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MelanomaMelanoma

HHISTORYISTORY

John Hunter (1728-1793) first published account of a patient with melanoma (a secondary deposit) 1787 – but was not

known as “melanoma”, histological confirmation only in 1968 by Bodenham described as “melanocytic sarcoma cells”

Rene Laennec (1781-1826) First to describe melanoma as a disease entity in a publication Others claim Dupuytren was the first to describe it in lectures as “cancer noire” First coined the word melanosis in 1812 Described metastatic deposits throughout the body in post mortems

William Norris (1792-1877) First to describe melanoma in English literature 1820 and study it in depth First noted hereditary tendency Also described metastatic deposits in 1857 English general practitioner in Stourbridge for 60 years Published the first comprehensive study of case series of patients with “melanosis” Norris alluded to several principles on melanoma:

o Epidemiological features (moles & melanomas, industrial > rural, light coloured, hereditary disposition, trauma accelerate growth)

o Pathological features (colour, variable pigmentation, satellite tumours, subcutaneous deposits, widespread dissemination)

o Clinical features (smokers, men, usually in good health until late stage)o Management (recurrence, wide excision, no effective treatment for disseminated

disease)Jonathan Hutchinson (1828-1913)

First described subungual melanoma in 1857 Described a series of cases of “Hutchinson’s melanotic freckle” in 1892 An English Generalised Specialist, wrote the Journal: Archives of Surgery for over 11 years

Other notable individuals in 19th and early 20th century Robert Carwell in 1834 used the term melanoma as a synonym for melanosis and then described

it in his book in 1838 David Williams in 1834 described the horizontal and vertical growth phases of a superficial

spreading melanoma Samuel Cooper in 1840 described enucleation of a an eye for melanosis James Paget 1853 described a large series of 25 patients Oliver Pemberton collected 60 patients, published 25 cases 1858, also described the first case of

melanoma in a black manLate 19th century - WLE of 1O melanoma accepted but controversies regarding ELN dissection began - Snow in 1892 wrote as proponent for elective lymph node dissections in LancetEarly 20th century - proponents of ELN dissection and WLE

- also greater awareness that melanoma arose out of both moles and clear skinWilliam Sampson Handley (1872 – 1962)

1907 recommendations in lectures (based on a single autopsy!) extensive excisions (an inch margin, to fascia) +/- amputation, regional lymph node dissection

Formed the basis for melanoma treatment for the following 50 years!Sophie Spitz (1910 – 1956)

With Allen delineated in 1948 the “benign juvenile melanoma” better diagnosis in children and avoided unnecessary surgery (named “Spitz naevus” in 1967 by McGovern)

Also recognised ulceration in melanoma as a major adverse prognostic factor Both were staff pathologists at Memorial Hospital

Vincent McGovern (1915 – 1983) Pathologist in Australia Published 100 articles and 3 books on melanoma Organised, chaired international consensus on classification and melanoma reporting 1972 – first international consensus meeting on melanoma 1972 classification Revised in 1982 at a second international pathologist meeting First to associated sunlight to development of melanoma First to delineated prognostic histopathological features First to describe regression in melanomas Documentation of tumour thickness as an independent prognostic factor using work from

Sydney Melanoma Unit databaseAlexander Breslow (1928 – 1980)

Professor of pathology at George Washington University Medical Centre

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Delineated primary melanoma thickness as easy prognostic indicator for risk of local recurrence and metastasis – results reproducible.

First paper published in 1970 – later increase in a series of 138 patients All those with 0.75mm survived, then staged as multiples of 0.75mm as prognostic thresholds 248 patients – results showed that tumour thickness was a better predictor of metastases &

survival than level of invasion or any other parameter! Subsequently examined margins of resection

Wallace H. Clark Jr (1924 – 1997) Physician at MGH, and University of Pennsylvania 1969 described the “Clark levels” of invasion prognostication Also described superficial spreading form of melanoma Described the B-K mole (i.e. dysplastic nevus or “Clark’s nevus) as a precursor or marker of

increased risk Developed concept of radial growth phase (no metastatic capacity) and vertical growth phase

(metastatic capacity) Described other prognostic factors: tumour site, patient sex, tumour thickness, mitotic rate,

regression and degree of host response (lymphocytic infiltration)

EEPIDEMIOLOGYPIDEMIOLOGY

Incidence Increasing () incidence in all Caucasian populations, ~5% per year

Racial Difference 2x in Hispanic from 1.5/100,000 (1986) to 3.0/100,000 (1996) with higher mean age

than Caucasian population (~60 y.o.) Extremely low rates in Asians, ~0.2/100,000, slight in women (Japan 1987) African-Americans have a male preponderance 4:1, majority are acral lentiginous

The Epidemiological Data Incidence Trends

o Melanoma risk is high in those born before 1950o Melanoma incidence is / for those born after 1950o Melanoma incidence is for females born after 1960

Anatomic Site trends studied in Canada and NZ – both showed rates for upper limb and trunk in both sexes

Age & Sexo Mean age of diagnosis range 50 – 58 years (10 years earlier than other common

tumours)o Ratio of male:female varies by countryo NSW, Australia study show: younger age groups are (males) and (females),

continuing to in those over 65o USA, males under 60 rates are or , but for over 60 rates are o USA, age specific rates show sharp in incidence in males over 45

Thickness of tumour – largest incidence is in thin melanomas (<0.75mm)o ANZ – in thick (>0.75mm) lesions in <65 y.o., in thick lesions >75 y.o., all

age group show in thin lesions except men <34 and women <49 y.o., no change in median tumour thickness

o Europe – median tumour thickness 1.2mm to 0.8mm, in thin melanomas (esp. females), incidence of thick melanomas, invasive melanoma during 1980’s then after 1989

o USA – in thin lesions (<1.00mm) in <65 y.o., in thick lesions in >65 y.o., Lee found in situ tumours were in older patients c.f. invasive tumours, incidence of in situ melanoma has a greater in incidence

World Incidence Incidence rate in the world range from 0.2/100,000 (China) to 40.5/100,000 (Males in

Australia) Australia Ranks no.1 for male (male 40.5/100,000 and female 31.8/100,000) New Zealand Ranks no.1 for female (male 36.7/100,000 and female 34.9/100,000)

Mortality Rates are 5x lower than incidence rates Female have better survival rates after diagnosis (?earlier detection or tumour biology)

Australia

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3rd most common cancer in Australia Risk <75 y.o. Male 1 in 25, Female 1 in 36 Peak risk in 4th decade of life Most common sites is face and ears in both sexes 52% at diagnosis is <0.75mm(Baade; Trends in melanoma mortality in Australia: 1950-2002 and their implications for melanoma control. Aust N Z J Public Health. 2005 Aug)

significant decreases in mortality rates for men and women younger than 55 years (percentage change per year, men 35-55 years: -2.4%; women: -2.9%)

For ages 55-79 years, rates are now stable for both men men and women 80 years or older, rates have continued their statistically significant

increase of 3-4% per year most likely cause of the recent statistically significant decreases in mortality is

early detection.

Western Australia Increasing incidence of 4-5% per year Most common cancer from 15-39 y.o. In WA 2000, 70% melanoma <1mm, median thickness is 0.6mm Melanoma diagnosed in older persons are thicker and more invasive at time of

diagnosis (up to 25% of diagnosed in >75y.o.)Summary

Incidence of melanoma continues to esp. in older males The incidence is highest in thin lesions Different countries are at different points along the melanoma epidemic in incidence

and mortality (Australia/Nordic/USA ing UK/Canada just started France/Italy/Eastern Europe still ing)

Evidence still not convincing that changed sun exposure patterns has led to ing incidence in countries such as Australia

PPATHOGENESISATHOGENESIS, R, RISKISK F FACTORSACTORS, P, PREVENTIONREVENTION & S & SCREENINGCREENING

Pathogenesis (Hypothesis) Melanocytes on basal membrane in epidermis produce melanin distributed to

surrounding keratinocytes by dendritic projections Melanin absorbs UV energy and free radicals produced by UV radiation (which would

normal act on membrane lipids and other cellular chromophores) Melanin is distributed within cells as supranuclear caps which protect cell nucleus

from injury Tanning increased rate of melanogenesis within melanocytes absorbs more UV

radiation (SPF ~3-5), epidermal melanocytes increase in number within 1-2 weeks but limited in proliferative ability

Melanocytes are more resistant apoptosis, after severe sun exposure, substantial damage to DNA in both melanocytes and keratinocytes occur with keratinocytes undergo apoptosis but melanocytes do not undergo apoptosis so melanocytes undergo DNA repair (limited ability in melanocytes) accumulation of minimal damage eventually lead to malignant change and melanoma

Environmental Risk Factors 1. Sun exposure

Principal risk factor for melanoma, 2/3 of cases strongly assoc. with history Early intermittent exposure more at risk than chronic exposure (but not shown in

Australian studies), supported in European studies and also because disease seen in higher socioeconomic class

Body site incidence assoc. with greater sun exposure areas Migrant study: childhood immigrant arriving >15y.o. has ¼ of the risk of residing

population, but those arriving earlier has higher risk than those arriving later Latitude variation (higher incidence in USA and Australia with closer to equator) – but

confounded by racial/skin colour difference in Europe, Nordic countries has higher rates than southern Europe

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UVA is major component of sun exposure, cause oxidative DNA damage, in animals can induce melanomas, also the ray used in tanning facilities

Long latent period from exposure to disease Sunlight damage is cumulative (D. Holman & P. Heenan)

2. Tanning Booths and Sunbeds UVA radiation delivery may be a risk factor but studies have been inconsistent

3. Ozone Layer depletion: Loss ability in blocking UVB, thus more reaches earth’s surface For each % decrease in amount of ozone, melanoma incidence increases by 1%

Some data not supporting sun exposure Higher incidence in countries further from equator racial/ethnic influence Almost 50% of cases worldwide occur on parts of the body not routinely exposed to

sunlight intermittent exposure theory?Genetic Risk Factors

Very small increase in melanoma incidence in families with member diagnosed 10% cases have FHx = family clusters with younger age onset 2% of all cases have genuine inheritance of susceptibility genes (e.g. CDKN2 tumour

suppressor gene on 9p21) Risk associated with one affected first degree relative is 2.2 Genetic disorders assoc with increased melanoma incidence: Xeroderma pigmentosum (3% will develop melanoma, RR 100 in < 20 y.o.) BK (dysplastic) mole syndrome (described by Clarke 1975) or familial atypical mole

and melanoma (FAMM) syndrome – multiple large dysplastic naevi (described by Lynch in 1978)

Other Associated Risk Factors

Fair complexion, inability to tan, freckles, solar lentigines, light coloured eyes, fair or red hair – increase in relative risk 2-4x (accounts for incidence difference in racial groups)

Past Hx of non-melanoma skin cancers = index of sun exposure RR 2.4-3.6 Past Hx of melanoma – 4.5% within 5 years Freckles – strongly associated with melanoma, but reflective of skin type and ethnic

background Number of nevi - >20 nevi on arm increases risk 10-20x. Multiple dysplastic naevi Large congenital melanocytic naevi Immunodeficiency states (studied in renal transplant patients) PUVA treatment (for psoriasis) studies inconsistent but relative increase of

melanoma incidence, and BCC has been shown in some long-term studies

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Risk Factors NOT Associated with Melanoma Smoking Diet Hormones

PreventionRecommendation by the Australian Cancer Society

Physical protection should be the primary preventive measure Avoidance of direct sunlight (esp two hours on either side of solar noon) Use of shade structures Wearing sun protective clothing, hats Sunscreens (only as an adjunct to above!) Min SPF of 15, broad spectrum These are filters only, not blocks, some sunlight damage still continues Studies on its effect is equivocal – but assoc. w greater sun exposure in subjects who

use sun-screen! Reapply at intervals, water-proofing Advise against tanning salons

Screening No data to show screening of general population to be effective in controlling mortality Surveillance of high risk group has been shown to detect disease at an earlier stage All those at high risk should be advised re: Education and self-examination Appropriate prevention Regular follow-up Baseline photography High Risk Groups requiring Surveillance:

1. Multiple dysplastic naevi2. Families with history of multiple dysplastic naevi syndrome or melanoma (1st

degree relative)3. Large congenital melanocytic naevus

MMOLESOLES ANDAND P PRECURSORRECURSOR L LESIONSESIONS

Superficial spreading melanoma is thought to arise from: Direct malignant transformation of epidermal melanocytes (60% of cases) Transformation of a dysplastic naevi melanoma in situ melanoma (40% of cases)

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Dysplastic Naevi/Atypical Moles Melanocytic lesions that are both precursors and markers for melanomas – a spectrum

of lesions Definition unclear and subjective: moles that deviated from “typical” features Melanocytic dysplasia = histopathological term implying disordered and

discontinuation of atypical melanocytes, criteria include:o Proliferation of intraepidermal melanocytes arranged single or irregular nests

in the basal epidermis or slightly above rete ridgeso Variable and discontinuous melanocytic cells with atypiao Lack of maturation in dermal component

These are clinically indistinguishable from melanoma in-situ with wide variation in shape, colour and irregular borders, no axis of symmetry, “fried egg”/”target” appearance,

o No ulceration, and usually no symptoms with and change slow and stableo Size 5 – 10mm and indistinct borders

10-20% of population have at least one dysplastic naevi, but only those with MULTIPLE are at increased risk of melanoma

Average age of first occurrence around 35 y.o. Risk of melanoma increase with increasing number of total and dysplastic naevi >10 elevated (or >20 total) naevi on arms increases RR of melanoma by 10x Prevalence of naevi on children has latitude gradient (QLD>VIC) Difficult to monitor clinically – require full body photograph Little correlation exists between clinical appearance and pathologic grading

o i.e. not all clinically dysplastic naevi are dysplastic on histopathology Degree of dysplasia does not correlate with chance of developing melanoma Severe dysplasia also does not imply others are at greater risk of becoming atypical Dysplastic Naevi Syndrome: defined as >100 naevi with at least one atypical

o autosomal dominant disorder with multiple dysplastic naevi o assoc. with deletion of CDKN2A gene for production of tumour suppressors o naevi usually larger and more numerous than normalo irregularly shaped, indistinct borders, variably pigmented, macular pebble

plaqueo naevi usually absent at birth but at puberty increase in number and sizeo Types of Dysplastic Naevi Syndrome (in increasing risk) Kraemer et al 1987

Type A = No personal or family Hx, moles uncommon in family – RR27 Type B = No personal or family Hx, moles common in family Type C = Personal or family Hx +ve, moles uncommon in family Type D1 = Personal or family Hx +ve, moles common in family Type D2 = Two or more family members with melanoma, moles common

in familyRR 148, 100% with disease by age 75

Extensive prophylactic excision not recommended not all will turn into melanoma Management:

o Regular follow-up with dermatologistso Screening of first degree relatives (10% found in <20 y.o.) from 7 – 8 yrs 2-3yrly

with or without clinical features of moleso Use of photographs and digital imaging to detect changeo Education in preventiono Prophylactic removal for lesions: difficult to monitor, will not cause cosmetic

defecto Excisional biopsy – changing lesions, suspicious lesions

Lentigo Maligna (= Hutchison’s melanocytic freckle)

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Described by Hutchison in 1890 Common pigmented lesions on the skin of older patients (esp face), peak incidence 7th –

8th decade More common in women Clinically irregular, ill-defined, large, variably pigmented macule, grows slowly Higher correlation with continuous sun exposure These are melanoma in situ “preinvasive” Intraepidermal melanocytic proliferation with fully evolved cellular atypia which is side

to side and continuous Overlying atrophic epidermis Solar elastosis can be prominent and inflammatory infiltrate usually present Characteristic extension of melanocytic proliferation into adnexal epithelium 5% progress to invasive melanoma (= lentigo maligna melanoma) Not an invasive lesion, no risk of metastases Management is surgical Require complete surgical excision 5mm margins recommended Alternative is radiotherapy (not as effective)

CCLINICALLINICAL F FEATURESEATURES

The key to minimising melanoma associated morbidity and mortality is via early detection of curable melanoma followed by prompt excisional therapy.History – Presenting Complaint

A changing skin lesion:o in size or colour of lesiono in surface or elevation of lesiono Duration of change varies widely, but 2-6 months predominantly (if change is in

days usually inflammatory) A mole that is ‘different’ from others Itch may be present Pain, bleeding are rare

History – Associated Details Past history of melanomas or other skin cancers 1/3 multiple primary is synchronous at first diagnosis 2/3 are metachronous during follow-up up to 30 years after first melanoma (must

differential from epidermotrophic mets diff Rx and Prognosis) Family history (esp. dysplastic naevi) increased risk 71% Systemic inquiry (immunosuppressants)

Examination Adequate exposure of patient Note other sites that may need to be examined apart from presenting lesion Current clinical detection by specialist is 80% sensitive and 64% accurate IRREGULARITY of the lesion Colour irregularity most important, presence of variety of colours Border irregularity second most common feature Surface irregularity (topography) Amelanocytic melanoma – enlarging smooth reddish nodule/patch, +/- area of brown

pigment Ulceration – sign of advanced local disease

ABCDE system of dianosiso A = Asymmetry: asymmetric lesions where ends and sides don’t matcho B = Border: irregular, but well-defined mostlyo C = Colour: variation – dark, red, blue

(Tyndall effect = light reflection from melanin at different levels in dermis)

+/- red halo around the edgeamelanocytic melanoma more difficult to recognise

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o D= Diameter: usually >6mm, nodules can be smaller shiny and dark, or reddish in amelanocytic types

o E = Elevation: suggestive of aggressive vertical growth Examine other lesions (esp those not yet elevated!)

Other features may be seen on melanoma lesions: Ground glass amorphous appearance to part of lesions (skin lines lost due to tumour

invasion) Small flakes of keratin on surface, very rarely heavity keratinised May be ulcerated Most hair bearing pigmented lesions are benign, but hair presence should NOT

exclude melanoma diagnosis – advance melanoma usually hairless as follicles destroyed by invasion

Thick melanoma often firm and non-compressibleSurface Microscopy/Dermatoscope

Incident light magnification system in combination with immersion oil at the skin-microscope interface (oil removes light scattering at stratum corneum epidermis become translucent allows visualisation of pigmented structures at epidermis and dermoepidermal junction)

Inconsistent results from studies but has been reported to increase diagnostic accuracy and sensitivity by 10-20%

Training and experience important factors in using surface microscopy for clinical diagnosis

Photography Used in specialist centre for high risk patients with computer archiving Documented benefit in diagnosing melanomas at early stage

CCLINICALLINICAL T TYPESYPES ANDAND G GROWTHROWTH P PATTERNSATTERNS

All melanoma have two biologic phases:o Horizontal (radial) growth phase epidermal involvement onlyo Vertical (dermal invasion) growth phase risk of metastases with depth of

‘growth’

Cellular classification1. melanoma in-situ2. Typical subtypes

a. Superficial spreadingb. Nodularc. Acral lentigenes and subungual melanomad. Lentigo maligna melanoma

3. Atypical subtypesa. Amelanoticb. Mucosal (lentiginous) melanomac. Desmoplasticd. Verrucouse. Melanoma arising from CMNf. Malignant blue nevusg. Nevoid melanomah. Melanoma of soft parts (clear cell sarcoma)

Superficial Spreading (70%) Most common subtype, account for most of the increase in incidence Mean age of diagnosis is 50’s (earlier than others) Slow growing and variable colour with radial pattern of growth Site: most frequently upper back in both sexes, upper arm in women Size >6-8mm

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Clinical features similar to that of dysplastic naevi, and often arise from precursor mole!

‘Lacking a propensity to metastasis’ (Clark)Verrucous variant Clinical appearance of seborrheic keratosis Also can occur as acral melanoma, misDx as wart

Nodular (15-30%) Aggressive tumours and more rapidly growing – immediate vertical growth phase, lack

of identifiable radial growth phase (i.e. aggressive growth early) Usually occur de novo in uninvolved skin, but may arise from pre-existing naevus Site: legs and trunk Dark, raised brown-balck nodule/papular +/- ulceration/bleeding Spitzoid melanoma: difficult to distinguish from Spitz naevus histologically

Lentigo Maligna Melanoma (4-10%) Usually in setting of sun-damaged skin 75% of cases >60 y.o. Arise from Lentigo Maligna (precursor lesion), usually present for 10-15yrs increase in

size Usually large lesions up to 3-6cm in diameter before progression to invasion Clinically: difficult to distinguish from solar lentigo, Tan-to brown macule/patch,

variable in pigment or areas regression become hypopigmented, may begin as fine reticular black pigmentation in solar lentigo, indistinct clinical borders

Malignant degeneration can be characterised by nodular development within lesion Site: most common the face Has the propensity to develop vertical growth phase (often assoc with desmoplastic

component) and metastasize Acral Lentiginous (2-8%)

Melanoma of the acral skin (thickened skin of soles & palms) or nailbeds (subungal melanoma)

Rarely associated with pre-existing lesions 50-60 y.o. Lesion evolves slowly Main melanoma of non-white populations (35-90% African Americans, Asians &

Hispanics) Irregular pigmentation, large size (>3cm diameter) Site: usally big toe and thumb ?worse prognosis - ?assoc with delayed diagnosesSubungal Melanoma

o Must be suspected for any pigmentation in the nailo Generally poor prognosis due to delayed diagnosis (usually deeply invasive)o DDx = haematoma under nail (should clear in 1-2 month), fungal infections,

pigmentation of nail fold can occur in dark-skinned persons, Peutz-Jehger syndrome, minocycline, radiation therapy, nevoid melanosis

o Clinical features: Hutchinson’s sign (development of pigmentation in skin around the nail

into fold or hyponychium) Pseudo-Hutchinson’s sign (visibility of pigment through nail fold, but not

pigmentation of nail fold itself. Pigmented band in nail plate for pale-skinned individuals – normal

variant in dark individuals - (melanoma in nail matrix under proximal nail fold)

Pigmented nail band with irregular edge, variegate pigmentation and width >3mm

o Eventually cause splitting and loss of nail plateo Amelanotic melanomas may also grow under nail – very difficult to Dx!

Palmar/plantar melanomao Often masked by stratum corneum – swab with oil or alcohol felps delinieateo May become verrucous thus misDx as warts

Mucosal Melanoma (<1%) Rare, on mucosal surfaces, usually asymptomatic

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Very poor prognosis because usually detected very late Sites: mouth, nose, oesophagus, gall bladder, urethra, anus, vulva and vagina DDx: intraoral tattoing, benign melanosis of vulva

Desmoplastic Melanoma (1%) Associated with high local recurrence due to

o poorly defined clinical borderso amelanosiso infiltration along nerve sheaths

incomplete excisions and persistent of primary tumour Wider margin of excision required (add 1cm) Does not have worse prognosis!! But has high recurrence rate Clinically has poor margins papule/plaque/nodule, may be non-pigmented, may be

subcut. nodule, may arise from lentigo maligna, Site: head and neck most commonly

Amelanocytic Melanoma (<5%) Any of the above four variants can occur as amelanocytic 50% of desmoplastic are amelanocytic Typically pink or flesh colour with/without hint of pigmentation at periphery In mucosal usually as mass or ulcer

Differential Diagnoses: Junctional, Compound or Intradermal naevi Dysplastic naevus Spitz naevus (esp children & adolescents – smooth surfaced domed pink red lesions

<6mm) Blue naevus (blue black lump <5mm) Pigmented BCC Haemangioma Pigmented seborrhoeic keratosis Adnexal tumours Pyogenic granuloma Haemangioma

Amelanocytic melanoma DDx: BCC Dermatofibroma Other spindle cell tumours

BIOPSYBIOPSY

Clinical inspection is 60-80% effective in identifying melanoma If clinical suspicion is high, then an excisional biopsy should be performed

Indications for biopsy Any lesions producing patient concern Clinically suspicious lesions Lesions with changing morphology Pruritic or bleeding lesions New pigmented lesions Any pigmented nail lesion, pigmented band in nail

Shave biopsy Best avoided Transection may compromise histopathologic interpretation cannot determine

invasion Transection may also prevent accurate thickness measurement However, shave biopsy can provide a large specimen with broad area that has greater

chance of diagnosing a microinvasive foci within a large lesionPunch or Incisional biopsy

Large pigmented lesions where primary closure not possible

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Pigmented lesions in areas of cosmetic importance Biopsy the region that appear darkest or thickest to palpation 6 mm punch would give better specimen Limitations: sampling error, inadequate specimen for Breslow depth, also still some

concern in it may produce haematogenous disseminationExcisional biopsy

Preferred method of diagnosis for suspected melanoma lesions 2mm lateral excision biopsy margin Depth to upper layer of fat

Subungual biopsies Removal of nail component to periosteum or window Punch or Incisional biopsy of nailbed adequate for diagnosis

PPATHOLOGYATHOLOGY

There are 3 clinically and histologically distinctive steps in melanoma progress:1. “Radial growth phase-confined melanoma in situ” = Melanoma confined above the

epidermal basement membrane 2. “Radial growth phase-confined microinvasive melanoma” = Melanoma that penetrates the

basement membane to enter the superficial papillary dermis 3. “Vertical growth phase melanoma” = Melanoma that has invaded the dermis as a

tumorigenic nodule and has acquired the capacity for metastatic growth Lentigo Maligna

Polygonal shaped melanocytes with hyperchromatosis, confined to basal layer of epidermis

Extends to eccrine ducts and epithelium of heair follicles Multinucleated giant melanocytes disposed along basal layer (“star-burst” giant cell)

with atypical nuclei Atrophic epidermis Lymphocytic infiltration usually herald the onset of microinvasion

Superficial Spreading Melanoma Four basic patterns of intraepidermal growth:

o Epithelioid and pagetoid disposition of cells percolating all layers of epidermis, these cells contan melanin granules of variable sizes and shapes, scattered mitotic figures and hyperplastic epidermis

o Continguous proliferation of singly disposed cells along dermoepidermal junction effaced rete ridges and obscured basilar keratinocytes. These cells have large nuclei and hyperchromatosis, again with melanin granules

o Confluent oblong nests of hyperchromatic spindle-shaped cells, with nuclear grooves and chromatinic rims, variable melanin and also retes ridge effacement

o Hybrid array of all of above Lymphocytic infiltration of subjacent papillary dermis herald the onset of

microinvasion In microinvasive melanoma – nests and dispersed cells papillary dermis, but no dermal-

based mitoses (otherwise it is vertical growth phase melanoma)Vertical Growth Phase

By definition: presence of dominant nest within the papillary dermis that is larger than nest within epidermis or surrounding dermis and forms small expansile nodule of shape distinct from adjacent nests, typically orientated vertically

Cells are often spindle cell, small cell or epithelioid cell, greater cytoplasmic pigmentation than intraedpidermal component

Desmoplastic Melanoma Spindle cell morphology with desmoplastic stromal response Poorly circumscribed with ill-defined deep and lateral margins, due to admixture of

stroma and tumour cells Neurotropism with infiltration along peripheral nerve sheaths Osteoid and bone formation may be seen in subungual desmoplastic melanomas

Level of Invasion Clark’s level defined:

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I Malignant melanocytes confined to epidermisII Partial infiltration of papillary dermis by single cells or small nests (do not exceed size of intraepidermal nest or it is vertical growth phase)III Tumour cells fill and expand papillary reticular dermal interface

(signifies vertical growth phase)IV melanoma cells infiltrate reticular dermisV infiltration of subcutaneous fat

Things on histopathology report:1. Diagnosis of malignant melanoma2. Diagnosis of primary tumour or cutaneous metastasis (i.e. deposit)3. Histological type (very little prognostic value)4. Thickness (Breslow’s) – most reliable and reproducible method5. Ulceration6. Completion of excision/margins 7. Level of Invasion (Clark’s)8. Desmoplasia, Neurotropism9. Lymphatic and Blood vessel invasion – not shown to be independent prognostic

variable10. Regression – an area of absent melanocytic growth in epidermis and dermis bordered

by melanoma, assoc with worse prognosis, usually assoc with attenuated epidermis, regression of >75% association ith critical volume which portends mets!

11. Mitotic index (>5mm2 has worse prognosis)12. Inflammatory host response – lymphocytic response to vertical growth phase13. Immunohistochemistry

a. S100 protein expressed by most melanomas, (also melanocytic naevi)b. HMB-45 monoclonal antibody has high specificity to melanoma (except

desmoplastic)14. Satellitosis (subcuticular or dermal nodules of tumour greater than 0.05mm in width

separated from main vertical growth phase component) – assoc with lymph node metastasis and decreased disease-free and overall survival

Studies convincingly show that distinguishing between benign pigmented lesions and early melanoma can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered

TTREATMENTREATMENT OFOF P PRIMARYRIMARY M MELANOMAELANOMA

Primary Excision Dependent on Breslow thickness Other feature may alter prognosis but does not influence treatment Complete excision is required to be confirmed by surgery Minimal margin of 1cm clearance of all level

pTis 5mm marginpT1 0 – 1 mm 1cm marginpT2 1.01 – 2 mm 1cm margin for restricted areas, 2cm margin

preferredpT3 2.01 – 4 mm 2cm marginpT4 >4mm Minimum margin 2cm

Maximum margin 3cm No evidence that a margin greater than 1cm offers additional benefit for survival, but it

may decrease local recurrence Depth of excision should equal the minimum excision margin but not require to go

deeper than deep fascia Reconstructive options should use principle of reconstructive ladder from simple to

complexAnatomical Considerations for Excision

Ear – wedge excision or partial amputation, total amputation reserved for locally advanced or extensive local recurrences

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Breast – not necessary to perform mastectomy, use same as for skin lesions, if involving or adjacent to nipple, NAC need to be sacrificed

Toes – amputation to closest proximal joint Fingers

o just proximal to DIPJ for subungual lesionso for proximal lesions and web space, excision bone has no oncological benefit,

adequate soft tissue excision is appropriate - full-thickness skin grafts, crossfinger flaps, dorsal hand flaps, or neurovascular island flap

o Web-space lesions of the hands or feet usually can be excised with adequate soft tissue margins, using skin grafts or local flaps to manage the wound. The need for formal ray amputations should be rare.

Umbilicus – removal of skin and umbilicus adequateMohs’ Surgery

Literary reports only on in situ or thin invasive lesions, but no comparison to surgical management

Should only be reserved for special circumstances such as anatomically restrictive sites in preserving vital structures

MMANAGINGANAGING L LOCALOCAL R RECURRENCEECURRENCE

Definition:= regrowth of melanoma in close proximity to the anatomic site from which the primary tumour was excised (difficult to distinguish with in-transit met or satellite), inconsistent rules/reports on parameter marginPathogenesis:

Several mechanisms for local recurrenceHorizontal contiguous melanoma growth beyond line of surgical excision (may

occur due to sampling error in histological reported margin)Lymphatic metastases or microsatellites that are discontinuous from primary

tumour and were not excised (esp those with microsatellites reported on their primary tumour histopath)

Misclassification of a de novo primary melanoma that has occurred in the context of a field defect at the periphery of previous melanoma excision

Haematogenous tumour dissemination with implantation of tumour cells in vicinity (those with local recurrence usually have haematogenous mets)

Risk factors for recurrence:Increased tumour thickness (despite wider margins)Presence of ulceration (6x more than non-ulcerated)Head and neck melanomas (9x more than upper limb lesions)Presence of satellite lesions (15x more risk)No difference in recurrence risk between 2cm to 5cm margins!

40% of recurrence occurs 5 or more years after primary excision – thinner the lesion, the later the recurrenceEffect on survival

Strongly associated with in-transit met, LN met and distant metTherefore very poor prognosis, with 5 year survival of 9% for first relapse, 10 year survival

of 5%Metastatic relapse more common than regional recurrence (62% vs 28%)Management

Surgery remains the mainstay of treatment – resection 1cm margin Hyperthermic isolated limb perfusion for extremity recurrence (80% response reported

with melphalan) either before or after resection, or non-resectable lesions, 5 year survival for local recurrence is 61%, also indicated for subsequent relapses after excision of first recurrence and for those with concurrent in-transit mets

Intratumoural therapy – BCG or IFNalpha2b, with 50-100% response of 50% size reduction of local recurrence (but less for systemic response)

Injection of other agents: lymphokines, cisplatin/epinephrine, bleomycin with electrical current (100% local response rate)

Radiotherapy – 2nd line therapy with up to 67% response locally

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AASSESSMENTSSESSMENT ANDAND T TREATMENTREATMENT OFOF L LYMPHYMPH N NODESODES

All Patients with invasive melanoma are at risk for metastases to lymph nodes (thus essential for follow-up examinations)

Metastatic disease often gives rapidly enlarging lymphadenopathy Clinically: firm, hard and rounded with irregular surface Uncommon if melanoma <1mm thickness 2.0mm – 4.0mm 25% have microscopic lymph node involvement >4.0mm 60% have lymph node involvement

Lymph Node Biopsy Fine needle aspiration preferred for clinically suspicious LN –ve needle biopsy is not conclusive should be repeated if node remains suspicious Open lymph node biopsy increase risk of tumour spillage and subsequent recurrence

Should be done as frozen section followed by subsequent radical lymphadenectomy if node +ve

Elective Lymphadenectomy (ELND) ELND = anatomic lymphadenectomy of primary draining nodal basin when it’s

clinically -ve Theoretical advantage of prophylactically disrupting spread of melanoma The role of ELND yet to reach consensus worldwide, has only shown benefit for a

subpopulation of melanoma, but others has failed to demonstrate improved survival in comparison with those who only had WLE. Recent 10 year follow-up has shown divergence in survival, with ELND showing statistically significant benefit (Balch et al, 2000)

Shown to offer moderate survival benefit for male patients with truncal melanoma of thickness 1.5mm – 4.0mm (Reintgen 1983, WHO)

ELND is not recommended in patients with thick melanoma (>4 mm), because of the high risk for regional and distant metastatic disease (60%–70%).

Survival advantage for non-ulcerated tumours 1-2mm thick (Balsch 1996 – Intergroup) Four reported RCT’s for ELND (with one very small group and statistically unreliable)

o Meta-analysis article: Lens MB, Dawes M, Goodacre T et al. Elective LN dissection in patients with melanoma: systematic review and meta-analysis of randomised controlled trials, Arch Surg 2002;137:458-61

o Fourth report: Sim FH, Taylor WF, Pritchard DJ et al. Lymphadenectomy in the management of stage I malaignant melanoma: a prospective randomised study. Mayo Clin Proc 1986; 61:697-705

RCT’s show weak benefit 14% improved survival up to 32% but all could be due to chance on statistical analysis!

Lymphoscintigraphy has shown that ELND may be misdirected in >50% of patients with H&N and truncal melanoma, and in transit nodes are missed.

Consensus with Australian guideline: ELND is NOT recommended Disadvantage:

o Does not prevent haematogenous spreado 80% with 1-4mm thickness melanoma have negative LNo High morbidity (20-25% lymphoedema)

Satellitosis or lymphatic invasion may warrant ELND – independent of pT thickness

Sentinel Node BiopsyRationale:

The presence or absence of LN mets is the single most powerful predictor of recurrence and survival in melanoma

Most primary tumour prognostic factors contribute relatively little to prognostic models once LN met is established (except for ulceration)

Therefore, melanoma patients might benefit from accurate nodal staging procedure ELND as a staging procedure is associated with significant morbidity 20% of patients with node negative intermediate thickness tumors will have

micromets.Principles:

Lymphatic mapping relies on two concepts:

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o Different regions of skin have specific patterns of lymphatic drainage to the regional lymphatic basin

o For a given skin region there is a specific lymph node or nodes (i.e. the sentinel node/s) in the basin to which the cutaneous lymphatic vessels drain first

First described by Morton et al using a vital blue dye method for melanoma patientso SLN is the first node/s in the lymphatic basin into which the primary melanoma

consistently drains (may not necessarily be the closest) Confirmed hypothesis which SLNB relies on:

o The status of SLN will reflect the status of higher nodes, demonstrated in studies

o Negative SLN means negative nodes in the basin Lymphatic drainage converge rather than diverge, thus specific nodes can be

harvested for testing Drainage patterns can be unpredictable and unusual

TrialsMSLT I Trial

SLNB currently being evaluated in National Cancer Institue’s randomised trial MSLT – goal is to determine whether SLNB demonstrated survival benefit

Randomise patients with melanomas over pT2 or greater into WLE with observation and WLE with SLNB groups

Current Results Reported:o SLNB is the most accurate, least morbid, most cost-effective means of

determining LN statuso SLNB allows nodal staging adjuvant therapy can be considered for

appropriate patientso No overall survival advantage for early lymphadenectomy c.f. with nodal

observation (87% c.f. 86% reported)

MSLT II Trial (commenced 2004) To determine whether SLN +ve patients require subsequent LND 80% of SLN +ve patients with subsequent LND has no other nodes Recruitment of 2000 SN+ve patients, randomised to receive LND + Interferon within 4

months or interferon only and observation with high-resolution U/SPatient selection:

pT1b (occult mets 5%) positive deep biopsy margin pT2 and 3 used for staging pT4 (occult mets 70%) – SLN status was the most important predictor of survival,

above tumour ulceration (Grenshenwald et al)Not recommended if:

Extensive surgery at primary site (e.g. rotational flaps etc) No nuclear medicine and pathology services

Technique Preoperative Lymphoscintigraphy with radioactive dye (Tc-99m) injection to identify

the first lymph nodes (i.e. sentinel nodes) to which the tumour may travel to, mark location on skin

Lymphoscintigraphy essential for: identification of all nodal basins at risk identification of any intransit nodes identification of the location of SLN within transit or basin Estimate number of SLN that will need to be harvested for testing

Operating technique (2-24hours after lymphoscintigraphy) – o Skin lesion area is injected with isosulfan blue or patent blue dye – allows

visualisation of node and lymphatic channels, allow 10 minuteso Nodes are selectively biopsied through small incisions with aid of Geiger

counter probe o SLN sent for histology and immunohistochemistryo Check basin with probe for residual nodes

Pathology: examined with H&E stain as well as S100 immunohistochemistry; but still no consensus as to methodology of sample preparation and staning, new controversy

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surrounding use of RT-PCR (too sensitive false +ve in clinically insignificant micromets?)

Complications: Uncommon Seroma (10% reported), wound problems, lymphoedema (0.7% only)

Limitations: Success in locating node is experience dependent WLE can potentially affect accuracy of mapping and drainage pattern Require supportive nuclear medicine and pathology facilities

Caution:Provides staging information only at this stage?Benefits in survival not yet establishedLack of procedural standardizationDoes not deter haematogenous spread

Those FOR SLNB claims:Power for staging: (AJCC database)

Clinically node negative pT2 or greater – 5ys 65%ELND node negative pT2 or greater – 5ys 75%SLNB negative pT2 or greater – 5ys 90%

SLNB improves survival but only for patients who are node-positive Those AGAINST SLNB claims:

Definition of Sentinel node – especially if more than one node is submitted for pathological examination

Paper claiming improved survival has flawed evidence and analysisNo place for SLNB except in trials

Current Australian Guideline Recommends: Selective sentinel node biopsy provides an alternative approach to treatment of

melanoma >1mm Should only be undertaken in context of a multicentre clinical trial Should only be undertaken in a centre equipped and experienced in this procedure (i.e.

expert lymphoscintigraphy, sentinel node surgeon, pathologist)See Attached Literature Review on Sentinel BiopsyTherapeutic Lymphadenectomy

Necessary for confirmed metastasis in regional LN Substantial risk of recurrence in dissected field (esp if extracapsular spread) can be

lowered by thorough dissection, or adjuvant radiotherapy

Adequate dissection assoc with good prognosis: If 1x LN 50% @ 10 years If 2-3x LN 30% @ 10 years

Groin dissection: superficial dissection decrease risk of lymphoedema c.f. radical dissection (including iliac inguinal and femoral nodes)

If only 1-2x LN involved, stop at superficial dissection If gross involvement deep dissection required to include iliac and obturator nodes Neck dissection: recurrence high up to 28% All patients with +ve LN have >50% risk of systemic dissemination

MMANAGINGANAGING R REGIONALEGIONAL R RECURRENCEECURRENCE

Prognostic indications for local, regional and nodal recurrence are similarBy the time regional nodal metastases are clinically obvious, 70 to 85 percent of patients havedistant occult metastases, from which they will eventually die.Treatment is either curative or palliativeIn-Transit Metastases:

Usually multiple and often harbinger of subsequent systemic disease Predisposing factors: node positive patients (theory of ‘trapped’ melanoma cells

between lesion and drainage node!) Median time range 13 -16 months, 70-80% within 3 years

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Incidence 2.3% in Stage I and 11% - 31% in Stage III disease Treatment:

o Surgical excision, wide margin unnecessary (recurrence in 55% at 2 yrs and 82% by 5 yrs), usually for first local recurrence, subsequent recurrence usually referred for adj Rx

o Intralesional injection (DNCB, BCG or interferon) response rate up to 96% reported

o CO2 laser ablation 54% reported to have controlled diseaseo Limb infusion (see later)o Radiation therapy 48% controlled

Prognosis: mean survival 19 months 5 year survival of 12%Nodal Recurrence:

Predictors include tumour burden in basin, extent of LND Recurrence rate: in –ve basins 6.7%, in +ve basins (2-3 nodes) 14%, in +ve basins (>4

nodes) 53% New group of nodal recurrence: those who had +ve or –ve SLNB Treatment:

o Surgical: excision of recurrence or re-dissection of LN basin (if suspect inadequate LND)

o Pre and post operative chemotherapy Prognosis: 5 years 11%, 10 years 5-36% reported Median survival 14 months

OOCCULTCCULT P PRIMARYRIMARY M MELANOMAELANOMA

4-12% of melanoma presentations Presentation with palpable lymph node or even systemic metastasis (rare), in the

absence of a recognisable coincident primary melanoma or past history of melanoma Thought to represent:

1. Regressed primary2. Overlooked primary3. Intranodal naevi undergoing malignant change

Systemic search for primary required History: of skin lesions, systemic symptoms Examination:

1. dermatological survey2. mucosal survery (endoscopy, anoscopy, ocular examination,

nasopharyngoscopy) Investigation: biopsies of suspicious skin lesions, imaging (CXR, CT, PET) Treat LN status as one would for known primary No difference in survival with patient with known or unknown primary +/- nodes

DDISSEMINATEDISSEMINATED M MELANOMAELANOMA

Very poor prognosis (<5% survival at 5 years), median survival is 7-8 months Hx (picked up 68%), Ex (picked up 72%), imaging and also biochemistry (LDH level) All patients with advanced disease should be considered for referral to a melanoma

centre for inclusion in clinical trials for systemic therapy Palliative care involvement Most commonly to lung, then skin, LN, brain, liver and GIT Role for surgical resection:

For solitary metastasis For palliative resection of symptoms e.g. bowel obstruction

AADJUVANTDJUVANT T THERAPYHERAPY

Some evidence that adjuvant therapy is beneficial for anyone with melanoma

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Indication for referral to melanoma centre for immunoTx, chemoTx, or gene Tx trialso Those with pT4o Those in Stage III – including +ve SLNB

Systemic therapy can be:o Chemotherapy o Immunotherapyo Combination of above- there’s no cross resistance i.e. those non-responsive to chemo should be given

immunotherapy- response rate does not equate to survival benefit- treatment should all be considered for enrolment in clinical trials

Chemotherapy Single agents used include DTIC, nitrosoureas, cisplatin, vinblastine, paclitaxel etc –

response no greater than 25% Combination chemotherapy: Bartmouth regime/CVD regime/BHD regime – response

rate no greater than 29%High-dose IL-2 Tx

complete response rate in 7% of patient (75% of these patients have sustained response) up to 16% response rate

Approved by FDA for use in metastatic melanoma since 1998 High dose results in better response than low dose Response rate higher if only subcutaneous and cutaneous mets (50%) S/E pyrexia, nausea, vomiting, diarrhoea, dermatitis, pruritis, neurological side effects Response rate not improved if combined with IFN-alpha, chemotherapeutic agents

Alpha-interferon has been approved by FDA in US as an adjunct for resected melanoma for patients at

high risk for systemic relapse Randomised trial showed at 6.9 median year follow-up, disease-free and overall

survival rates better with high dose interferon alpha 2b. Trials determining benefits of high dose vs low dose

o ECOG E1684 first randomised trial high dose IFN-alpha regime – high dose beneficial

o ECOG E1690 randomised high dose/low dose/observe only – all same!o ECOG E1694 randomised high dose Vs ganlioside vaccine – high dose beneficialo ECOG E1697 randomised to 4 wks of high dose to observation for recurrence -

ongoingBiochemotherapy

Randomised trials comparing chemo alone and chemo with IFN, response rate comparable to chemo alone, highest 20% response rate

Vaccines Several vaccine approaches are under investigation, divided according to what part of

the tumour cell is used for immunological priming Melanoma is a very immunogenic tumour, thus should be responsive to vaccines Failure of vaccine is in tumour cell’s ability to evade host immune system, unable to

find an antigen that can elicit appropriate and targeted immune response1. Cell-based vaccine – limited potential for developing tumour antigens but are

closest to completing controlled clinical trials2. Ganglioside vaccines – have been shown not as effective as interferon3. Peptide vaccines – early development stage only, suffers from MHC restriction

Radiation Therapy: Melanoma is usually responsive to radiation, higher response with higher dose Doses based on normal tissue tolerance, volume, size of area and anatomical site Response can be augmented with concurrent hyperthermia Treatment is mostly as palliative role, some for adjuvant therapy Primary tumours

only for large unresectable lesions (esp mucosal) lentigo maligna melanoma in elderly, frail as an adjuvant to wider excision when margins are restrained by

anatomical constraints or tumours with poor prognosticators Loco-regional Recurrence:

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Reduce local recur. if surgical margins are close or further resection not possible

Neurotropism Palliation for symptomatic lesions (e.g. bleeding ulcerating nodule) Reduction of multiple in transit metastases As an adjuvant post resection of local recurrence

In nodal disease: Gross unresectable disease Adjuvant after debaulking surgery Postoperative after LND for extensive nodal involvement, extracapsular

extension, electively to decrease nodal relapse in high risk patients Postoperative after nodal recurrence disease surgery

Use as alternative to ELND to improve locoregional control in cases of high risk primary tumour

TROG Trial (trans-tasman radiation oncology group) randomise patients with completely resected macroscopic nodal metastatic melanoma into adj radiotherapy or observation only: looking for regional relapse

Limb perfusion Described by Creech et al in New Orleans 1950’s Limb perfusion isolated and connected to an extracorporeal heart-lung machine Controlled intravascular delivery of chemotherapeutic agents to an extremity Control for temperature (hyperthermia) Agents used: Melphalan, TNF (hypotension), cisplatin (neuropathy), dacarbazine,

mitrogen mustard Cx: common are oedema and skin changes, myopathy, neuropathy, compartment

syndrome from muscular necrosis, systemic toxicity Indicated for patients who have

o regionally recurrent melanoma with or without nodal involvement o as an adjuvant for those with stage II primary lesions or resected stage III

satellites/in transit 5 year survival: 30% in transit disease, 38% LN mets, 16% with both, 61% for

recurrence No evidence for prophylactic Rx after primary excision

Limb Infusion

Thompson et al describe use of hypoxic isolated limb infusion – percutaneous catheter placement followed by temporary tourniquet occlusion of arterial and venous flow, tolerated by elderly with minimal systemic toxicity

Used for those with symptomatic limb disease and as for limb perfusion 73% complete response, 13% partial response, remission in 46%

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Results comparable to those of conventional limb perfusion

SSURVEILLANCEURVEILLANCE, F, FOLLOWOLLOW--UPUP ANDAND I IMAGINGMAGING

See attached for recommended surveillance (figure 28.4)Surveillance

based on tumour thickness <1mm – no prolonged F/U required unless high risk group (e.g. multiple

dysplastic naevi, family Hx etc) >1mm: 3-4 monthly for first 2 years, 6 months until 5 years, yearly life-long Examination: palpation of primary site and along draining lymph channels

basin These patients – the risk of second primary is higher than recurrence!

Recurrence often within 2 years Those with >4mm have 50% chance of developing mets within 5 years Met can develop 20 years later

Investigations Should only be utilised where specific symptoms suggest mets Extensive investigation for systemic mets in patient with primary melanoma is not

recommended Imaging modalities CT, MRI and PET – used for staging PET:

o Based on metabolic changes that could detect early metastatic disease in high-risk patients

o Sensitivity of 78% in detecting metastatic melanoma, metastases <5mm not picked up

o Miss 16% of those with positive SLNo Indication:

those with stage III or IV disease clinically where surgical resection is planned

for monitoring systemic treatmento Use in thick lesions with no nodal disease is still being investigated, but not

currently indicated!

CCHILDHOODHILDHOOD M MELANOMAELANOMA

Epidemiology Uncommon in children Incidence has been stable (unlike adults – increasing) Mainly in Caucasians

Congenital melanoma Small subset of childhood melanomas Definted as melanoma diagnosed at birth or in neonatal period May occur as

o mets from mother to foetus via placentao May arise from congenital melanocytic naevus de novoo May originate as primary tumour of CNS in neurocutaneous melanosis

Congenital Melanocytic Naevi Defined as naevus which was present at birth Occurs in 1% of newborns, No clear histologic definition but histologic features:

o Naevus cells in the lower third of dermiso Naevus cells between collagen bundles singly or in short fileso Naevus cells involving appendages

Divided into size groups:1. Small (<1.5cm) does not have increased malignant potential

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2. Medium (1.5 – 20cm) – malignant potential in this group unclear, observation only required

3. All large (>20cm) congenital naevi (giant congenital naevi GCN) are predisposed towards malignant change

o Occur in <1 in 200,000o Risk of melanoma reported range from 3% to 20%o 70% of these melanoma develop before pubertyo Originates from aberrant development and/or migration of pluripotential neural

crest cellso Plaque of pigmented lesion with uneven, verrucous surface, irregular

pigmentation, hypertichosis, with small satellite melanocytic lesions surrounding main naevus

o 2/3 lesion in non-epidermal sites (thus dermabrasion or tangential excision not adequate for these)

o no reports of melanoma from GCN restricted to extremities, or from satellite lesions

o Life-long close surveillance required, excision on cosmetic groundso If head-neck lesions, also increased risk from neurocutaneous melanosis (MRI

required for screening) Prophylactic excision not recommended Other methods of treatment: dermabrasion, cryotherapy, curettage, laser (only

improves appearance, not risk of melanoma)Xeroderma Pigmentosum

Autosomal recessive genetic disorder, with inability to repair DNA damaged by UV radiation

Early onset of multiple cutaneous malignancies Associated ocular abnormalities, neurologic complications

Differential Diagnosis Spitz Naevi (smooth, pinkish tan, elevated lesions in children), is benign and no

predilection towards malignancy Haemangioma Pyogenic granuloma Atypical melanocytic naevi

Prognosis & Surveillance mean five year survival is 88% Regular skin examinations for routine paediatric visits Education re: sun exposure (but not proven to be a risk factor in pre-pubertal

melanoma) Management of developed melanoma as that for adults

MMELANOMAELANOMA & P & PREGNANCYREGNANCY

Melanocytic activity can be stimulated by oestrogens, but relationship between hormonal stimulation and melanoma susceptibility or effect on prognosis is not clear

Melanoma is now the most common diagnosed malignancy during pregnancy! >10% of women has clinical change in naevi in 1st trimester of pregnancy (darkening) Becoming pregnant after melanoma treated does not alter prognosis or survival

compared to other melanoma patients No evidence that melanoma diagnosed and treated during pregnancy has an adverse

effect on clinical course or overall survival of melanoma c.f. non-pregnant individuals Transplacental metastases (21 cases reported worldwide) with 20% chance of

metastases to foetus, (report of one infant survived long-term due to rejection of maternal melanoma cells!) Placental histology need to be obtained in pregnant women with melanoma as well as cord blood for cytology.

A child born in mother with Stage III or IV disease should be closely monitored for metastatic disease during the first 6-12 months of life

Termination of pregnancy also doesn’t affect prognosis of mother

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Management: pregnant melanoma patients are currently limited to surgical management as sole modality, sentinel node biopsy is not recommended for the first trimester.

In women with intermediate thickness melanoma, pregnancy is not advised for 2 years. In women with Stage III disease, pregnancy is not advised for 5 years.

Oral contraception and HRT are both no associated with prognosis in those treated for melanoma previously

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