Malignant Melanoma

INTRODUCTION
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)


EPIDEMIOLOGY

Incidence

Rising worldwide.
- 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.

Age
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 in adolescents.

Sex
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.

Geography
95% whites.
Rare in Polynesians.
Reasons unknown.

Risk Factors
Sun exposure interplays with other factors.

Personal:

White skin, light hair, blue eyes, red hair.
- up to 2x risk with these features.

Environmental:

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 common.
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 (Sabiston).
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 risk.
- 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 below

Albinism.

Genetics:

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 finding.
Genetic counselling and screening can be performed in high risk individuals.

Rarer:
- familial dysplastic naevus syndrome (have >50 dysplastic naevi).
- familial atypical multiple mole melanoma (FAMMM).

D I A B M I M


AETIOLOGY

Tumour of melanocytes.

Melanocytes
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.

D I A B M I M


BIOLOGICAL BEHAVIOUR

Precursor Lesions

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 features.

Dysplastic naevi
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.

Spitz Naevi
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 pathologist.
Completely excise them.

Hutchinson's Melanotic Freckle
See card and lentigo maligna below

Natural History

Most arise de-novo
Not from above precursors.

Spread

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
(~10%)
Arises in a Hutchinson's melanotic freckle
Mostly older patients with sun-damaged skin; large doses of UV light.
- 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

(~70%)
Not necessarily associated with sun-damaged skin.
Slightly elevated, variegated and irregular.
Initially growth is radial and does not penetrate the dermis.
May last for weeks, months or years before progressing to vertical growth.
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
(~5%).
Affect palms, soles (glabrous skin) and nail beds and mucous membranes.
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

Amelanotic
Lack pigment; delayed diagnosis often with lymph mets at presentation.

Noncutaneous Melanoma
<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 enucleation.
Other
Mucosal = oral, oropharynx, nasopharynx, paranasals, esophagus typically.
Anal canal, rectum, female genitalia.
These usually advanced and have worse prognosis (<10% survive 5yrs).
- excise to negative margins and treat as possible.
- lymph node excision not indicated unless lymphadenopathy clinically evident.
- SLN biopsy now being performed for vulva melanoma disease.

D I A B M I M


MANIFESTATIONS

Symptoms
Local
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.

Metastatic

Lymphadenopathy.
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 excised
- don't forget scalp, ears & nose (in & out), nail beds, genitalia, anal canal and eye (see below).

Signs


Observe

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:
Major:
i) change in size
ii) change in shape
iii) change in colour
Minor:
i) inflammation
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)

Amelanotic Melanoma
Raised papules may be pink, red, purple or of normal skin colour.


Desmoplastic Melanoma
Specific type of amelanotic melanoma arising on face / associated with lentigo maligna.
- eshibit neurotropism; poor prognostic factor.

Satellite lesions
Small nodules growing adjacent to the primary.


Metastatic Spread
If a melanoma is found, question about:
- constitutional symptoms
- CNS symptoms
- pulmonary, GI and soft tissue symptoms.
Pleural effusions, hepatomegaly, jaundice and neuro abnormalities are indicative.
Other skin / subcutaneous tissue deposits are not uncommon.
- palpate route to lymph nodes.
Stage (as below).

Differential Diagnosis
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 previously cauterised.
Melanomas may be subtle in this contect

D I A B M I M


INVESTIGATIONS

Diagnostic Aids

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 specialists
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 1.5-4.4 m
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
- diagnosis
- Breslow thickness
- margins
- 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
- regression
- desmoplasia
- neurotropism
- 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

Appropriate Investigations

Primary Melanoma

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 routinely.
- adds prognostic value in advanced disease if raised.

Locoregional Disease

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 much better
- then do CT chest abdo pelvis, whole-body PET.

4. If risk of lymph node mets, then FNAB to confirm stage III disease.

Metastatic disease
Perform serum LDH, CT, MRI, and/or PET scan as per directed symptoms
Only investigate with PET and further Ix if will indicate surgery or change management.


Prognosis
Used to be that all melanoma received radical surgery.

Clark's Level
Less predictive value, less reproducible and more operator dependent;
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 information.
- 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%.

<0.76mm - 98% 10 year survival.
0.76-1.5mm - 91%.
1.51- 3.0 - 75%.
>3.0mm - 55%.

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)
Female
(0.836)

Prognostic 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:


Staging Investigations
Clinical Stage 0 and I pts need no further tests.
Stage II and III: can do a CXR and serum lactate dehydrogenase +/- LFTs
- 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.
- Satellite lesions 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


N classification
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 nodules
N3 = 4+ nodes or matted nodes or in-transit / satellite lesions.

M classification
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 dehydrogenase.

Stage
Primary
N
M
0
Tis
0
0
IA
T1a
0
0
IB
T1b / T2a
0
0
IIA
T2b / T3a
0
0
IIB
T3b / T4a
0
0
IIC
T4b
0
0
IIIA
T1-T4a
N1a / N2a
0
IIIB
T1-T4b
T1-T4a
T1-4a/b
N1a / N2a
N1b / N2b
N2c
0
0
0
IIIC
T1-4b
T1-4b
Any T
N1b
N2b
N3
0
0
0
IV
Any T
Any N
1

Survival Rates per Stage
Stage
Ulceration
10-yr Survival
IA
Yes or No
90%
IB
Yes or No
80%
IIA
Yes or No
65%
IIB
Yes
No
50%
55%
IIC
Yes or No
35%

Stage
Ulceration
N-stage
5-yr Survival
IIIA
No
No
N1a
N2a
70
60
IIIB
Yes
Yes
No
No
N1a
N2a
N1b
N2b
55
50
55
45
IIIC
Yes
Yes
Yes or No
N1b
N2b
N3
30
25
30

Stage
1-yr Survival
M1a
60%
M1b
55%
M1c
40%

D I A B M I M


MANAGEMENT

Prevention
Suspect Lesions
Proven Lesions
Lymph Node Treatment
Follow-up
Loco-Regional Recurrence
Advanced Disease
Adjuvant Treatments

Prevention
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 screening programs
- moreso if pts >50y
Bottom line:
- currently no evidence of mortality reduction (no trials), so screening cannot be recommended.

High-Risk Individuals
Based on risk factors above, high risk patients should have regular surveillance
- education to self-screen or done by gp
Document / photograph any lesions
6 monthly intervals.

Suspicious lesions

Remove anything suspicious.
Concern is a valid indication.

Small lesion

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 litigation.
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 accuracy.
- multiple such biopsies may reduce risk of error.
- incisional biopsy with as much tissue as possible is a useful tool.


Proven lesions

Evidence

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

Recommended Margins
Excise to deep hypodermis (not beyond).
Measure from scar of narrow excision.
- so take a very narrow excision if possible.
In-situ melanoma - 0.5cm-1cm margin.
<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.

Subungual Melanoma
Hand: Amputate digit to a preceding phalanx such as to allow a 1cm margin
- reimplantation of flexor and extensor tendons
Foot: amputate to metatarsal head.

Mucosal Melanoma
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 delay pregnancy?
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 evaluation.

Lymph Node Management

Rationale
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 (ELND).
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 disease.

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 lesions)
Is both the best prognostic test for melanoma as well as informs therapy.

Note
- 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 treatment)

Multicentre Selective Lymphadenectomy Trial (MSLT)
In patients with tumor-negative SLN biopsies, significantly higher 5-y survival rates cf tumor-positive SLN biopsies

Micromets?
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 survival.

Technical notes
i) with gamma probe and blue dye, the SLN can be identified in >95% cases
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.

Method
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 become hot.
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 radiotracer activity.
12. If node appears grossly metastatic then frozen section and wait for result
- 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 hot?
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 seroma 5%
But lymphedema very rare <1%

Regional / Completion Lymphadenectomy

Perform if:
- 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 or macroscopic
One third of patients with macroscopic nodal disease are cured with regional lymphadenectomy
- hence removal of the entire involved nodal basin is of paramount importance
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 lymphocele
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 healed
- 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 lymphoscintigraphy use.
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 one step.
New recommended margin guidelines have allowed wide undermining in many cases.
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 point)
- 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 disease
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 up

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 anniversary.
- annual exams thereafter for thicker melanoma.
- end exams at 1 year for in-situ lesions.

What investigations are required?

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 lymph nodes)
- 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 lesions.

Loco-Regional Recurrence

20% of melanoma patients are not cured; 80% are.

Regional Node Recurrence

FNA performed
- if +ve, radical lymphadenectomy will control regional disease in most.
- if -ve / insufficient, excision biopsy should be performed +/- radical lymphadenectomy
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 locoregional recurrence.
- post-op radiation has not been evaluated but is advocated in some centres.

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 tissue.

Incidence

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 y.
A poor prognostic sign: <20% long-term survival.

Treatment
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 amputation.
If multiple lesions, consider infection with bacillus Calmette-Guerin or dinotrochlorobenzene.
Interferon-alpha may have some effectiveness in conjunction with these therapies.
External beam rads and CO2 laser have been used with limited success.

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 utilised)
- response rates exceed 80%, complete in 10-15%; however often short-lived.
- prophylactic use on people with high-risk lesions (>1.5mm) showed no overal survival, though in-transit mets reduced from 6.6% to 3.3%.
--> 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 Disease

Consult MDT

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 doubling time
- 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 metastesectomy (Sabiston)
- 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 poor
- 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 III
- and IL-2 trialled but significant toxicity.
Antibodies - monoclonal antibodies to T cell melanoma and cell surface antigens
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 cell-signalling pathways:

Venurafenib
BRAF inhibitor (V600E is key cancer mutation)
Targets cell cycle regulators involved in promoting cancer cell growth
Used in stage 4 melanoma in patients V600E positive (+/- V600K, others)
Response can be dramatic though only 6-8m max

Ipilumumab
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 pathway.


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 confirm.
- 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 possibly suicide

D I A B M I M


Melanoma

What is a melanoma

• malignant neoplasm arising from melanocytes

•        Overall 4th most common cancer

•        3rd most common in women (After breast and colorectal)

•        3rd most common in men (after prostate and colorectal). 

• median thickness at diagnosis 0.75mm

What is the incidence of melanoma

• increasing

• 4-5% of all skin malignancies

• males>females

• highest incidence in Australia

• males    410.4 per 1,000,000 (1 in 25 before age 75)

• females 310.1 per 1,000,000 (1 in 35 before age 75)

• median age late forties

• 80% present between age 25-65

What are the risk factors for melanoma

Risk factor

 

Genetic

 

Strong family history >3 first degree relative

35-75

Weak family history

3

Naevi

 

Multiple benign naevi (>100)

11

Multiple atypical naevi (>5)

11

Previous skin cancer

 

Melanoma

8.5

Non-melanoma

3

Immunosupression

 

Transplant

3

AIDS

1.5

Surrogates for sun sensitivity

 

Type 1 skin (Burns without tanning)

1.7

Freckling

2.5

Blue eyes

1.6

Red hair

2.4

UV exposure

 

History of blistering sun burn

2.5

Actinic skin damage

2

 

 

• age (risk increases exponentially)

What are the genetic risk factors

• germ line mutations in CDKN2A gene encoding for tumour suppressor proteins p16 and p19 (chromosome 9p21) – accounts for 0.5-2% of melanoma. Risk conferred by this mutation is 10-20 fold.

• xeroderma pigmentosum (deficient repair of DNA photoproducts induced by UV radiation, increased risk melanoma, SCC, BCC)

FAMMM syndrome – Familial atypical multiple mole melanoma syndrome (AD)

—    Large dsyplastic nevi in sun-protected areas. Very high life-time risk melanoma.

What is the dysplastic naevus syndrome

• autosomal dominant, high penetrance

• chromosome 1p32, 1p36

• dysplastic naevi

• large >5mm

• variable colour

• indistinct border

• ± centrally raised

• trunk > limbs > face

• usually have > 100 melanocytic naevi, some large and atypical

• groups of patients at increased risk

• numerous dysplastic naevi (relative risk of melanoma 50x)

• dysplastic naevi with family history of melanoma (risk approaches

100% - relative risk 150x)

• increased risk of

• melanoma

• pancreatic cancer

• myeloma

• breast cancer

What is the management of dysplastic naevus syndrome

• full body photographs 6 monthly

• screening from puberty onwards

• excision biopsy of any lesions that change clinically

• prophylactic excision not recommended

What is a Spitz naevus

• spindle cell naevus

• well circumscribed and raised

• most common in young adults

• complete excision recommended

What are congenital melanocytic naevi

• melanocytic naevi present at birth

• histological features

• naevus cells present in lower two-thirds of dermis

• naevus cells between collagen bundles singly or in short files

• naevus cells involving appendages

• small lesions

• <1.5cm

• 1% of births

• no increased malignant potential

• medium lesions

• 1.5 – 20cm

• malignant potential uncertain

• excise during teenage years

• giant congenital naevi

• >20cm

• crude risk 3%

• 70% of melanomas develop before puberty

• naevi on head and neck at risk of neurocutaneous melanosis (MRI

for screening)

• 5-8% risk of melanoma

What is the management of congenital melanocytic naevi

• monitor all congenital lesions >20cm and possibly medium lesions for person’s lifetime

• excision biopsy of suspicious area

• surgical excision where acceptable cosmetic outcome can be achieved (tissue expanders)

What 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 legs (women)

• 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

• Ultraviolet radiation

• UV-B (290-320 nm)

• Responsible for formation of principal DNA lesions

(cyclobutane 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 potentially mutagenic

• Contributes to immunosuppression in mice

What 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 recommended.

• 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 required.

Describe 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 UV

• increased ability to repair UV damage

• melanocyte division

• keratinocytes are damaged but undergo apoptosis and don’t perpetuate mutations

• melanocytes are damaged but tend to survive and perpetuate mutations, encouraged by the post-exposure melanocyte division

What are the layers of the skin (epidermis?)

• Stratum basale

• Stratum spinosum (prickle cell)

• Stratum granulosum (Granular) Intracellular granules which contibute to keratinization

• Stratum Lucidum – present only in thick skin

• Stratum Corneum

 

  

 

 

Where are melanomcytes

• scattered in the basal layers in contact with the basement membrane.

• The ratio of melanocytes to basal epithelial cells is 1:5 to 1:10.

• 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 keratinocytes.

• The epithelial cells contain much more melanin than melanocytes.

• Sunlight promotes melanin synthesis and darkening of previously synthesized melanin.

What is the immunohistochemical marker for melanoma

• S100

What are Clark’s levels

• I – confined to epidermis

• II – papillary dermis

• III – papillary-reticular junction

• IV – reticular dermis

• V – subcutaneous tissue

What are the types of melanoma

• lentigo maligna

• superficial spreading (most common)

• nodular

• acral-lentiginous

• amelanotic

• desmoplastic

What are the examination features of a melanoma

• Asymmetry

• Border (irregular but well defined, dysplastic naevus ill-defined)

• Colour variation

• Diameter (>6mm)

• Elevation

What are the sites of development of melanoma

• skin

• mucous membranes (nose, mouth, oesophagus, gall-bladder, urethra, anus, vulva, vagina)

• genitalia

• ano-rectum

• primary visceral lesions (oesophagus, lung, adrenal)

• dura, meninges

• ocular (most common, 4%)

What is the differential diagnosis of melanoma

• pigmented lesions

• melanoma

• dysplastic naevus

• Spitz naevus (children)

• pigmented BCC

• blue naevus

• haemangioma

• pigmented seborrhoeic keratosis

• rare adnexal tumour

• dermatofibroma

• spindle cell tumour

• amelanotic lesions

• amelanotic melanoma

• dermatofibroma

• desmoplastic melanoma

• BCC

• spindle cell tumours e.g. Merkel

What are the histological features of melanoma

• Melanoma cells are larger, have large irregular nuclei, chromatin clumped at the periphery of cell membrane and prominent nucleoli.

• Melanin either in H&E or with a Fontana stain can easily identify melanotic melanomas.

• Immunohistochemistry can be used to confirm that cells are melanoma, particularly when amelanotic.

Melan A, S-100 protein, and HMB-45 .

• The sensitivities of S-100, HMB-45, and Melan-A are 97%, 75%, and 96% respectively.

What 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.

What are the clinical features of a melanoma

• A – Assymetry

• B – Border irregularity

• C – Colour variagation

• D – Diameter >6mm

• E – elevation, evolution, examination for other lesions

• Suspicion should be aroused by any significant change in an existing naevus or other skin lesion.

What history is important in the assessment of a pigmented lesion

• change in size

• change in colour

• change in surface characteristics

• itch

• bleeding

• family history of melanoma

• past history of melanoma or other skin cancer

What proportion of melanoma are non-pigmented

• 5% are non-pigmented

• This is more common amongst nodular melanoma

What are the clinical types of melanoma

• Superficial Spreading  – 65% Most common in women

• Nodular – 25% pure vertical growth phase ab intio.

• Lentigo Maligna Melanoma – 5% Slowest growing with best prognosis. (melanoma in situ)

• Acral Lentiginous  – 5% commonest in unpigmented parts of pigmented skin

(Lentigo=pigmented lesion; Acral = limb)

 

What do you do when unsure

• When the 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.

What 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 avoided

What 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.

• Shave biopsy

            • Partial biopsy may not be representative of the lesion and need to be interpreted in the light of    clinical findings

            • Partial biopsy is clinically indicated only in selected circumstances – larger facial or acral lesions             or where suspicion of melanoma is low.

What is dermoscopy

• Dermoscopy, or  epiluminescence microscopy (ELM), can aid identification of the early phase of melanoma by lens examination under a liquid interface (oil/alcohol).

• Evaluates colors and microstructures of the epidermis, the dermoepidermal junction, and the papillary dermis not visible to the naked eye.

•        Dermoscopy by skilled practitioners improved diagnostic accuracy, but in the hands of untrained or less experienced examiners is no better than clinical inspection.

 

 

What 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

• Ulceration – most significant next to depth

• Regression: worse prognosis than apparent

• Mitotic activity

• Tumor infiltrating lymphocyte response

• Neural or vascular infiltration

 

How 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 stage.

• Tumor thickness is the most accurate predicator of prognosis. Mortality reaches a plateau at about 8mm. Even up to 13mm thickness mortality is not 100%.

What is Clark level

—         I – intra-epidermal

—         II – Papilary dermis

—         III – papillary-reticular dermis junction

—         IV -  Reticular dermis

—         V – Subcutaneous fat

•  Clark level of invasion is significant in lesions <1mm thick where lesions

•  Clark level II/III are T1a

•  Clark level IV/V are T1b

 

What are the important features of a histopathology report

Essential

•  Breslow thickness

• Clark level

• Mitotic rate/mm2

• Ulceration

• Margins

Other factors which are of prognostic or other value include

• Vascular invasion,

• Local metastasis, microsatellites, in-transit metastasis,

• Tumour-infiltrating lymphocytes, regression, desomplasia, neurotropism, associated benign melaoytic lesions, solar elastosis, predominant cell type,

• Growth pattern (pagetoid, lentiginous and mixed) and growth phase

• Immunohistochemistry.

 

What is the staging of melanoma

T:

T1 - ≤1mm (a- without ulceration and level II/III, b- with ulceration or level

IV/V)

T2 – 1.02 – 2.0mm (a- without ulceration, b- with ulceration)

T3 – 2.01 – 4.0mm (a- without ulceration, b- with ulceration)

T4 - >4.0mm (a- without ulceration, b- with ulceration)

N:

N1 – 1 node (a- micrometastasis, b- macrometastasis)

N2 – 2-3 nodes (a- micrometastasis, b- macrometastasis, c- in-transit mets without

metastatic nodes )

N3 – 4 or more nodes, matted nodes, in-transit/satellite mets with metastatic nodes

M:

M1a – distant skin, subcutaneous or nodal mets, LDH normal

M1b – lung metastases, LDH normal

M1c – all other visceral mets with normal LDH, any mets with LDH elevated

 

 

 

 

 

 

What is in transit metastasis

• Any skin or subcutaneous metastasis that are > 2cm from the primary lesion but not beyond the regional nodal basis

What are satellite lesions

• Skin or subcutaneous lesions < 2cm of the primary tumour that are considered intra-lymphatic extension of the primary mass.

Both in transit and satellite metastasis are a component of nodal staging and assigned as N2c in the absence of nodal metastasis.

The prognosis is similar to that of multiple nodal metastasis.

Patients with combined in transit/satellite and nodal metastasis and nodal metastasis have a worse prognosis than either alone (N3).

What are the appropriate investigations for patients diagnosed with melanoma

• STAGE I/II: 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

• STAGE III: 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 not recommended.

• STAGE 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 of metastases.

 

 

 

 

 

 

What margins are appropriate for melanoma

Tumor Thickness (mm)

Margin (cm)

In situ

0.5

<1

1

1-4

1-2

>4

2

• no evidence that <1cm offers additional benefit for long term survival but may decrease local recurrence

• 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

This is based on evidence from four RCT and a number of retrospective studies

WHO melanoma group

•        612 patients; <2mm thick; 1-cm or 3-cm margin of excision.

•        There was no significant difference in survival between the 1- and 3-cm surgical margin groups.

•        No local recurrences among patients with primary melanomas thinner than 1 mm.

•        4 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 mm thick

•        5- and 2-cm margins

•        No differences in local recurrence rate or survival between the two groups.

United Kingdom Trial: 900 patients with melanomas at least 2 mm thick

•        1- and 3-cm margins

•        1-cm margin associated with a significantly increased risk of locoregional recurrence

•        Overall survival was similar in the two groups.

Intergroup Melanoma Committee

•        Melanoma 1-4mm

•        2- and 4-cm margins of excision

•        No difference in local recurrence

•        46% in the 4-cm group required skin grafts

•        11% of patients in the 2-cm group did (p <0.001).

•        These data support the use of a 2-cm margin for intermediate-thickness lesions.

For thick melanoma

•        Optimal margin for melanomas >4 mm is still unknown.

•        A 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 excision

•These patients should be referred to a specialist melanoma centre

What is the risk of lymph node metastasis in melanoma

• <1mm – rare

• 1.5-4.0mm – 25%

• >4mm – 60%

What is the role of lymph node dissection in melanoma

•        10% of patients present with clinically positive nodes

•        5% of patients present with distant metastasis

•        85% present with clinically negative nodes

What 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).

•        FNA or Core BX under US guidance (if required) yield a diagnosis with clinically enlarged regional nodes.

•        Open biopsy is rarely warranted but if used the incision should be placed so that it can be excised with the incision used for radical lymphadenecomy.

•        For patients with a positive SLN biopsy TLND is recommended.

What is the rationale for elective lymph node dissection

•        Lesions less than 1mm have low risk of nodal involvement (<3%)

•        For 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

•        Four 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

1. WHO Melanoma Trial I (Veronesi U.N Engl J Med. 1977;297:627-630).

- RCT of 553 pts treated by WLE +/- ELND.

- No OS difference

2. Mayo Clinic (Sim FH. Mayo Clin Proc. 1986;61:697-705).

- Similar design, no OS difference.

3. 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:

i) < 60 yrs : 74% ΰ 81%

ii) 1-2mm thick: 80% ΰ 86%

iii) Non-ulcerative: 77% ΰ 84%

4. WHO Melanoma Trial 14 (Cascinelli N. Lancet. 1998;351:793-796).

-        RCT of pts with trunk melanomas > 1.5mm thick to WLE +/- ELND.

-        Trend toward improved survival in the ELND arm (p = 0.09).

5. Meta-analysis   - 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 breslow thickness

What is SLNB

• 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.

•        Positive SLNB should have completion dissection and consideration of systemic adjuvant treatment

What is the evidence of benefit for SLNB

Multicentre Selective Lymphadenectomy Trial

-       Randomised 1327 patients to SLNB or observation.

-       Completion lymph node dissection for positive SLN

- Intermediate thickness melanoma (1.2 – 3.5mm)

At 5yrs, no difference in OS, but improved DFS (78% vs 73%; p < 0.05)

- 5yr survival higher in SLN group with +ve nodes, compared to pts who relapsed on observation (72% vs 52%).

•        Incidence 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 regional LNs

What proportion of SLN positive patients had positive non-sentinel lymph nodes

• Less than 20%

•        MSLT-II examines the benefit of completion LND in SLND positive patients

What is the technique of sentinel node biopsy on melanoma

• Performed prior to wide local excision of melanoma scar

• 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

• preoperative lymphoscintigraphy

• 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.

•        95% success with both lymphoscintigraphy and blue dye

•        Only 80% when either alone used

• After SLN removal, resection bed count should decrease to <10% of hottest node.

• focused pathologic evaluation

• multiple sections

• immunohistochemical (S-100, HMB-45)

• PCR

What 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 Sappey’s line by 10cm where lymphatic drainage is unpredictable.

What are the discordance rates for lymph drainage identified by lymphoscintigraphy

• 37% head and neck

• 25% trunk

• 14% upper limb

• 5% lower limb

What is the survival after therapeutic node dissection in melanoma

• 10YS 50% if only one node involved

• 10YS 30% if 2 or 3 nodes involved

What is the role of interferon in melanoma

• high dose interferon-α2b

• ECOG trials E1684, E1690 and E1694

• improve survival by 10%

What is the role of radiotherapy to the site of the primary

•        Rarely indicated as low recurrence rates with surgery alone

•        Exception:

–       Desmoplastic neurotopic histology

–       Close or positive margins where re-excision impossible

–       Primary lesions with high risk features such as >4mm or with satellite lesions.

What is the role of radiotherapy to nodal basins

•        Adjuvant postoperative radiotherapy may be offered after TLND to decreasing local recurrence after LN dissection if:

1. ECE (60% LR)

2. > 4 nodes

3. Bulky LN > 3cm

4. Cervical LN’s

5. Recurrent nodal disease

6. Positive SLNB and completion dissection not planned

7. Positive margins

In what other circumstances may radiotherapy have a role

• postop adjuvant XRT for mucosal melanomas

• primary XRT for unresectable lentigo maligna

• XRT for extensive cutaneous metastases

• cerebral and bone metastases

What is the role of surgery for metastatic melanoma

• surgery should be considered for isolated melanoma metastases to lung, brain and peritoneal cavity

What is the role of adjuvant systemic therapy

•        There is level I evidence that adjuvant IFNa is of benefit for high risk patients:

•        Primary tumour >4mm

•        node positive

•        DFS 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.

What 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.

• often amelanotic

• 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

What is lentigo maligna

• Hutchinson’s melanotic freckle

• in-situ melanoma

• 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

What 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 primary melanoma.

• In-transit metastasis or satelliteosis due to lymphatic or haematogenous spread

• Regional lymph node metastasis

• Can occur in isolation or association with systemic disease.

• Local recurrence is generally a harbinger of disseminated disease.

What 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

What about in transit metastasis and satelliteosis

• Can be managed with excision  or a variety of other local treatments (cryotherapy, Co2 laser, XRT, intra-lesional immunomodulators or drugs.

What about patients with multiple, rapidly growing or rapidly progressive lesions of the limbs not suitable for local treatments

• 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

• Melphalan (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 often added.

• 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 Hartmann’s at room temperature

• Heparin reversed and pressure to groin punctures

•  Postop – circulation obs, limb elevated, heparin 5000u TDS, serum CK and limb toxicity clinically assessed

What is the management of loco-regionally recurrent melanoma

• wide local re-excision (without skin graft where possible)

• node dissection if not already done

• consideration for adjuvant therapy trials

• consideration of isolated perfusion