotherapy. Although durable responses are occasionally seen, the
         data do not support its routine use outwith a clinical trial.219

          A     Dacarbazine (DTIC) is the standard single agent of choice in stage IV melanoma.

          A     Multiple drug regimens including those with tamoxifen and interferon a do not improve
                survival compared to single agent DTIC and are not recommended outside of clinical

          þ     Patients should be evaluated before every cycle of chemotherapy and treatment discontinued
                if there is poor tolerance or lack of benefit after three cycles.

          þ     Patients with metastatic melanoma should be treated within a clinical trial wherever
                possible and be offered palliative care.


         There is evidence that melanoma cells in vitro have a spectrum of radiosensitivity and that
         melanoma should not be considered a uniformly radioresistant disease.220 Experimental studies
         have suggested that atypical, large radiotherapy fraction sizes may be more efficacious than
         standard treatments but at present there are no randomised trials to support the use of large
         fraction sizes routinely.220,221

         Studies looking at the treatment of bone metastases usually include only a small percentage of
         patients with melanoma. Recommendations have been extrapolated from the data available
         from studies of bone metastases from various tumour types. When using single fractions to             2+
         palliate pain from bone metastases, an 8 Gy fraction is effective and provides superior pain relief   2++
         to lower doses.222 There does not appear to be an advantage to using 20 Gy in four fractions over
         an 8 Gy single fraction.223 Some patients may benefit from higher dose, fractionated regimens,
         although this has not been fully established. 224

          D     Single dose radiotherapy of a least 8 Gy is an effective treatment for bone metastases.

          þ     All patients with painful bone metastases should be offered radiotherapy.

         There is no clear evidence to support or refute the use of radiotherapy (in combination with other
         treatments) to alleviate the pain and neurological deficit associated with spinal cord compression
         caused by metastatic melanoma.225,226                                                                 3
         The value of surgical intervention in such patients has been established.226 Patients with symptoms
         of spinal cord compression should be referred urgently to an appropriate surgeon.227

          þ     All patients with spinal cord compression should be referred urgently for surgical
                intervention and/or palliative radiotherapy.

                       http://chn-health.com OF STAGE IV DISEASE
                                        8 MANAGEMENT

        Although central nervous system (CNS) involvement by melanoma is a common finding at autopsy,
        brain metastases are diagnosed in only approximately 10% of patients before death.228 For cerebral
        metastases from all tumour types, good performance status, favourable response to corticosteroid
        treatment, and the absence of systemic disease are statistically significant predictive factors for a
        better survival. 229
        Postoperative radiotherapy has been used as adjuvant treatment following the resection of CNS
        disease. However, no survival benefit of postoperative radiotherapy has been demonstrated.230,228
        Radiotherapy without surgery, combined with corticosteroids appears to palliate the symptoms
        of some patients with inoperable cerebral metastases from melanoma but again there is no                    3
        evidence of a survival benefit.220,230,231 Radiosurgery (stereotactic radiotherapy) has been used to
        treat inoperable patients who are fit enough to undergo this procedure, and the results may be
        equivalent to radiotherapy alone.232 Radiosurgery remains an experimental technique in the
        treatment of this disease.

         D     Patients with good performance status, favourable response to corticosteroid treatment,
               the absence of systemic disease and who harbour favourable CNS disease should be
               considered for surgical resection of their CNS disease.

         D     If surgery is not possible, whole brain radiotherapy combined with corticosteroids may
               help palliate neurological symptoms.

        The General Medical Council has stated that basic palliative care skills are required by every
        member of the medical profession.233 The Clinical Standards Board for Scotland (CSBS) has
        agreed standards for the provision of both basic and specialist palliative care.234 Specialist palliative
        care is an integral component of the care of patients with advanced malignancy, required at
        varying times during their illness. SIGN guideline no. 44 (Control of pain in patients with
        cancer) covers the evidence base for pain control in all cancers.235
        Patients who develop metastatic melanoma require input from a number of agencies both within
        and outwith the health service. They may need rehabilitative, functional, social and/or financial
        support services, most of which are available in specialist palliative care settings, as well as in
        primary care and cancer centres. The evaluation of the effectiveness of specialist palliative care
        involves assessment of the different dimensions of care provided, such as pain and other symptom
        control, psychological care, care of the family and carers, rehabilitation and terminal care.
        Three RCTs were identified that included all carcinomas, which, in the context of palliative care,
        are reasonable to relate to patients with melanoma.236-238 The first two studies looked at the effect
        of coordinating all services available within the NHS, local authorities and the voluntary sector
        via the addition of nurse coordinators. A total of 203 cancer patients expected to live for less
        than one year were randomly assigned to either the intervention or the routine services group.
        Patients assigned to the intervention group spent fewer days in hospital, required fewer home
        visits and their family were less likely to feel angry about their relative’s death.236,237 The third
        RCT used place of death as the outcome measure in a study of 434 patients with incurable
        malignant disease.238 The intervention group had inpatient and outpatient hospital services provided
        by the palliative medicine unit, the unit served as a link to community services, predefined
        guidelines maintained communication between services and community staff took part in an
        educational programme. Significantly more intervention group patients died at home and spent
        less time in nursing homes in their last months of life.
        A systematic review of the effectiveness of specialist palliative care teams identified 18 studies,
        including five randomised controlled trials.239 Specialist palliative care teams were associated
        with more time spent at home by patients, satisfaction of patients and their carers, symptom
        control, a reduction in the number of inpatient hospital days, a reduction in overall cost, and
        with the patient dying where they wished.

CUTANEOUS MELANOMA  http://chn-health.com

         B   Patients with advanced melanoma require a coordinated multiprofessional approach with
             input from a specialist palliative care team.

         D   Patients with poorly controlled symptoms should be referred to specialist palliative care
             at any point in the cancer journey.

                     http://chn-health.com MELANOMA IN WOMEN

9     Melanoma in women
      Pregnancy is frequently associated with increased activity of benign melanocytes leading to
      pigmentary changes. This has led to concern that pregnancy is deleterious for women with
      The prognoses of women with thickness-matched melanomas who embarked on a pregnancy
      after apparently successful surgical treatment of AJCC stage I or II melanoma have been
      compared.240-243 No difference in disease-free or overall survival is found between women who           2++
      have, and women who have not, become pregnant after melanoma treatment. Prognosis is mainly
      dependent on tumour thickness.240-243
      There is no substantial evidence of an effect of pregnancy in women with stage III and IV
      melanoma, but as the prognosis for these groups is already poor, the possibility of a maternal
      death during pregnancy or when the child is an infant is high. Obstetricians and others managing
      pregnant women with advancing stage IV melanoma should be aware that terminating the pregnancy
      will have no effect on the outcome for the mother.
      The placenta of an infant born to a mother with stage III or IV melanoma should be examined for
      the presence of melanoma metastases. If they are present there is a 20% risk of death of the baby
      from transplacental melanoma.244-246
      Women who develop melanoma during a pregnancy show a greater mean thickness of the primary
      lesion at the time of excision than age-matched non-pregnant women.242,243 This suggests either
      delayed diagnosis or accelerated growth due to the hormonal and immunological environment               2++
      of pregnancy. There is no evidence to support the suggestion that it is physiological for melanocytic
      naevi to change during pregnancy.247
      There are no good data on prognosis for women who embark on a pregnancy having had a
      melanoma diagnosed and treated during a previous pregnancy. One paper reports that patients             4
      with stage I or II disease have no greater recurrence rate than non-pregnant age-matched controls
      but that those with nodal disease have significantly higher recurrence rates.248

       þ     Women with a significant risk of recurrence (localised disease of >1mm thickness) who
             wish to become pregnant after surgery for stage I or II melanoma should be advised to
             delay pregnancy for two years postsurgery, as the likelihood of recurrence is highest during
             this period.

       þ     Pregnant women who present with growing or changing pigmented lesions should be
             treated as non-pregnant women.

      Meta-analysis provides no evidence that use of the oral contraceptive is a risk factor for
      melanoma.249 Five large studies indicate that oral contraceptive use by women after surgery for         2++
      stage I or II melanoma does not adversely affect their prognosis.248,250-254

       þ     Women who have had a melanoma treated should select contraception in the same way
             as women who have not had a melanoma.

      Five case controlled studies show no effect of HRT as a risk factor for melanoma.251,252,255,256,257    2+

       þ     Women who have had stage I and II melanoma and who wish to take HRT should be
             treated as women who have not had melanoma.

CUTANEOUS MELANOMA     http://chn-health.com

 10     Information for patients
        Patients and their families need information to help them understand and cope with the diagnosis
        of melanoma, the treatment options and possible outcomes.

        Twelve focus groups with melanoma patients in three different areas of Scotland were held in
        July and August 2002. To protect patient confidentiality clinicians wrote to patients directly
        asking them to contact SIGN if they were interested in taking part in a focus group. An external
        consultant led each group and SIGN Executive staff took notes. All focus group participants
        agreed to the discussions being recorded on audiotape for the purposes of analysis. A total of 75
        people attended the groups, 27 men and 48 women.
        The key messages from the focus group reports were fed back to the guideline development group
        and guided both the good practice points in this section and The Notes For Discussion With
        Patients and Example Patient Information Leaflet (sections 10.5 and 10.7).

        Most patients would prefer the diagnosis to be given face to face, with exceptions in the interest
        of receiving the diagnosis in a speedy manner. Diagnoses given on answerphones, via letters that
        arrived at the weekend, or by ‘phone calls to the workplace were generally unacceptable.
        Information giving at diagnosis
        Many people reported that their minds “went blank” at diagnosis, and that some basic written
        information to take away (including definitions of terms), and scheduling a follow up appointment
        shortly afterwards to answer patients’ and/or families’ questions would be helpful.
        Information giving throughout the journey of care
        The best approach is a mix of verbal and written information. The level of detail required is
        personal and varies from patient to patient. Information for family and friends is also required.
        Patient anxiety
        Most reported profound anxiety as a result of a cancer diagnosis, with no clear time limit when
        this fades. Patients had many unanswered questions, such as: What caused my melanoma? What
        is melanoma? How can I prevent it in the future? What changes should I make in my life? How
        do I break this news to partners, families and friends?
        Frequency of follow up
        Every three months in the first year then every six months in or after the second year were
        perceived to be adequate follow up schedules for most patients. After year two, most patients are
        happy to be seen annually or to be discharged with open access back to see a specialist if
        required: specialists should make it clear to patients to get in touch if they are worried.
        Which clinician?
        Patients in various locations reported seeing different clinicians: general practitioners, surgeons,
        oncologists and dermatologists. Some patients reported having had no contact with a dermatologist.
        Many patients reported feeling ill-equipped to check their own skin and felt confused and anxious
        about this. Many patients felt that they had been rushed through appointments. The majority of
        patients liked the idea of having access to a specialist nurse who could spend more time with
        them and who could also have a psychological counselling role.

                                             10 INFORMATION FOR PATIENTS

       An RCT of stage I melanoma patients suggests that a structured information programme to
       inform patients about melanoma progression and treatment options increased patients’ knowledge
       of the disease, the risk factors involved and possible preventative measures.258 The study reported                    1-
       no difference in psychological variables. A second RCT found that facilitated education programmes                     1+
       for stage I and II melanoma patients, in which one element was an information programme in                             2
       relation to cancer recurrence, had a positive effect on coping behaviour and affective distress
       values.259 A prospective cohort study with patients with metastatic disease found that patients
       who understood the expected outcomes of their disease had higher quality of life scores and
       longer survival periods.260
       The provision of information to patients increases their knowledge of the disease, can enhance
       coping behaviour and reduce levels of affective distress.

           C      Patients should receive targeted information throughout their journey of care.

           þ      Healthcare professionals working with cancer patients should have training in
                  communication skills.

       Patients benefit from psychoeducational interventions provided in a structured group, facilitated
       by qualified personnel.258-261 The studies suggest that facilitated groups can help patients cope                      1-
       better at all stages of the disease, increase knowledge levels and reduce affective distress.

           þ      Health service patient support groups should be structured, facilitated by trained
                  professionals and incorporate health education.

           þ      Information on all patient support groups should be made easily available to patients.

       The following points were drawn up by the guideline development group using the feedback
       from the focus groups held with patients (see section 10.1). These notes may be of use to health
       professionals when discussing melanoma with patients and carers. They may also be useful in
       guiding the production of local patient information materials. The advice is divided into sections
       to highlight the issues that patients and carers might wish to discuss at each stage of care.
       ‘The information that I got was really very factual about what it is and what will happen now and I found that very
       helpful ‘cause I got it before the diagnosis and they told me that it could’ve been malignant and so I was expecting
       it and I knew what would come next and I was quite fine with that.’ (patient quote)
       n       How long will it be before the results are back?
       n       How will I receive my diagnosis?
       n       If the results are negative, how likely is it that I may get skin cancer in the future?
       n       How accurate are the test results?
       n       How will I be given the results?
       n       What happens next if it is cancer?
       n       Where can I get more information in the meantime and who can I speak to?

CUTANEOUS MELANOMA        http://chn-health.com

        ‘When I went out I said to the nurse “what’s a melanoma?’’.’
        ‘I think a good simple leaflet would’ve been good at the time and then maybe a recommended website, I’m always
        kind of wary going into websites, you want something that’s recommended by them, a good website.’
        ‘I wanted to know how not to make it happen again.’ (patient quotes)
        n   What is melanoma?
        n   What does malignant mean?
        n   What caused it?
        n   Why did this happen to me – I’m not a sun worshipper and never have been?
        n   Who can I talk to?
        n   What are my treatment options?
        n   Where can my family and I find more information?
        n   Are my family and/or other relatives likely to get melanoma?
        n   How will I tell my family? Can I get help to do this?
        n   How long will treatment go on for?
        n   Will it be painful treatment?
        n   Am I going to die?
        n   What is involved in the surgery?
        n   What are the types of surgery and their success rates?
        n   How long will I need to wait?
        n   What happens after surgery?
        n   Will the scarring be bad? Will I need skin grafts? Where will these be taken from?
        n   Will I get all my treatment here, or will I have to go somewhere else? Where will that be?
        n   How do I get to that hospital?
        n   Will I have to see lots of different doctors, or will it be the same one?
        n   Which specialists am I likely to see?
        n   If I want to ask questions who should I ‘phone? What’s the ‘phone number?
        n   How long will my treatment last?
        n   Will I be able to drive to and from hospital?
        n   Will I be able to carry on working? How much sick leave will I need?
        n   Am I entitled to any benefits (if I have to stop work for a long time)? Who do I ask?
        n   What are the side effects of chemotherapy?
        n   When will I know if I am cured?
        FOLLOW UP
        ‘I would like to be on top of the facts and to be in control of the situation so that I know what I’m looking for and know
        what to do to prevent it as far as is possible.’ (patient quote)
        n   How often will I be followed up and for how long?
        n   Who will I see in the clinic?
        n   What should I do if I am worried in between hospital appointments?
        n   How is my GP involved?
        n   Can I ‘phone someone in the clinic?
        n   How do I check my skin in between visits? What am I looking for?
        n   What is a body map?
        n   Why do some patients have photographs taken?
        n   How can I check my back if I live alone or if my partner feels uncomfortable helping me?
        n   Can melanoma come back somewhere I can’t see it?
        n   Can I still go out in the sun?
        n   Can I still holiday in sunny destinations? What precautions should I take?
        n   Where can I get information and support for myself and my family?

                                          10 INFORMATION FOR PATIENTS

         n   How long have I got?
         n   Will there be a lot of pain? How will the pain be controlled?
         n   Can I stay at home? Who will care for me?
         n   Which specialists am I likely to see?
         n   Is there a local respite unit for day care?
         n   Is there a hospice, or are there “hospice beds” in hospital? How are they accessed?
         n   How do I access advice from occupational therapy on coping with practical problems and on
             provision of equipment to help me cope at home?
         n   Where can I get advice about or obtain a loan or provision of a wheelchair?
         n   Where can I get advice or help with coping with symptoms like extreme tiredness or general

         Please note that the information from some organisations will be particularly focussed on advanced
         stages of cancer and should be accessed with caution as the information may not be relevant and
         could be upsetting to some patients and their carers. This information is correct at the time of
         going to press.

         Marcs Line Resources Centre
         Dermatology Treatment Centre, Level 3, Salisbury District Hospital,
         Salisbury, Wiltshire, SP2 8BJ
         Tel: 01722 415071
         Email: marcsline@wessexcancer.org
         MARCS Line (Melanoma And Related Cancers of the Skin) is a national resource on matters
         pertaining to skin cancer.

         CancerBACUP Scotland
         Suite 2, 3rd Floor, Cranston House, 104-114 Argyle Street, Glasgow G2 8BH
         Tel: 0141 223 7676, Fax: 0141 248 8422, FREEPHONE: 0808 800 1234 Mon-Fri 9-7
         Offers a free cancer information service staffed by qualified and experienced cancer nurses, a
         growing number of CancerBACUP centres in hospitals up and down the country and a freephone
         information service on all types of cancer, staffed by specialist cancer nurses. Produces over 60
         booklets and ‘CancerBACUP News’ three times a year.
         Cancer Research UK
         P.O. Box 123, Lincoln’s Inn Fields, London WC2A 3PX
         Tel: 020 7009 8820, Fax: 020 7269 3100
         A new charity that was formed in 2002 as a result of the merger between The Cancer Research
         Campaign and Imperial Cancer Research Fund.
         Macmillan Cancer Relief Scotland
         Osbourne House, 1-5 Osbourne Terrace, Edinburgh, EH12 5HG
         Tel: 0131 346 5346, Fax: 0131 346 5347, Helpline:0808 808 2020 Mon-Fri 9-6
         A UK charity supporting people with cancer and their families with specialist information,
         treatment and care.

CUTANEOUS MELANOMA      http://chn-health.com

          Maggie’s Centres Scotland
          The Stables, Western General Hospital, Edinburgh, EH4 2XU
          Tel: 0131 537 3131, Fax: 0131 537 3130
          Maggie’s Centre Glasgow
          The Gatehouse, Dumbarton Road, Glasgow, G11 6PA
          Tel: 0141 330 3311, Fax: 0141 330 3363
          Email: maggies.centre@ed.ac.uk, www.maggiescentres.org
          The goal of Maggie’s is to keep people who have cancer as healthy in mind and body as is
          possible, by enabling them to participate actively in the treatment of their disease. A Maggie’s
          Centre is also opening in Dundee.
          Marie Curie Cancer Care Scotland
          29 Albany Street, Edinburgh, EH1 3QN
          Tel: 0131 456 3700
          Dedicated to the cure of people affected by cancer and the enhancement of their quality of life
          through its caring services, research and education.
          Tak Tent Cancer Support Scotland
          Flat 5, 30 Shelley Court, Gartnavel Complex, Glasgow, G12 0YN
          Tel: 0141 211 0122, Fax: 0141 211 3988
          Email: tak.tent@care4free.net, www.taktent.org.uk
          Promotes the care of cancer patients, their families, friends and the staff involved professionally
          in cancer care by providing practical and emotional support, information, counselling and therapies
          as required. Network of local support groups throughout Scotland. The Youth Group, conTak,
          provides support for 16 to 25 year olds affected by cancer.

          NHS Health Scotland (formerly known as the Health Education Board for Scotland or HEBS)
          Woodburn House, Canaan Lane, Edinburgh, EH10 4SG
          Tel: 0131 536 5500, Textphone: 0131 536 5503, Fax: 0131 536 5501
          Scotland’s national agency for health education, promotion, advice and information.

          The Skin Cancer Foundation
          A North American website with some useful sections and resources.

          An example information sheet for patients who have had a level II or III melanoma <1 mm thick
          removed is given on the next page. Healthcare professionals may wish to adapt this for use in
          their own departments, remembering to insert the relevant local details.

                                 10 INFORMATION FOR PATIENTS

                           MELANOMA OF THE SKIN
You have recently had a small operation on your skin and examination of the sample under
the microscope showed that the problem was a malignant melanoma, a type of skin cancer.
You may have a lot of questions and worries, and the purpose of this leaflet is to help with
some of them but not to be a substitute for a good conversation with your specialist. It is a
good idea to:
n   write down all the questions you would like answered and bring them to your next
    hospital visit
n   bring another family member or close friend so that you can both discuss the information
    after your visit and be sure that you both have the same memory of what was said. This
    will help your family understand what has happened which makes it in turn easier for you
    to cope with a worrying situation.
                         HOW WILL I BE FOLLOWED UP?
Your melanoma was in the skin and has been removed by either one or two operations. After
these the majority of people who have had melanomas of a similar thickness as yours remain
well with no further problems, but because just over one in ten do develop signs of melanoma
spread, we plan to see you back at the clinic for check ups every (insert local details). At
these visits we will:
n   look at and feel your scar
n   check the lymph glands in your groin or armpit to be sure none are bigger than normal
n   give you a total body skin examination to be sure that you do not have another small early
    treatable melanoma (once you have had one melanoma you are at increased risk of
    developing a second so we aim to identify and treat this as soon as possible).
Some people with melanoma have a very large number of moles. If you are in this group we
may take photographs of some of these moles, and compare your skin with these photos at
your clinic visits. Not everyone however needs these photographs.
If you have any worries between visits we will always see you early so do not hesitate to
‘phone (insert relevant phone number) and ask for your pigmented lesion clinic appointment
to be brought forward.
                          WHY DID I GET A MELANOMA?
We also want to know the answer to this question so that we can try to prevent other people
developing melanoma in the future. In about two thirds of people with melanoma too much
sun exposure is important. This may be a childhood spent in a sunny country, or a history of
many sunny summer holidays, particularly if you remember severe sunburn with blistering or
peeling. People with melanoma are usually white skinned and have very pale skin which does
not tan easily but goes red in the sun. They are often fair or red haired, have blue eyes and
may have a lot of both moles and freckles. However, about one third of people with melanoma
do not fit in to the group described above and may have inherited genes which makes them
more likely to develop melanoma. Research in this area is ongoing.
In Scotland, one melanoma patient in 50 has a history of melanoma in a close relative. If you
are in this group your children could be at increased risk. In these families we offer regular
skin examinations to all family members. If you do not have a close relative who has also had
melanoma your children are not at greater risk, but most families that have had a person with
melanoma become very careful and sensible about avoiding sun damage. If any of your family
members have moles on their skin, which you would like us to check, please ask. We will be
happy to help.

CUTANEOUS MELANOMA    http://chn-health.com

                                        WHAT DO I DO NOW?
        Most people with melanoma do not tolerate sunbathing well and sunburn could increase your
        risk of a second melanoma. We therefore suggest that you become very sensible over sun
        exposure. This does not mean never having a holiday in a sunny country but it does mean
        avoiding strong Mediterranean noonday sun. Comfortable cotton clothing is an excellent
        sunscreen so plan your holiday wardrobe around long cotton trousers or skirts, long- sleeved
        cotton tops and a hat.
        Sunscreen creams, even those called total sunblock, have not yet been shown to protect
        against melanoma. They do prevent sunburn, so use them as part of your skin protection
        routine, but not in place of clothing. Remember that you can get sunburned in Scotland as
        well as on a Spanish beach so do follow the safe sun routine during good weather in this
        country as well as abroad.
                                      FURTHER INFORMATION
        Please ask us any other questions that are important to you. Women may want to ask about
        future pregnancies, use of the oral contraceptive or hormone replacement therapy. Advice is
        best tailored to you personally so do tell us your particular worries. Although there is a large
        amount of information on the Internet, much of it is aimed at the minority of patients whose
        melanoma has spread beyond their skin. It therefore does not apply to you, and you may find
        it unnecessarily alarming.
                    CONTACT TELEPHONE NUMBER (insert relevant number)
        Please try to have your clinic card with you when you telephone as it carries your hospital
        number which will help us obtain your records as quickly as possible.

                                           11 IMPLEMENTATION AND AUDIT

11       Implementation and audit
         Managed Clinical Networks (MCNs) are defined as:
         ‘linked groups of health professionals and organisations from primary, secondary and tertiary
         care, working in a coordinated manner, unconstrained by existing professional and Health Board
         boundaries, to ensure equitable provision of high quality clinically effective services throughout
         Scotland.’ 262
         Managed Clinical Networks allow representatives from relevant specialties to discuss individual
         treatment plans and be aware of those patients likely to progress from an early stage in their
         disease. In the case of melanoma, the likely specialists who would be included in a MCN may
         be GPs, dermatologists, pathologists, surgeons in subspecialties, medical and clinical oncologists
         and palliative care specialists. Managed Clinical Networks are particularly beneficial for patients
         being cared for by health professionals unfamiliar with melanoma and they should also ensure
         that all eligible patients are offered the opportunity to enter into appropriate trials of new therapy.
         They require an administrative infrastructure and specialist nurse support which means they may
         have financial implications.

         The development process for this guideline has included explicit consideration of economic and
         resource issues. This has been achieved through a review of the economics literature on specific
         recommendations and through the use of the SIGN resource use implications checklist. The aim
         of considering health economic aspects as an integral part of the guideline was to ensure the
         efficient use of healthcare resources and to provide information to assist implementation.

         A systematic literature review was performed for a number of specific recommendations in the
         guideline. Each study identified was reviewed according to a standard checklist used to critique
         economic evaluations.

         A well conducted cost-effectiveness analysis using a hypothetical cohort of 50 year old Australians
         suggested that screening for melanoma by primary care physicians may be relatively cost effective.263
         Comparing an organised programme of screening to the existing opportunistic regime, the model
         predicted that the cost per life year saved for men was Aus$6,853 to $12,137 for five-yearly and
         two-yearly screening respectively. The programme was less cost effective in women principally
         due to lower mortality from melanoma. The cost effectiveness of screening in high-risk populations
         has also been addressed in two American studies.264,265 The findings suggested that such programmes
         were cost effective compared to other screening programmes used in the USA. The cost-effectiveness
         ratios were however sensitive to changes in the cost of the screening test and the prevalence of
         disease and hence the economic efficiency of screening high-risk individuals in Scotland may
         differ. No economics evidence was found which would support mass screening programmes.

         The key interest here is how the information obtained from the SLNB changes patient management,
         subsequent outcomes and associated costs. Only one study was identified, a cost analysis of 73
         patients in the USA undergoing SLNB or an elective lymph node dissection (ELND).266 The results
         indicate that significant cost savings could be made by using SLNB rather than ELND. The study
         was non-randomised and hence subject to potential bias in the distribution of cost drivers between
         the groups, making the conclusion unreliable. Information on final patient outcomes was also
         lacking making it hard to be certain of the cost effectiveness of the intervention, particularly
         when applied to the UK setting.

CUTANEOUS MELANOMA       http://chn-health.com

          Five economic evaluations or cost studies relating to adjuvant interferon therapy were
          reviewed.270-274 Three studies used the trial results from the E1684 trial and hence investigated the
          cost effectiveness of adjuvant high-dose interferon therapy versus observation alone. 270-272 These
          studies all found cost per life year gained and cost per QALY (Quality Adjusted Life Years)
          figures that would be considered broadly acceptable by current conventions. The UK meta-
          analysis and economic analysis however found insufficient evidence of benefit and thus, given
          its considerable incremental cost, concluded that it could not be recommended for routine use
          in the UK.273 The remaining economic evaluation was a French study examining the cost
          effectiveness and cost utility of low-dose interferon in patients with surgical resection of AJCC
          stage II melanoma versus observation alone.274 The cost effectiveness ratios in this study represent
          reasonable value for money. The majority of economic evaluations were based on the E1684 trial
          however that had the most positive findings, therefore cost effectiveness will tend to have been
          overstated. Further, if no significant difference exists in overall survival (as was found in the
          E1684 and French studies), the use of life years gained as an outcome is not tenable (since
          obviously no life years have been gained) rendering the cost-effectiveness results invalid. The
          robustness of the findings of the economic evaluations must be questioned.

          A German study used retrospective case note review to examine the relative cost effectiveness of
          various tests used in the follow up of patients with stage I-III disease.275 The study did not assess
          the value of surveillance per se nor the cost effectiveness of various frequencies of contact. The
          results indicated that at any stage of melanoma and follow up the most cost-effective test was
          physical examination and that lymph node sonography was the best performing imaging procedure,
          albeit less cost effective than physical examination. Similar conclusions were reached in a French
          study of patients with stage I melanoma.181 Both studies suffered from methodological weaknesses
          but they tend to support the recommendations made in section 7.

          n   Are resource implications of implementation of the guideline likely to be significant nationally
              or locally such that they cannot be absorbed within existing resource allocations?
              It is hard to ascertain whether the implementation of this guideline can be met within existing
              resources. This is because the guideline contains both recommendations that may require
              new funds for implementation and recommendations that may halt certain existing practices,
              thereby freeing up resources. The net effect of this is hard to quantify and will depend on
              current standards, practices and resources in each Health Board area.
          n   Will the guideline affect outcomes or resource use in other areas of the NHS (such as primary
              care, other clinical specialties, support departments)?
              By recommending that all health professionals should be encouraged to examine patients for
              potential melanomas, there is likely to be a potential impact on all areas of clinical practice
              in NHSScotland. Resources for staff training and education may be required to implement
              this recommendation. Many of the recommendations made in section 2 will have an impact
              on pathology departments. Similarly, the need for appropriate palliation services recommended
              in section 8.4 may require investment if adequate services are not already available.
          n   Will guideline implementation affect outcomes or resource use in partner organisations (eg
              social work or the voluntary sector)?
              Palliative care services provided by charitable organisations may experience resource effects
              through the implementation of the guideline. Such organisations may also be involved in the
              provision of patient/carer information and support groups.
          n   Will guideline implementation affect costs to patients, for example will they face additional
              visits to hospital/GPs or have to spend longer in hospital?

                                         11 IMPLEMENTATION AND AUDIT

           The costs of appropriate primary preventative products recommended in the guideline
           (sunscreens, hats and clothing) will result in costs to patients.
       n   Impact on other groups?
           Implementation of the guideline is unlikely to affect other groups.

       n   A quantitative questionnaire study exploring patients’ views of melanoma care in Scotland,
           focussing on their views on diagnosis, follow up and education for self examination.
       n   A long term follow up trial to evaluate the Cochran model of survival, using survival statistics
           from the Scottish Melanoma Group database with reference to the following histological
           prognostic parameters:
           n    ulceration
           n    the relationship between the presence of regression and follow up
           n    the role of melanoma cell type
           n    the plasma cell in the inflammatory infiltrate
           n    sentinel node pathology.
       n   A study of negative SNLB patients that correlates tumour thickness, negative SNLB status and
       n   A prospective trial to define the role of CT, MRI and PET in staging patients with stage II and
           III (in both gross- and micro-metastatic) disease.
       n   The role of specialist melanoma nurses.
       n   Health professionals’ communications skills in caring for patients with cancer.
       n   Who uses sunbeds and why?
       n   The role of PET scanning to identify distant disease.
       n   Does psychological and emotional support from an early stage of diagnosis influence outcomes
           for patients?

11.4   AUDIT
       The Scottish Executive publication, Cancer in Scotland: Action for Change, highlighted the
       importance of prospective clinical audit of cancer services.276 In Scotland, through the Scottish
       Melanoma Group (SMG), there has been a long tradition of data collection relating to melanoma
       of all sites other than the eye.277 The development of this guideline provides an opportunity to
       review the content of the SMG dataset, taking account of the measurable recommendations, as
       well as the needs of other stakeholders (in relation to clinical standards, waiting times etc). A
       multidisciplinary group has been convened to review the SMG dataset, with a view to developing
       a draft dataset and data definitions for consultation through the three cancer networks in Scotland,
       prior to implementation. The dataset produced will be available from the SIGN website

CUTANEOUS MELANOMA    http://chn-health.com

 12     Development of the guideline
        SIGN is a collaborative network of clinicians, other healthcare professionals, and patient
        organisations, funded by NHS Quality Improvement Scotland. SIGN guidelines are developed by
        multidisciplinary groups using a standard methodology based on a systematic review of the
        evidence. Further details about SIGN and the guideline development methodology are contained
        in “SIGN 50: A Guideline Developer’s Handbook”, available at www.sign.ac.uk

        Dr Valerie Doherty (Chairman)       Consultant Dermatologist, Royal Infirmary, Edinburgh
        Mr Taimur Shoaib (Secretary)        Specialist Registrar in Plastic Surgery,
                                            Canniesburn Hospital, Glasgow
        Ms Moira Black                      Health Visitor, Perth
        Dr David Brewster                   Director of Cancer Registration in Scotland,
                                            Information and Statistics Division, Edinburgh
        Dr Graham Duncan                    General Practitioner, Kirkcaldy
        Dr Alan T Evans                     Consultant Histopathologist,Ninewells Hospital, Dundee
        Dr Marie Fallon                     Senior Lecturer in Palliative Medicine,
                                            Western General Hospital, Edinburgh
        Mrs Carol Horne                     Manager, TakTent Cancer Support, Glasgow
        Professor Rona MacKie               Consultant Dermatologist, Glasgow University
        Mrs Lesley Marley                   Senior Health Promotion Officer, NHS Tayside, Dundee
        Mr Alan J McKay                     Consultant Vascular Surgeon,
                                            Gartnavel General Hospital, Glasgow
        Dr Kathryn McLaren                  Senior Lecturer, Pathology, University of Edinburgh
        Dr Iain McLellan                    General Practitioner, Kilmalcolm, Renfrewshire
        Dr Nigel McMillan                   Consultant Radiologist, Western Infirmary, Glasgow
        Mr Jack Miller                      Consultant Surgeon, Dr Gray’s Hospital, Elgin
        Dr Marianne Nicolson                Consultant in Medical Oncology, Aberdeen Royal Infirmary
        Dr Jonathan Norris                  Consultant Dermatologist,
                                            Dumfries and Galloway Royal Infirmary
        Dr Gerry Robertson                  Consultant Clinical Oncologist,
                                            Beatson Oncology Centre, Glasgow
        Mr Duncan Service                   Information Services Officer, SIGN
        Mrs Karen Smith                     Specialist Nurse, Plastic Surgery,
                                            Ninewells Hospital,Dundee
        Mr David Soutar                     Consultant Plastic Surgeon, Canniesburn Hospital, Glasgow
        Ms Joanne Topalian                  Programme Manager, SIGN
        The membership of the guideline development group was confirmed following consultation
        with the member organisations of SIGN. Declarations of interests were made by all members of
        the guideline development group. Further details are available from the SIGN Executive.
        The development group is also very thankful to the following people for their contributions to
        the development of this guideline:
        Dr Douglas Adamson                  Consultant Clinical Oncologist,
                                            Ninewells Hospital, Dundee
        Ms Ailsa Brown                      Health Economist, Greater Glasgow Health Board

                        http://chn-health.com OF THE GUIDELINE
                                          12 DEVELOPMENT

         Literature searches were initially conducted in Medline, Embase, Cinahl, Cancerlit, and the
         Cochrane Library using the year range 1993-2001. The literature search was updated with new
         material during the course of the guideline development process. A final update literature search
         was performed in March 2003. Key websites on the Internet were also used, such as the National
         Guidelines Clearinghouse. The searches were extended back to 1970 in areas where evidence
         was scarce. These searches were supplemented by the reference lists of relevant papers and group
         members’ own files. The Medline version of the main search strategies can be found on the SIGN


         The national open meeting is the main consultative phase of SIGN guideline development, at
         which the guideline development group presents its draft recommendations for the first time.
         The national open meeting for this guideline was held in March 2002 and was attended by all of
         the key specialties relevant to the guideline. The draft guideline was available on the SIGN
         website for a limited period at this stage to allow those unable to attend the meeting to contribute
         to the development of the guideline.

         The guideline was also reviewed in draft form by a panel of independent expert referees, who
         were asked to comment primarily on the comprehensiveness and accuracy of interpretation of
         the evidence base supporting the recommendations in the guideline. SIGN is very grateful to all
         of these experts for their contribution to this guideline.
         Dr Alan Begg              General Practitioner, Montrose
         Dr Frederick Benton       Medical Director, St Columba’s Hospice, Edinburgh
         Ms Elizabeth Boon         Lay reviewer, Annan, Dumfriesshire
         Professor Martin Cook     Consultant Pathologist, Royal Surrey County Hospital, Guildford
         Dr Michael Cornbleet      Senior Medical Officer, Scottish Executive
         Mr Neil Cox               Consultant Dermatologist, Cumberland Infirmary, Carlisle
         Ms Ashley Duff            Lay reviewer, Edinburgh
         Dr Tim Eisen              Consultant Medical Oncologist,
                                   The Royal Marsden Hospital, London
         Dr Jeffrey Evans          Consultant Oncologist, Beatson Oncology Centre, Glasgow
         Professor Martin Gore     Consultant Medical Oncologist,
                                   The Royal Marsden Hospital, London
         Dr Dermot Gorman          Consultant in Public Health, Lothian NHS Board
         Dr Robert Grant           General Practitioner, Markinch Medical Practice, Fife
         Dr Iain Henderson         General Practitioner, Kingsway Medical Practice, Glasgow
         Dr Richard Johnson        Consultant Radiologist, Christie Hospital, Manchester
         Dr Hassan Kamel           Consultant Pathologist, Medical School, Edinburgh
         Mr Peter Lapsley          Chief Executive, Skin Care Campaign, London
         Professor Hugh MacDougall Consultant Clinical Oncologist,
                                   Western General Hospital, Edinburgh
         Dr Graham McKillop        Consultant Radiologist, Royal Infirmary, Edinburgh
         Dr Allan Merry            General Practitioner, Ardrossan
         Dr Wolter Mooi            Consultant Pathologist, Amsterdam
         Dr Julia Newton Bishop    Dermatologist, St James’s University Hospital, Leeds
         Dr Pawlam Patel           Consultant Medical Oncologist,
                                   St James’s University Hospital, Leeds
         Professor Bruce Ponder    Consultant Oncologist, Addenbrooke’s Hospital, Cambridge
         Professor Roy Rampling    Consultant Oncologist, Beatson Oncology Centre, Glasgow
         Dr Robin Russell Jones    Consultant Dermatologist, St Thomas’s Hospital, London

CUTANEOUS MELANOMA       http://chn-health.com

          Ms Jeanette Semple         BACP Accredited Counsellor, Glasgow
          Professor Anthony Swerdlow Professor of Epidemiology,
                                     The Institute for Cancer Research, London
          Mr Meirion Thomas          Consultant Surgeon, The Royal Marsden Hospital, London
          Ms Margaret Thomson        Senior Occupational Therapist, Scottish Occupational Therapy
                                     Network in Oncology and Palliative Care,
                                     North Glasgow Hospitals Trust
          Professor John Thompson    Director, The Sydney Melanoma Unit, Professor of Surgery
                                     (Melanoma and Surgical Oncology),
                                     The University of Sydney, Australia
          Ms Jennifer Whelan         Head of CancerBACUP Scotland, Glasgow

          As a final quality control check, the guideline is reviewed by an Editorial Group comprising the
          relevant specialty representatives on SIGN Council to ensure that the specialist reviewers’ comments
          have been addressed adequately and that any risk of bias in the guideline development process as
          a whole has been minimised. The Editorial Group for this guideline was as follows:
          Professor Peter Donnelly        Academy of Medicine
          Mr Douglas Harper               Royal College of Surgeons, Edinburgh
          Dr Grahame Howard               Royal College of Radiologists, Faculty of Oncology
          Professor Gordon Lowe           Chairman of SIGN, Co-editor
          Dr Safia Qureshi                SIGN Programme Director
          Dr Sara Twaddle                 Director of SIGN, Co-editor
          Dr Peter Wimpenny               School of Nursing and Midwifery
          Each member of the guideline development group then approved the final guideline for publication.

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Update to printed guideline  http://chn-health.com
20 Feb 2004

Section 10.6.2 Cancer Research UK

Changed from -

Cancer Research UK
P.O. Box 123, Lincoln's Inn Fields, London WC2A 3PX
Tel: 020 7269 3100


Cancer Research UK
P.O. Box 123, Lincoln's Inn Fields, London WC2A 3PX
Tel: 020 7009 8820, Fax: 020 7269 3100

Section 10.6.2 Maggie's Centres Scotland

Changed from -

Maggie's Centres Scotland
The Stables, Western General Hospital, Edinburgh, EH4 2XU
Tel: 0131 537 3131, Fax: 0131 537 3130
Maggie's Centre Glasgow
The Gatehouse, Dumbarton Road, Glasgow, G11 6PA
Tel: 0141 330 3311, Fax: 0141 330 3363
Email: maggies.centre@ed.ac.uk, www.maggies.ed.ac.uk


Maggie's Centres Scotland
The Stables, Western General Hospital, Edinburgh, EH4 2XU
Tel: 0131 537 3131, Fax: 0131 537 3130
Maggie's Centre Glasgow
The Gatehouse, Dumbarton Road, Glasgow, G11 6PA
Tel: 0141 330 3311, Fax: 0141 330 3363
Email: maggies.centre@ed.ac.uk, www.maggiescentres.org

15 Aug 2003

Amendments to quick reference guide and back page of guideline

Risk factors for cutaneous melanoma

Changed from -

Giant congenital melanocytic naevi ≥ 20 mm diameter


Giant congenital melanocytic naevi ≥ 20 cm diameter
ADJUVANT TREATMENT OF STAGE II & III DISEASE                            MANAGEMENT OF STAGE IV DISEASE                                            INFORMATION FOR PATIENTS

D   The routine use of adjuvant radiotherapy is not recommended         A   § Dacarbazine (DTIC) is the standard single agent of choice           C   Patients should receive targeted information throughout their
    for patients who have had therapeutic lymph node dissections              in stage IV melanoma                                                    journey of care
                                                                            § Multiple drug regimens (eg with tamoxifen and interferon α)
A   Adjuvant interferon should not be used for AJCC stage II & III            do not improve survival compared to single agent DTIC
    melanoma patients other than in a trial setting                           and are not recommended outside clinical trials                     Marcs Line Resources Centre
                                                                                                                                                  MARCS Line (Melanoma And Related Cancers of the Skin)
þ   § Patients with AJCC stage II & III disease should be offered       þ   § Metastasectomy should be considered in patients with stage
      entry into trials to confirm whether or not interferon                  IV disease                                                          Dermatology Treatment Centre, Level 3
      therapy extends the disease-free interval after surgery               § All patients with painful bone metastases should be offered         Salisbury District Hospital, Salisbury, Wiltshire, SP2 8BJ
    § Patients should be entered into vaccine clinical trials as              radiotherapy                                                        Tel: 01722 415071
      appropriate                                                                                                                                 Email: marcsline@wessexcancer.org
                                                                        D   Single dose radiotherapy of at least 8 Gy is an effective treatment   CancerBACUP Scotland
PATIENT FOLLOW UP IN STAGE I, II & III DISEASE                              for bone metastases
                                                                                                                                                  Suite 2, 3rd Floor, Cranston House, 104-114 Argyle Street,
D   Patients who have had melanoma in situ do not require follow up     þ   All patients with spinal cord compression should be referred
                                                                                                                                                  Glasgow G2 8BH
                                                                            urgently for surgical intervention and/or palliative radiotherapy     Tel: 0141 223 7676, Fax: 0141 248 8422
þ   § Patients with an invasive melanoma should be followed up                                                                                    FREEPHONE: 0808 800 1234
    § The frequency and duration of follow up should be                 D   § Patients with favourable CNS disease, good performance              www.cancerbacup.org.uk
      determined from the timing and rate of recurrence of the                status, favourable response to corticosteroid treatment,            Tak Tent Cancer Support Scotland
      individual patient’s melanoma, taking into account the                  and without systemic disease should be considered for
      patients’ psychological and emotional needs                             surgical resection of their CNS disease                             Flat 5, 30 Shelley Court, Gartnavel Complex
    § Stage III patients with lymph node metastases may need                § If surgery is not possible, whole brain radiotherapy                Glasgow, G12 0YN
      lifelong follow up                                                      combined with corticosteroids may help palliate                     Tel: 0141 211 0122 Fax: 0141 211 3988
                                                                              neurological symptoms                                               Email: tak.tent@care4free.net, www.taktent.org.uk
B   Routine full blood counts, liver function tests, tumour markers,
                                                                                                                                                  Maggie’s Centres Scotland
    chest X-rays and lactate dehydrogenase are not recommended          þ   Patients with metastatic melanoma should be treated within a
    as part of a follow up schedule in the asymptomatic patient             clinical trial wherever possible and be offered palliative care       maggies.centre@ed.ac.uk, www.maggies.ed.ac.uk

þ   § Patients should be educated in self assessment techniques to      B   Patients with advanced melanoma require a coordinated
      detect local and nodal recurrent disease and secondary                multiprofessional approach with input from a specialist palliative
      lesions and appraised of the possibility of late recurrence           care team
    § There should be an easy route into the clinic if problems
      occur between clinic visits or after discharge                    D   Patients with poorly controlled symptoms should be referred to
                                                                            specialist palliative care at any point in the cancer journey

                                                                        MELANOMA IN WOMEN

                                                                        þ   § Women with a significant risk of recurrence (localised
                                                                              disease of >1mm) who wish to become pregnant after
                                                                              surgery for stage I & II melanoma should be advised to
                                                                              delay pregnancy for two years postsurgery, as the
                                                                              likelihood of recurrence is highest during this period
                                                                            § Women who have had a melanoma treated should select
                                                                              contraception in the same way as women who have not
                                                                              had a melanoma
                                                                            § Women who have had stage I & II melanoma and who
                                                                              wish to take HRT should be treated as women who have
                                                                              not had melanoma
                                                                       CUTANEOUS MELANOMA

PREVENTION, SURVEILLANCE & GENETICS                                   DIAGNOSIS & PROGNOSTIC INDICATORS                                    SURGERY

B    Healthcare professionals and members of the public should be    D    § Clinicians should be familiar with the 7 point or ABCDE        RECOMMENDED EXCISION MARGINS
     aware of the risk factors for melanoma                                 checklist for assessing lesions
                                                                          § Clinicians using hand held dermatoscopy should be                   STAGING                                  MARGINS
D    Genetic testing should only be undertaken in the context of            appropriately trained                                          B    pT1 (melanoma 0 to 1 mm)                1 cm
     appropriate research studies                                         § Health professionals should be encouraged to examine
                                                                                                                                           B    pT2 (melanoma 1 to 2 mm)                1 to 2 cm
                                                                            patients’ skin during other clinical examinations
RISK FACTORS FOR CUTANEOUS MELANOMA                                                                                                        B    pT3 (melanoma 2 to 4 mm)                2 cm
                                                                     þ    § Emphasis should be given to the recognition of early           D    pT4 (melanoma >4 mm)                    2 cm
                              11-50 common moles >2mm                       melanoma by both patients and health professionals
       RISK                   51-100 common moles >2mm                    § Patients with suspicious pigmented lesions should be seen
                              >100 common moles >2mm                        at a specialist clinic in a time commensurate with the level   þ   § The deep excision margin should incorporate adipose tissue
                                                                            of concern indicated by the GP referral letter                       down to but not including the deep fascia
Family history of melanoma                                                § GPs should refer urgently all patients in whom melanoma is a       § Excision margins should be recorded by the surgeon
Previous history of melanoma                                                strong possibility rather than carry out a biopsy in primary       § In open biopsy the incision must be placed in the same line
Presence of 1-4 atypical moles                                                                                                                   as for a potential radical lymphadenectomy
Red or light coloured hair                                           D    A suspected melanoma should be excised with a 2 mm margin
Presence of actinic lentigines                                            and a cuff of fat                                                B   § Radical lymph node dissection requires complete removal
Giant congenital melanocytic naevi ≥ 20 cm diameter                                                                                              of all draining lymph nodes for pathological examination
Unusually high sun exposure                                          C    § If complete excision cannot be performed as a primary              § Elective lymph node dissection should not be performed
Reported growth of a mole                                                   procedure a full thickness incisional or punch biopsy of the         routinely in patients with primary melanoma
Skin that does not tan easily                                               most suspicious area is advised                                    § SLNB should be considered as a staging technique in
Light coloured eyes                                                       § A superficial shave biopsy is inappropriate for suspicious           patients with a primary melanoma >1 mm or a primary
Light coloured skin                                                         pigmented lesions                                                    melanoma <1 mm of Clark level 4
Female sex
                                                                      PATHOLOGY                                                            þ   § ILP is the treatment choice for bulky limb disease for
                                                                                                                                                 patients fit to undergo the procedure
                                                                     D    The macroscopic description of a suspected melanoma should:          § Carbon dioxide laser ablation can be considered for
C    Individuals identified as being at higher risk should be:            § state the biopsy type (excision, incision, or punch)                 multiple lesions of trunk or abdomen and for limb disease
     § advised about appropriate methods of sun protection                § describe and measure (in mm) the biopsy                              when ILP is not appropriate
     § educated about the diagnostic features of cutaneous
                                                                          § describe and measure (in mm) the lesion
       melanoma                                                                                                                            OTHER INVESTIGATIONS/NON-SURGICAL STAGING
     § encouraged to perform self examination of the skin
                                                                     D    § Submit the entire lesion for histopathological exam
                                                                          § Section the lesion transversely at 3 mm intervals              C   Chest X-ray, ultrasound and computerised tomography scanning
THE 7 POINT CHECKLIST            THE ABCDE SYSTEM                                                                                              are not indicated in the initial assessment of primary melanoma,
                                                                          § Do not select cruciate blocks
                                                                                                                                               unless indicated for investigation of clinical symptoms and
MAJOR FEATURES                   A. Geometrical Asymmetry
§ Change in size of lesion          in 2 axes                         Features of a melanoma pathology report
§ Irregular pigmentation         B. Irregular Border                 Essential features                   Desirable features               D   Routine blood tests should not be used to stage asymptomatic
§ Irregular border               C. At least 2 different Colours     B Breslow thickness                    B Histogenetic type                melanoma patients
                                    in lesion
MINOR FEATURES                                                       B Clark level (if Breslow Thickness    þ Cell type
                                 D. Maximum Diameter >6mm                <1mm)
§ Inflammation
                                 E. Elevation of lesion
§ Itch/altered sensation                                             B Ulceration                           þ Host inflammatory
§ Lesion larger than others                                                                                    response
§ Oozing/crusting of lesion                                          B Growth phase characteristics         þ Mitotic rate

                                                                     C Regression

                                                                     B Lymphovascular space invasion

                                                                     B Microscopic satellites

                                                                     D Microscopic clearance (mm)

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