Use the term malignant
melanoma, not just melanoma.
- technically it is probably a carcinoma.
For benign lesions, use the terms 'mole' or 'pigmented nevus' (see notes). Definitions
<1mm = thin (<5% risk LNs; no SLNB)
1-4mm = intermediate (15-20% risk LNs, SLNB)
>4 mm = thick (high risk)
- more than doubling every 10 yrs.
New Zealand incidence 2nd only to Queensland.
78 / 100,000 / year in this ANZ.
- has quadrupled in last 30 yrs.
<5% of skin cancers.
- but accounts for vast majority of deaths from skin cancer.
Increases with age; one of the strongest RFs.
- median age at diagnosis 45-55 years.
- rare before puberty.
- but most common form of cancer in young adults, second most common
1:57 M > 1:81 F (Sabiston)
F get it most on lower legs
M get it most on back / trunk.
- these differences not accountable by sun exposure alone.
Rare in Polynesians.
Sun exposure interplays with other factors.
White skin, light hair, blue eyes, red hair.
- up to 2x risk with these features.
Sunlight most important risk modifier.
- rates relatively low in persons with indoor occupations.
- Sunburn conveys a 2x risk.
- but limited predictive value in our population where sunburn so
Both UVA and B
- UVB (280-320nm) induces sunburn, increases melanin and is the most
carcinogenic of the UV spectrum.
- UVA penetrates deeper, can damage dermal c.t. losing elasticity
and causing wrinkling. Emitted by sunbeds.
Blistering sunburn and intermittent sun exposure, especially during
early life, are probably more important than cumulative sun exposure
Skin type probably also important.
- those that tan easily are less likely
- those who are fair more likely.
Evidence of actinic sun damage is important. Other conditions:
Past hx of melanoma or other skin cancers.
Risk increases with naevus count.
- those with >100 naevi have 7x risk of those with <15
Congenital naevi, dysplastic naevi (DNs), Spitz naevi all raise
- number and size of congenital naevi correlate increased risk.
- small congenital naevi represent low risk (can be watched)
- rare giant congenital melanocytic naevi convey risk of ~5%, see
5-10% have a family history (Sabiston).
- earlier age
- more DNs and multiple primaries.
- linked to chromosomes 1p and 9p
One first-degree relative conveys a 2x risk
Dysplastic naevi plus two or more first degree relatives with
dysplastic naevi and melanoma convey estimated life-time risk of
melanoma approaching 100%.
Specific Genetic Panels
Xeroderma pigmentosum (defect in DNA repair genes).
Inherited mutations of certain genes have been identified
CDKN2A mutations cause high risk for melanoma; in context of
familial melanoma; but low prevalence
- unclear if should change practice based on CDKN2A mutation
Genetic counselling and screening can be performed in high risk
Neural crest cells that migrate to multiple sites, principally skin.
- melanoma can arise in eye, meninges, mucocutaneous jxs eg mouth.
- but most arise in the skin
Skin melanocytes found in nests along the epidermo-dermal junction.
Congenital Melanocytic Naevi Pigmented naevi, present at birth.
Involve lower dermis; may vary from small to giant.
- small = <1.5cm; minimal risk; rare melonomas
- medium = 1.5-20cm; probably minimal risk
- large = >20cm; risk~2-5%, mostly in first decade of life.
--> remove small, medium as per cosmetic concern, and biopsy or
remove if suspicious concern
--> for large ones, lifetime surveillance, biopsy any suspect
Potential precursor lesion.
Generally large (6-15mm) pigmented flat skin lesion with indistinct
margins and variable colour.
- difficult clinical diagnosis.
Treatment difficulty lies in pts with many (see above conditions).
- besides excision, monthly self exam and three-monthly clinic
recommended, with reference photography.
Aka juvenile / spindle cell melanoma.
Pink or brown skin lesions that grow rapidly.
Benign but may give rise to melanoma.
- difficult to distinguish from malignant melanoma for the
Completely excise them. Hutchinson's Melanotic
Freckle See card and lentigo maligna
below Natural History Most arise de-novo
Not from above precursors.
Spread locally or via blood or lymph.
- may embolise to local lymph or permeate lymph channels with local
satellite and /or 'in-transit' deposits along the way.
- blood borne to lungs, liver, brain, skin, rarely bones, small
intestine, heart, breasts.
30-40% of patients with malignant melanoma die from it.
See investigations for staging.
Classification Four major types according
to growth pattern / location
- this used to guide treatment, no longer.
1. Lentigo Maligna Melanoma
Arises in a Hutchinson's melanotic
Mostly older patients with sun-damaged skin; large doses of UV
- predilection for head and neck.
Malignant chance signalled by formation of darker discrete nodules
or a general thickening.
Generally more superficial, so prognosis better.
Initial flat phase may be prolonged.
2. Superficial spreading
Not necessarily associated with sun-damaged skin.
Slightly elevated, variegated and irregular.
Initially growth is radial and does not penetrate the
May last for weeks, months or years before progressing to vertical
No capacity to metastasise before this point.
3. Nodular (~15%)
EFG; elevated, firm and growing
Tends to be in older people, particularly men.
- common on head and neck
Vertical growth pattern earlier; thicker; worst prognosis.
- early mets, often via blood
Often a uniform shade with a palpable nodularity.
May ulcerate early with weeping / bleeding.
Frequently nonpigmented - note longstanding benign mole around this lesion.
4. Acral lentiginous melanoma
Affect palms, soles (glabrous skin) and nail beds and mucous
Sun exposure does not seem to be involved.
- main form in blacks.
May look light coloured or pink.
Vertical growth often present at diagnosis (often delayed due to
site); poor prognosis.
Subungual Variant of acral lentiginous melanoma.
Usually first presents as longitudinal melanonychia
Also similar incidence in dark races and not clearly related to sun
exposure. Other types
Lack pigment; delayed diagnosis often with lymph mets at
<10%; 5.2% in eye, 1.3% mucosal, 2.2% unclear (Sabiston) Eye
The most common malignancy of the eye.
- rarely metastasise to lymph (uvea has no lymph drainage)
- most commonly spread to liver
- treat primary by photocoagulation, resection, radiation or
Mucosal = oral, oropharynx, nasopharynx, paranasals, esophagus
Anal canal, rectum, female genitalia.
These usually advanced and have worse prognosis (<10% survive
- excise to negative margins and treat as possible.
- lymph node excision not indicated unless lymphadenopathy
- SLN biopsy now being performed for vulva melanoma disease.
An unusual looking mole which has grown rapidly or changed in shape,
size or colour.
- often spreading flat lesion that has become elevated.
Maybe itchy, painful, ulcerate and bleed.
Change most important symptom.
- any change is significant.
- usually become darker.
Secondary skin deposits are usually black but may be apigmented.
Extensive visceral disease may cause melanuria.
Nodal or distant disease is first evidence in 2%.
- search for primary, question past lesions that disappeared or were
- don't forget scalp, ears & nose (in & out), nail beds,
genitalia, anal canal and eye (see below).
A - asymmetry in shape, colour or appearance. B - border irregularity. C - colour varied from one area to another. D - diameter > 6mm. E - elevation. S - symptoms (itching, burning, bleeding, pain, scaling,
ulceration). S - surrounds (eg may have grown in a DN)
Suspect a benign lesion has become malignant if:
i) change in size
ii) change in shape
iii) change in colour
ii) crusting / bleeding
iii) sensory change, eg itch
iv) diameter >5mm.
v) loss of normal skin surface markings
vi) halo (pink inflammatory reaction, later brown)
Raised papules may be pink, red, purple or of normal skin colour.
Specific type of amelanotic melanoma arising on face / associated
with lentigo maligna.
- eshibit neurotropism; poor prognostic factor.
Small nodules growing adjacent to the primary.
If a melanoma is found, question
- constitutional symptoms
- CNS symptoms
- pulmonary, GI and soft tissue symptoms.
Pleural effusions, hepatomegaly, jaundice and neuro abnormalities
Other skin / subcutaneous tissue deposits are not uncommon.
- palpate route to lymph nodes.
Stage (as below).
Lesions confused with melanoma include moles,
pigmented BCCs, seborrhoeic keratosis.
NB: Past Cauterised Lesion
Mandatory excision biopsy f a skin lesion appears at a site
Melanomas may be subtle in this contect
Dermoscopy Hand-held magnifying device and liquid or cross-polarized light
- see features not visible with naked eye.
Diagnostic accuracy 15x greater in experienced hands.
Reduces # of benign excised lesions and number referred to
Training and utilization of dermoscopy recommended for all doctors
routinely looking at pigmented skin spots
Features of a melanoma
- broad pigmented network
- blue-white vail
Sequential digital dermoscopic imaging Capture and assessment of serial dermoscopic images; us. over
Successfully picks up extra lesions that change but did not
originally show concern.
Its use should be considered.
Total body photography
Evidence not as good but serial body photography can be used to help
observation in high-risk pts. Histopathological Reporting: Advised Criteria (These all have some prognostic evidence) 1. Macroscopic dimensions.
2. Key microscopic descriptors
- Breslow thickness
- level of invasion (Clark)
- mitotic rate per mm2; may be more important than ulceration
- ulceration (present / extent)
3. Other microscopic descriptors
- vascular invasion (marker of poor prognosis)
- microsatellites (strong predictor of poor outcome)
- lymph infiltration
- histologic growth pattern
- predominant cell type (spindle cells may be better)
- immunohistochemistry (S100 expressed by most melanoma)
4. For SLNs
- should report presence / extent
- S100 staining
5. For LN dissections
- number of nodes / number +ve
- size of macroscopically detected deposits.
- matted nodes
- largest mets
- extranodal extension
1. USS of regional lymph nodes - detects if >4.5mm in size
- better than PET but not as good as SLNB
- so not routinely recommended
2. Routine PET, CT, XR, not recommended in Stage I or II disease
- for more advanced disease, can stage extent.
3. Elevated serum LDH
- not useful for occult metastatic disease and not recommended
- adds prognostic value in advanced disease if raised.
1. Perform a detailed hx and physical
- FNA of significant nodes is adequate; no cores.
2. There is a low rate of useful diagnostic yield (<2%) for
occult metastatic disease
--> routine investigations including radiology are not indicated
when SLNB +ve but no symptoms suggesting metastatic disease.
3. If symptoms suggestive of metastatic disease, yield obviously
- then do CT chest abdo pelvis, whole-body PET.
4. If risk of lymph node mets, then FNAB to confirm stage III
Metastatic disease Perform serum LDH, CT, MRI, and/or PET scan as per directed
Only investigate with PET and further Ix if will indicate surgery or
Used to be that all melanoma received radical surgery.
Less predictive value, less reproducible and more operator
In AJCC 2010, prognostic significance only for <1mm melanomas.
- here, may help to guide SLN biopsy decision.
Clark et al (1969) showed invasive depth correlated with survival.
Anatomical depth of invasion
- Level 1 and 2 have an excellent prognosis.
- Level 3 convey significant risk
- Level 4-5 convey major risk of metastatic disease.
Breslow's thickness (1970) Simpler than Clark's and easier so more accurately reproducable.
Replaces Clark's as it adds little additional prognostic
- measured via an optical micrometer from top of granular layer of
epidermis to deepest melanoma cells.
- excellent correlation with 10yr survival in logarithmic curve.
- this plateaus at ~8mm and does not reach 100%.
Proven prognostic factors (RR) Bach et al; 17,600 pts / AJCC melanoma database. Thickness (1.56) - strongest predictor of outcome Ulceration (1.9) Age>60 (1.1) Site (1.34) - mucosal, subungual, back, arm, neck, scalp. Level (1.21)
Pathology Factors High mitotic rate = worse
Regression = worse
- presumably because thickness has artifically reduced. Inadequate excision margins. Lymphoid infiltration = better. Satellite lesions = worse # nodes involved = worse Lymphovascular invasion /
neurotropism = worse LDH elevation = worse Staging
TNM; Am Jt Committee on Cancer (AJCC) Schema
Provides clear differentiation of prognostic groups by stage:
Clinical Stage 0 and I pts need no further tests.
Stage II and III: can do a CXR and serum lactate dehydrogenase +/-
- rarely abnormal in the asymptomatic; is optional.
System: - Thickness categories
simplified to 1.0, 2.0 and 4.0mm. - Ulceration is included
in T, upgrading stage.
- Satellitelesions come in the N category.
- N staging includes size
of mets in nodes & number of nodes.
- Lung mets are a
subcategory of M1, as survival is longer.
T classification (thickness)
Tis = in-situ melanoma
T0 = no tumour
T1 = <=1mm
T2 = >1-2mm
T3 = >2-4mm
T4 = >4mm T1 is appended a without ulceration and mitosis <1mm2 b with ulceration or mitoses >1mm2 T2,3,4 are appended a without ulceration b with ulceration
[note also, in common clinical language:]
<1mm = thin
1-4mm = intermediate
>4mm = thick
N0 = nil.
N1 = one node.
- a. = micromets
- b. = macromets
N2 = 2-3 nodes
- a. micromets
- b. macromets
- c. in-transit met(s) / satellite(s) without metastatic
N3 = 4+ nodes or matted nodes or
in-transit / satellite lesions.
M0 = nil
M1a = mets to skin / subcut or distant nodes
M1b = mets to lung
M1c = mets to other viscera/ distant sites with raised serum lactic
Slip/slap/slop, monthly self examination.
First degree relatives of a patient diagnosed with melanoma should
be checked regularly.
Depends on type, location, depth, stage.
Resect primary and minimise chances of recurrence
Screening? No substantial evidence of effectiveness but being conducted.
- either by medical specialists or in skin screening clinics.
- maybe 40% of population being screened by GPs in recent 5y, but
not all body
PPV for melanoma in suspicious lesions found by skin screening by a
medical specialist is 6-20%
- yield perhaps 1-9 per 1000 pts screened.
But some evidence that screened melanomas are thinner.
- more likely to be <0.75mm than those found incidentally.
Cost-effective studies suggest as beneficial as other active
- moreso if pts >50y
- currently no evidence of mortality reduction (no trials), so
screening cannot be recommended.
Based on risk factors above, high risk patients should have regular
- education to self-screen or done by gp
Document / photograph any lesions
6 monthly intervals. Suspicious
Remove anything suspicious.
Concern is a valid indication.
2mm margin recommended
- larger excisions can interfere with lymph mapping.
Only total excision advised, down to subcut tissues.
- shave biopsy distorts thickness reporting and is to be avoided.
- partial biopsies are bad; and are a source of misdiagnosis
Take care to consider where repeat excision may be sited.
- e.g. longitudinally on extremities
Atypical naevi should be similarly excised
Large lesion If >2cm, incisional biopsy or punch biopsy may be used.
- or, when proximity to eye / nose / ear means wider excision will
be impairing or cosmetically deforming.
--> when the histo returns, a best-possible treatment excision
may then be planned as appropriate.
Take full thickness and include a margin of normal skin.
- include most elevated area, and deeply pigmented areas, to improve
- multiple such biopsies may reduce risk of error.
- incisional biopsy with as much tissue as possible is a useful
4 randomised studies looked at lesions <4mm or less.
- WHO 1991, Melanoma Intergroup Trial, Swedish Melanoma Trial,
French Melanoma Trial.
--> No benefit extending WLE beyond 2cm
For lesions >4mm we rely on retrospective data
--> No benefit extending WLE beyond 2cm
Excise to deep hypodermis (not beyond).
Measure from scar of narrow excision.
- so take a very narrow excision if possible. In-situ melanoma -
<1.0 mm - need 1.0cm, 1-2mm - need 2.0cm; 1cm ok if difficult area
2-4mm - need 2cm >4.0mm - need 2 or more cm.
Hand: Amputate digit to a preceding phalanx such as to allow a 1cm
- reimplantation of flexor and extensor tendons
Foot: amputate to metatarsal head.
Most are extensive by time of discovery.
Excise to clear margins, though no evidence this increases cure.
AP resection for anorectal lesions reduces local and regional
recurrence but does not improve survival.
Radiation for head / neck melanomas and pelvic mucosal melanomas
decreases local recurrence.
Do I need to tell patients to
Some melanoma have estrogen receptors, but pregnancy is not a
particularly adverse influence.
No need to terminate or delay pregnancy after treatment.
Atypical melanocytic lesions Diagnostic dilemma - careful pathological consideration.
When confusion exists, treat as for worst case scenario as
misdiagnosis is high.
Lentigo maligna As for in-situ melanoma
Lentigo maligna melanoma, however, is invasive
- sun-exposed areas can be restrictive to conventional resection
- may need reconstruction of defects with flaps
- may need delayed or staged reconstruction with interim margin
Most sites of recurrence are regional (nodes, in-transit or local)
Nodal lesions appear in basins draining the primary site
- predictable for extremity melanomas
- but head / neck / trunk melanoma may drain to multiple sites.
- truncal lymph usually drains according to midline and line of
Sappey (level of L2 around umbilicus, across iliac crests).
Elective lymph node dissection
Originally commonly performed for much melanoma
- with attending lymphoedema, weakness and muscle restriction.
Later applied selectively to 1mm-4mm melanomas where likelihood and
survival benefits maximal.
- large RCTs now largely dismiss this idea as having no benefit, and
generally not advised.
Evidence from Intergroup Trials did
support ELND for lesions 1-2mm in size.
- & WHO trial for >1.5mm melanoma showed 5yr survival gain
from 51.3% to 61.7% (p=0.09)
So evidence is arguable; but in any case debate was largely ended by
evolution of SLN techniques.
Sentinal Lymph Node Biopsy Described by Cabannas in 1974 for penile carcinoma, popularised
by Morton in 1994 for melanoma.
Aims to identify pts appropriate for completion lymphadenectomy by
detecting micrometastasis in a sentinel node.
- SLN = first node to receive lymph from the tumor site
- lymphoscintography using intradermally injected radioactive
colloid; stimulates lymph flow.
- and blue-dye intradermally.
Minimal risk and morbidity, while properly identifying occult
When do I use SLN Biopsy? Currently recommended in all patients with: 1. Negative lymph nodes clinically and radiologically 2. Lesions > 1mm; or <=1mm but with ulceration OR high
mitotic rate OR Clark IV-V (12% risk in these thin high-risk
Is both the best prognostic test for melanoma as well as informs
- status of the sentinal node is the most powerful predictor of
outcome in these pts.
- however, at present, no improvement in overall outcome as
a result of SNLB (may not actually be important for overall
Multicentre Selective Lymphadenectomy Trial (MSLT)
In patients with tumor-negative SLN biopsies, significantly higher
5-y survival rates cf tumor-positive SLN biopsies
Discuss at MDT
At 0.2mm micromet size, reasonable to do a CLND or not, can be
argued either way
-- risk of more nodes is ~5% and no evidence yet that it improves
i) with gamma probe and blue dye, the SLN can be identified in
ii) great anatomic variation results in drainage to multiple sites iii) path examination should be detailed and using 'step
sections' allows detection of micromets that are normally missed.
iv) in most cases, the +ve SLN is the only positive node.
v) no prognostic factors accurately identify those SLN +ve pts not
requiring completion lymphadenectomy; they all do.
vi) when regional nodal mets appear after -ve SLN biopsy, micromets
can later be found on further examination of the original node.
1. Lymphoscintigram obtained afternoon before or morning of surgery.
- multiple Tc-99 injections given at biopsy scar site.
2. Lymphatic mapping should image all areas
- there are instances where drainage is uncertain, e.g. primary
lesions of trunk, head, and neck.
3. Sites of uptake noted on gamma counting.
4. Blue dye is injected intraoperatively, prior to skin prep.
5. Palpate nodal basin; n.b.: nodes obliterated by tumour may not
6. Prior to incision, gamma probe used to localise radioactive areas
7. Make a 2-3cm incision over the site
8. Dissect down until a dye-colored lymph vessel is seen
- continued scanning of the area can help to direct.
9. Trace it to the co-localized blue / hot nodes and remove.
- careful ligation of vessels and lymphatic channels.
10. Ex-vivo tracer count on the SNL to confirm it.
11. Remaining tissue basin scanned for other areas of increased
12. If node appears grossly metastatic then frozen section and wait
- else better to leave for permanent section and close to come back.
13. Would closed in 2 layers.
What if I have two nodes coming up
The hottest node is not always the +ve sentinel node
- all nodes with counts >10% of the hottest node should be
resected for analysis (Sabiston's)
Complications Seen in up to 10%.
MSLT showed wound infection in 4%, separation in 1%, hematoma or
But lymphedema very rare <1% Regional / Completion Lymphadenectomy
- positive SNLB (supported by MSLT1 trial = 15-20% survival
advantage for completion vs watch and wait approach)
- or if any macroscopically evident nodal disease (palpable nodes
and pathology +ve)
--> i.e. any patients with metastatic nodal disease, microscopic
One third of patients with macroscopic nodal disease are cured with
- hence removal of the entire involved nodal basin is of paramount
See algorithm for recommended harvest
Technical notes 1. Create flaps with sharp dissection, aid of skin hooks.
2. Particularly important for inguinal dissection; tenuous flaps
3. Ligate all lymph channels encountered to reduce chance of
4. Closed suction drainage through a separate skin stab; left 2-5d;
until drainage <20-25 ml/day
- avoid strenuous exercise until all drains removed and wounds
- simple range of motion exercises encouraged
Neck Dissection Extent variable; depends on site and degree of nodal disease.
Rarely 'radical' (SCM, spinal accessory nerve, and internal jugular
v.) as functional deficits --> 'Modified radical' approach
--> i.e. ipsilateral cervical nodal tissue, preservation of above
structures sacrificed in a radical dissection.
Consider superficial parotidectomy if melanoma of anterior face,
scalp and upper neck with clinically-apparent cervical disease.
Axillary Dissection Unlike in breast, need removal of all three levels with
skeletonization of the axillary vein.
Pec minor typically sacrificed, taken it close to the coracoid.
Long thoracic and thoracodorsal should be identified and preserved,
if not grossly involved.
Intercostobrachial is sacrificed
--> sensory changes in upper medial arm.
Groin Dissection 2 nodal basins here: inguinofemoral and iliac/obturator
Inguinofemoral = (formerly) superficial inguinal dissection
- all lymph tissue over lower external oblique, inguinal ligament
and within femoral triangle.
Iliac / obturator = (formerly) deep inguinal dissection
- removal of nodal tissue adjacent to iliac vessels, obturator nerve
and node of Cloquet at iliofemoral jx.
--> this only performed if radiologic staging demonstrates
involvement of these deep nodes.
--> or positive Cloquet node, >4 nodes on inguinofemoral
dissection, or palpable or extracapsular extension of femoral nodes
Radical groin dissection = both; rarely performed.
Ectopic nodal sites E.g. popliteal and epitrochlear; has increased since
Rarely taken unless palpable disease is evident. Reconstruction Proper closure essential for adequate wound healing
- want stable soft-tissue coverage and prompt healing, ideally in
New recommended margin guidelines have allowed wide undermining in
Primary closure generally requires that longitudinal axis of
elliptical incision is >3x length of short axis.
- then two-layer (dermal and subcuticular) closure.
Larger lesions may need plastic surgeon involvement for optimal
cosmetic and functional results
- also if in complex areas.
Flap options include rotational or transposition (around a fixed
- or single-pedicle / bipedicle, or V-Y advancements.
- i.e. only when sufficient tissue not available locally.
Skin grafting is another option; full or split thickness.
- split are more likely to shrink and cause hyperpigmentation, but
also more likely to survive
- full require a well-vascularized recipient bed.
- simplest technique is a split-thickness graft, pie-crusted and
stapled to the edges of then wound
- then bolster dressing or negative pressure wound management
system. Adjuvant local
radiotherapy to node field? No.
Intergroup Trial (Aus/NZ)
Examined role of RadioRx in patients with high risk features of LN
Showed a 15% reduction in local field relapse at 5y, but no change
in systemic disease or survival
And high toxicity with skin fibrosis, nerve damange, lymphoedema;
persistant swelling >3m Follow
Inform patients about warning signs:
- local swelling / itching
- new lesions in and beneath the skin
- enlarged lymph nodes
- CNS / pulmonary / GI symptoms. How long do need to follow up
for? - at 3yr anniversary, 75% of those destined to develop
recurrence will have done so.
- 3monthly exams for first 18mo or so, then 6monthly to 3rd
- annual exams thereafter for thicker melanoma.
- end exams at 1 year for in-situ lesions. What investigations are
IA = nothing
Asymptomatic others = CXR and serum lactate dehydrogenase every
6-12mo (no evidence for survival gain though)
CT, MRI, PET is not cost effective and under investigation.
- PET changes treatment decision in 20% of stage III patients.
What should I do at each visit?
- examine scar ?local recurrence
- look for satellite lesions (between primary site and regional
- in-transit lesions may be palpable but not visible.
- examine all regional lymph nodes.
- rest of skin for distant spread and / or new primary melanomas (8%
will get one).
Look especially carefully at distant sites for thick / node +ve
Recurrence 20% of melanoma patients are not cured; 80% are.
Regional Node Recurrence
- if +ve, radical lymphadenectomy will control regional disease in
- if -ve / insufficient, excision biopsy should be performed +/-
If nodes are +ve, long-term survival is low.
- even with 1 palpable node, it is 40-50% at 5 years.
Prior to lympadenectomy, perform a full metastatic work-up:
- CT head, chest, abdo, pelvis
- normal mostly in the otherwise asymptomatic.
If multiple positive nodes are found, high risk of further
- post-op radiation has not been evaluated but is advocated in some
Satellite and In-Transit Lesion Management
Satellite = Tumour appearing in skin / subcut tissue in 2 cm
radius of primary. In-transit = At a distance >2cm from primary, between
lesion and primary nodal basin
Both are thought to be tumor emboli trapped in dermal and subdermal
5-20% depending on initial stage of primary and treatment.
- risk: thickness, ulceration, lower extremity, +ve nodes (11% with
1 node, 33% with 3 nodes), inguinal disease
Typically occurs after 1 year of primary treatment, and 80% within 3
A poor prognostic sign: <20% long-term survival.
Divided into local, regional and systemic.
- and depends on number, size, and other disease.
Local treatments include surgery, intralesion injection, CO2 laser,
and external beam radiation.
Surgical excision indicated if few lesions
- wide margins not necessary
- rarely controls the disease, further recurrence is the rule.
- amputation is seldom indicated (long-term survival poor anyway).
- rarely, indolent disease may linger eventually indicating
If multiple lesions, consider infection with bacillus
Calmette-Guerin or dinotrochlorobenzene.
Interferon-alpha may have some effectiveness in conjunction with
External beam rads and CO2 laser have been used with limited
Isolated Hyperthermic Limb Perfusion
- cannulation of artery and vein with tourniquet.
- hyperthermic (40oC) perfusion of limb with melphalan;
L-phenylalanine mustard (IL2, TNF and other agents also have been
- response rates exceed 80%, complete in 10-15%; however often
- prophylactic use on people with high-risk lesions (>1.5mm)
showed no overal survival, though in-transit mets reduced from 6.6%
--> so reserved for pts with established multiple in-transit
lesions, and in experienced centres. Systemic chemo
May be of use if not candidates for any of the above.
Single agent regimens of dacarbazine, temozolomide
Response rates are low, mostly partial and transient. Advanced
Isolated metastatic lesions
In general, role of surgery limited to isolated accessible distant
disease; 2-3 sites max
- irrespective of if primary site identified.
Behavior and operability is a function of growth kinetics and
- if tumour is slow to double during observation, usually 3-6m, and
does not metastasize, then pt is a good candidate.
- else spare them the trouble.
Most common met sites lung, skin, nodes, brain, liver, bone and gi
tract (in decreasing order)l
Isolated GI lesions should be evaluated for surgical resection
- long-term disease free survival reported at 10-20% for
- disease-free interval is an indicator
- complete staging with CT / PET
- highly selective multiple intra-abdominal excisions have been
effective in reports
- occasionally these pts can present with intussusception
Isolated lung lesions warrant observation +/- chemo / investigations
- those without additional lesions in 4-6weeks warrant pulmonary
resection if no other lesions found.
Isolated adrenal mets also warrant excision.
Isolated CNS mets = less success, but treated with resection and
radiation have been effectively managed in reports.
--> brain mets often considered for resection as they can bleed,
with devastating consequences.
Bone = also bad.
If multiple, refer oncology.
Palliate boney mets with radiation.
Dicarbazine (DTIC) most commonly used drug
- response rate just 15-30%, complete responses rare.
Any increases in survival from combination chemotherapy have been
- limited to nothing or ~4 month effect
- randomised double-blind trial of cisplatin, vinblastine,
dicarbazine vs DTIC = no improvement
CVD + interferon + interleukin 2 has a response rate of 50% and
complete response rate of 15%
- however effects are brief and several trials show no useful
prolongation of life.
Immunotherapy and Modern approaches
Stage IV pts are candidates for immunotherapy trials.
Active research area.
Cytokines = high dose interferon alpha2b is available for stage IIb
- and IL-2 trialled but significant toxicity.
Antibodies - monoclonal antibodies to T cell melanoma and cell
Adoptive T-cell transfer - infusion of expanded autologous T cells
into lymphodepleted pt
Vaccines - phase III trial; can be immunized against specific
melanoma peptides, proof of principle established.
Molecular therapies; BRAF and NRAS targeted therapies in
Venurafenib BRAF inhibitor (V600E is key cancer mutation)
Targets cell cycle regulators involved in promoting cancer cell
Used in stage 4 melanoma in patients V600E positive (+/- V600K,
Response can be dramatic though only 6-8m max
Blocks CTLA-4 inhibitory signal to cytotoxic T-cells
Ie an immune cell activator.
Can improve survival by 6-10m for stage 4 melanoma
Can even offer a chance of disease remission or cure in lucky cases.
- another PD1 blocker drug is in near-term development for similar
Adjuvant Systemic Therapy
Distinctly poor efficacy.
Interferon-alfa-2b approved in US and Australia for pts with
expected survival <50%.
- single trial evidence for which subsequent RCTs have failed to
- meta-analysis: no consistent benefit; perhaps overall 3-5%
survival advantage at 5y follow up
- controversial; highly toxic with only 30% of pts tolerating 12m
- major quality of life impact; hepatotoxicity; all pts need
prophylactic antidepressants as neuropsychiatric side effects and
dsyplastic nevi in sun-protected areas. Very high life-time risk
is the dysplastic naevus syndrome
autosomal dominant, high penetrance
chromosome 1p32, 1p36
± centrally raised
trunk > limbs > face
usually have > 100 melanocytic naevi, some
large and atypical
groups of patients at increased risk
naevi (relative risk of melanoma 50x)
dysplastic naevi with
family history of melanoma (risk approaches
100% - relative risk 150x)
increased risk of
is the management of dysplastic naevus syndrome
full body photographs 6 monthly
screening from puberty onwards
excision biopsy of any lesions that change
prophylactic excision not recommended
is a Spitz naevus
spindle cell naevus
well circumscribed and raised
most common in young adults
complete excision recommended
are congenital melanocytic naevi
melanocytic naevi present at birth
naevus cells present in lower two-thirds of dermis
naevus cells between collagen bundles singly or in short files
naevus cells involving appendages
1% of births
no increased malignant
malignant potential uncertain
excise during teenage
giant congenital naevi
crude risk 3%
70% of melanomas develop
naevi on head and neck at risk of neurocutaneous
5-8% risk of melanoma
is the management of congenital melanocytic naevi
monitor all congenital lesions >20cm and
possibly medium lesions for persons lifetime
excision biopsy of suspicious area
surgical excision where acceptable cosmetic
outcome can be achieved (tissue expanders)
is the role of sun exposure in development of melanoma
associated with intense intermittent exposure
BCC/SCC occur most commonly in maximally
sun-exposed areas (face, back of hands, forearms
Intermittent exposure areas back (men), lower
Persons with indoor occupations who limit sun-exposure to
weekends and vacations
Associated with exposures inducing sunburn
5 or more severe sunburns during adolescence doubles the risk
UV-B (290-320 nm)
Responsible for formation of principal
pyrimidine dimers and pyrimidine pyrimidone photoproducts)
Incorrect repair leads to mutations
UV-A (320-400 nm)
More abundant in sunlight than UV-B
Causes oxidative DNA damage that is
Contributes to immunosuppression in mice
are the prevention strategies for melanoma
Sun protection behavior: Shade, sun protective clothing, peak
hours of sun intensity avoided, sunburn prevented, sun screen
(No evidence that sunscreen is effective).
Population based screening population screening is not
High risk individuals: Increased surveillance and prevention
programs education about sun protection and features of
melanoma, routine self or partner examination, regular screening
by dermatologist using whole body photography and dermoscopy as
melanocyte response to UV damage
melanocytes are more-resistant to UV-damage
induced apoptosis than basal (dividing) keratinocytes
UV-damage induces changes
increased production of melanin with resultant less exposure to
increased ability to repair UV damage
keratinocytes are damaged but undergo apoptosis
and dont perpetuate mutations
melanocytes are damaged but tend to survive and
perpetuate mutations, encouraged by the post-exposure
are the layers of the skin (epidermis?)
Stratum spinosum (prickle cell)
Stratum granulosum (Granular) Intracellular
granules which contibute to keratinization
Stratum Lucidum present only in thick skin
scattered in the basal layers in contact with the
The ratio of melanocytes to basal epithelial cells is 1:5 to
This ratio is similar in all races. Differences
in skin colour are due to amount of melanin produced.
The melanin is synthesised from tyrosine and accumulates in
granules called premelanosomes. These mature to form melanosomes which are transferred via the long cytoplasmic processes of the melanocyte to the
The epithelial cells contain much more
melanin than melanocytes.
Sunlight promotes melanin synthesis and darkening
of previously synthesized melanin.
is the immunohistochemical marker for melanoma
are Clarks levels
I confined to
II papillary dermis
IV reticular dermis
V subcutaneous tissue
are the types of melanoma
superficial spreading (most common)
are the examination features of a melanoma
(irregular but well defined, dysplastic
Melanoma cells are larger, have large irregular nuclei,
chromatin clumped at the periphery of cell membrane and
Melanin either in
H&E or with a Fontana stain can easily identify melanotic
be used to confirm that cells are melanoma, particularly when
Melan A, S-100 protein, and HMB-45 .
The sensitivities of S-100, HMB-45, and Melan-A are 97%, 75%, and 96% respectively.
are the growth phases of melanoma
Radial growth horizontal growth within the epidermal and
superficial dermal layers. Not
tumorogenic when implanted into non-immune mice.
Vertical phase growth into
deeper dermal layers often associated with loss of cellular
maturation and cells becoming smaller. These cells grow
autonomously in cell culture and are
tumorogenic when implanted into non-immune mice.
are the clinical features of a melanoma
B Border irregularity
C Colour variagation
D Diameter >6mm
evolution, examination for other lesions
Suspicion should be
aroused by any significant change in an existing naevus or
other skin lesion.
history is important in the assessment of a pigmented lesion
change in size
change in colour
change in surface characteristics
family history of melanoma
past history of melanoma or other skin cancer
proportion of melanoma are non-pigmented
5% are non-pigmented
This is more common amongst nodular melanoma
are the clinical types of melanoma
Spreading 65% Most common in
Nodular 25% pure vertical growth
phase ab intio.
Slowest growing with best prognosis. (melanoma in situ)
Lentiginous 5% commonest in unpigmented parts of pigmented skin
lesion; Acral = limb)
do you do when unsure
diagnosis is uncertain the safest course of action is an excisional
biopsy with 2mm margin.
Longitudinal excision on limb facilitates later
re-excision if required.
about if the diagnosis is clinically certain
Excisional biopsy with narrow margin is still appropriate so
that subsequent definitive treatment is not compromised.
Primary closure is preferred and skin flaps and grafts should be
do you do when a pigmented lesion is very large
Incisional biopsy used only where
an excisional biopsy cannot be achieved
If used, punch biopsies should be performed at
the most raised or darkest area of the lesion.
Partial biopsy may not be
representative of the lesion and need to be interpreted
in the light of clinical
Partial biopsy is clinically indicated
only in selected circumstances larger facial or acral
lesions or where suspicion of melanoma is low.
microscopy (ELM), can aid identification of the early phase of
melanoma by lens examination under a liquid interface
Evaluates colors and
microstructures of the epidermis, the dermoepidermal junction,
and the papillary dermis not visible to the naked eye.
by skilled practitioners improved diagnostic accuracy, but in
the hands of untrained or less experienced examiners is no
better than clinical inspection.
are the histological determinats of prognosis
The four common clinical
subtypes have a biological prognostic behavior (risk
mets/death) which correlates with Breslow depth.
Histological determinants of poor prognosis:
Breslow depth (more
reliable) or Clark level
significant next to depth
Regression: worse prognosis
Neural or vascular
is Breslow depth measured
The Breslow depth is
measured from the granule cell
layer (just below Stratum Corneum) of the epidermis to the
deepest point of invasion using eyepiece graticule.
This is the most accurate and reproducible measure of local
Tumor thickness is the
most accurate predicator of prognosis. Mortality reaches a
plateau at about 8mm. Even up to 13mm thickness mortality is
is Clark level
papillary-reticular dermis junction
Clark level of invasion is
significant in lesions <1mm thick where lesions
Clark level II/III are T1a
Clark level IV/V are T1b
are the important features of a histopathology report
factors which are of prognostic or other value include
microsatellites, in-transit metastasis,
4 or more nodes, matted nodes, in-transit/satellite mets with
distant skin, subcutaneous or nodal mets, LDH normal
lung metastases, LDH normal
all other visceral mets with normal LDH, any mets with LDH
is in transit metastasis
Anyskin or subcutaneous metastasis that are> 2cm from the primary lesion but not beyond the regional nodal basis
are satellite lesions
Skin or subcutaneous lesions < 2cm of the primary tumour
that are considered intra-lymphatic
extension of the primary mass.
in transit and satellite metastasis are a component of nodal
staging and assigned as N2c in the absence of nodal metastasis.
prognosis is similar to that of multiple nodal metastasis.
with combined in transit/satellite and nodal metastasis and
nodal metastasis have a worse prognosis than either alone (N3).
are the appropriate investigations for patients diagnosed with
Extensive imaging studies (CT, PET, PET/CT) are not recommended since the yield is extremely low and the false
positive rate is unacceptably high. Even the use of routine
chest X-ray cannot be recommended in asymptomatic patients
In patients with advanced regional disease for whom surgery is
being considered, PET/CT scan is recommended, as the
yield is higher than with CT (chest/abdomen/pelvis) scans alone. The detection of
distant metastasis in patients with macroscopic stage III
Cutaneous melanoma is 20%; the false positive rate is 10%.
For a patient with
a positive sentinel node in the absence of symptoms of
metastatic disease, the true positive rate of radiological
investigations is 2%. Routine radiological investigations are
IV:For patients with symptoms suggestive of metastasis
investigations should include LDH, CT,
MRI brain and PET. For patients with a single site of
metastasis disease who are being considered for surgical
resection, PET/CT is recommended to complement conventional
imaging studies (MRI scan of the brain and CT scans of the chest
and abdomen and pelvis) prior to surgery to exclude other sites
What margins are appropriate for melanoma
Tumor Thickness (mm)
no evidence that <1cm offers additional benefit for long term
survival but maydecrease
The margin should be measured clinically from the edge of the
melanoma before excision
The excision is down to but not
including the deep fascia
A flap repair or skin graft is sometimes necessary
is based on evidence from four RCT and a number of
WHO melanoma group
patients; <2mm thick; 1-cm or
3-cm margin of excision.
was no significant difference in survival between the 1- and
3-cm surgical margin groups.
local recurrences among patients with primary melanomas thinner
than 1 mm.
local recurrences in the 100 patients with melanomas 1 to 2 mm
thick, all in patients with 1-cm margins.
Narrow excision margin (i.e., 1 cm) is safe for
thin (<1 mm) melanomas.
French Trial: 319 patients lesions at least 2
and 2-cm margins
differences in local recurrence rate or survival between the two
United Kingdom Trial: 900 patients with
melanomas at least 2 mm thick
and 3-cm margins
margin associated with a significantly increased risk of
survival was similar in the two groups.
Intergroup Melanoma Committee
and 4-cm margins of excision
difference in local recurrence
in the 4-cm group required skin grafts
of patients in the 2-cm group did (p <0.001).
These data support the use of a 2-cm margin for
For thick melanoma
margin for melanomas >4 mm is still unknown.
retrospective review of 278 patients showed width of the
excision margin (<2 cm vs. >2 cm) did not significantly
affect local recurrence, disease-free survival, or overall
survival rates after a median follow-up of 27 months. (Heaton
KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and
prognostic factors in patients with thick (>4 mm) primary
melanoma. Ann Surg Oncol 1998)
What is the significance
of lesions >1mm thick
These are the patients where
SLNB should be considered
SLNB should be performed before the wide-local
These patients should be referred to a specialist
is the risk of lymph node metastasis in melanoma
is the role of lymph node dissection in melanoma
of patients present with clinically positive nodes
of patients present with distant metastasis
present with clinically negative nodes
is management of clinically positive nodes
Palliation and sometimes survival advantage
can be achieved in patients with clinically involved regional
metastases through therapeutic lymph node dissection (TLND).
This is beneficial only if distant metastatic
disease is excluded (CT/PET).
or Core BX under US guidance (if required) yield a diagnosis
with clinically enlarged regional nodes.
biopsy is rarely warranted but if used the incision should be
placed so that it can be excised with the incision used for
For patients with a positive SLN biopsy TLND is
is the rationale for elective lymph node dissection
less than 1mm have low risk of nodal involvement (<3%)
lesions >4mm depth there is a higher risk of distant
metastasis determining prognosis.
Elective Lymph Node Dissection (ELND) was proposed
for patients with intermediate thickness lesions (1-4mm) with
clinically negative draining nodal basin.
High morbidity and 80% negative
prospective RCT conducted comparing ELND to surgery delayed
until clinical recurrence.
no evidence of survival benefit for ELND for
clinically negative nodes in prospective trials
WHO Melanoma Trial I (Veronesi U.N Engl J Med.
RCT of 553 pts treated by WLE +/- ELND.
No OS difference
Mayo Clinic (Sim FH. Mayo Clin Proc. 1986;61:697-705).
Similar design, no OS difference.
Intergroup Melanoma Trial (Balch CM. Ann Surg Oncol. 2000;7:87-97).
RCT of 740 pts with 1-4 mm melanomas
Compared WLE +/- ELND.
At 10 yrs non-significant diff OS (73% vs 77% ELND; p = 0.12).
Significant difference was found in unplanned subset analyses:
< 60 yrs : 74% ΰ
1-2mm thick: 80% ΰ
Non-ulcerative: 77% ΰ
WHO Melanoma Trial 14 (Cascinelli N. Lancet. 1998;351:793-796).
of pts with trunk melanomas > 1.5mm thick to WLE +/- ELND.
toward improved survival in the ELND arm (p = 0.09).
The lack of survival benefit of ELND is confirmed by
meta-analysis. Arch Surg. 2002;137:458-461
Thus ELND is not recommended regardless of
Biopsy of first node(s) to receive drainage directly from the
primary tumour site.
Indication for SLNB
melanomas >1mm thickness, or
<1mm thickness but higher mitotic rate(≥5/mm
2), Clark level 4-5 or ulceration and patient <60 yrs.
SLNB should have completion dissection and consideration of
systemic adjuvant treatment
is the evidence of benefit for SLNB
Multicentre Selective Lymphadenectomy Trial
1327 patients to SLNB or observation.
lymph node dissection for positive SLN
Intermediate thickness melanoma (1.2 3.5mm)
5yrs, no difference in OS, but improved DFS (78% vs 73%; p <
5yr survival higher in SLN group with +ve nodes, compared to pts
who relapsed on observation (72% vs 52%).
of positive SLN was 16%, and rate of nodal relapse in observed
group was 16%.
Mean number of nodes in SLN group was 1.4, and observation group
3.3, suggesting disease progression during observation.
3.4% of pts with negative SLNB subsequently relapsed in the
proportion of SLN positive patients had positive non-sentinel
Less than 20%
examines the benefit of completion LND in SLND positive patients
is the technique of sentinel node biopsy on melanoma
Performed prior to wide local excision of
99Tm-sulfur colloid (about 3 hours pre-op)
injection into dermis (not subcutaneous) in 4 quadrants around
the melanoma excision scar to map dermal lymphatic drainage
The nuclear medicine physician marks the location(s) of highest
isotope uptake as the SLN(s) on the skin.
patent blue V is injected
intradermally in 4 quadrants around the scar by the surgeon
immediately prior to surgery
Any blue and hot nodes are removed through a small incision and
sent histology using H&E and S-100, HMB-45 and Melan-A. Frozen section is not used because of the
false negative rate of 10%.
Intra-operative mapping is achieved by hand held gamma probe and
visual staining of blue dye.
success with both lymphoscintigraphy and blue dye
80% when either alone used
After SLN removal, resection bed count should decrease
to <10% of hottest node.
focused pathologic evaluation
immunohistochemical (S-100, HMB-45)
is the line of Sappey
An imaginary circumferential line around L2 vertebra
posteriorly to umbilicus anteriorly
As originally described
by Sappey lesions above this line
drain to axillay nodes and below to inguinal.
Drainage across the
midline is quite common
It is now clear that
there is a zone of ambiguity
straddling Sappeys line by 10cm where lymphatic drainage is
are the discordance rates for lymph
drainage identified by lymphoscintigraphy
37% head and neck
14% upper limb
5% lower limb
is the survival after therapeutic node dissection in melanoma
10YS 50% if only one node involved
10YS 30% if 2 or 3 nodes involved
is the role of interferon in melanoma
high dose interferon-α2b
ECOG trials E1684, E1690 and E1694
improve survival by 10%
is the role of radiotherapy to the site of the primary
Rarely indicated as low recurrence rates with
Desmoplastic neurotopic histology
Close or positive margins where re-excision
Primary lesions with high risk features such as
>4mm or with satellite lesions.
is the role of radiotherapy to nodal basins
postoperative radiotherapy may be offered after TLND to
decreasing local recurrence after LN dissection if:
ECE (60% LR)
> 4 nodes
Bulky LN > 3cm
Recurrent nodal disease
Positive SLNB and completion dissection not planned
what other circumstances may radiotherapy have a role
postop adjuvant XRT for mucosal
primary XRT for unresectable lentigo
XRT for extensive cutaneous metastases
cerebral and bone metastases
is the role of surgery for metastatic melanoma
surgery should be considered for isolated
melanoma metastases to lung, brain and peritoneal cavity
is the role of adjuvant systemic therapy
is level I evidence that adjuvant IFNa
is of benefit for high risk patients:
Primary tumour >4mm
benefit of 9% at 5 yrs, and one RCT demonstrates an OS benefit
of 9% at 5 yrs.
It is approved on PBS in Australia only for LN+ patients.
is a desmoplastic melanoma
uncommon variant of melanoma (1-3%, older age
group, more common in head and neck).
Histologically: Atypical dermal spindle
cells separated by collagen with sclerosis of dermis.
Extension of desmoplasia into the margins of excision is an
indication for wider excision
may be associated with neurotropism (40%)
infiltration along nerve sheaths.
commonly on the head and neck
Wide local excision with same margins as for other forms of
melanoma provided the desomplastic change is completely excised
postoperative XRT unproven recommendation
is lentigo maligna
Hutchinsons melanotic freckle
common pigment lesion on the exposed skin of older patients
predominantly occur on the face
may progress to invasive melanoma (lentigo maligna melanoma)
5mm margins for excision recommended
is locoregional recurrence
Recurrence of melanoma in the anatomical
region from the primary site to the regional lymph nodes after
apparent complete excision of a primary melanoma with
appropriate surgical margins. Includes:
Local recurrence within
2cm of the surgical scar following definitive excision of a
In-transit metastasis or
satelliteosis due to lymphatic or haematogenous spread
Regional lymph node
Can occur in isolation
or association with systemic disease.
Local recurrence is generally a harbinger of disseminated
is the management of localregional recurrence
Excision with margins similar to those used for
primary lesion if feasible
Adjuvant XRT for close or positive margins
unsuitable for re-excision
about in transit metastasis and satelliteosis
Can be managed with excisionor a variety of other local treatments (cryotherapy, Co2
laser, XRT, intra-lesional immunomodulators or drugs.
about patients with multiple, rapidly growing or rapidly
progressive lesions of the limbs not suitable for local
Managed with regional drug therapy using isolated limb perfusion
or infusion can be used.
Complete response in up to 50% and partial response in another
30 40% of patients
(L-phenylalanine mustard) is the benchmark agent
Synergy between cytotoxics and hyperthermia in the limb
Staging investigations to exclude disseminated Melanoma
ILI is a simpler technique and may produce equivalent results
The response rate to repeat ILI/ILP is similar to initial ILP
What is the technique for ILP
tourniquet is placed on the limb and with an extracorporeal
bypass circuit the limb is perfused with melphalan and/or tumor
necrosis factor for 60-90 minutes. Hyperthermia of 39-40°C is
This procedure obviously avoids systemic toxicity while
delivering high doses of antitumor agents to the affected area.
Isolated Limb Infusion
Measured limb volume with water bath dose melphalan 7.5mg/L
Heparin infusion, affected limb warmed and tourniquet applied
Esmarch bandage applied to unaffected hand or foot
Melphalan infusion and continuous circulation for 30 min
Limb flushed 1L Hartmanns at room temperature
Heparin reversed and pressure to groin punctures
obs, limb elevated, heparin 5000u TDS, serum CK and limb
toxicity clinically assessed
What is the management of loco-regionally
wide local re-excision (without skin graft where