Subungual

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

• 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

• 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% à 81%

ii) 1-2mm thick: 80% à 86%

iii) Non-ulcerative: 77% à 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