MALIGNANT MELANOMA

MALIGNANT MELANOMADR.M.GOBINATH., THIRD SURGICAL UNIT

UNDER THE GUIDANCE OFPROF.DR.M.S.VARADARAJAN.,M.S.,DR.IRENE ARUNA EDWIN.,M.S.,DR.BETHSY PRISCILLA.,M.S.,

Melanocytes:Melanocytes aremelanin-producing neural-crest derived cells located in thestratum basale of the epidermis, uvea of eye ,meninges and the inner ear.Melanin is thepigmentprimarily responsible forskin color. Once synthesised, melanin is contained in a special organelle called amelanosomeand moved along arm-like structures calleddendrites, so as to reach thekeratinocytes.Skin colour depends on melanocytes activity, rather than the number present

There are both basal and activated levels of melanogenesis; in general, lighter-skinned people have low basal levels of melanogenesis. Exposure to UV-B radiation causes an increased melanogenesis. The purpose of the melanogenesis is to protect theunderlying layer ,from the UV-B light that can damage it (DNA photodamage).The color of the melanin is black, allowing it to absorb a majority of the UV-B light and block it from passing through this skin layer.

Typically, between 1000 and 2000 melanocytes per square millimeter of skin are found. Melanocytes comprise from 5% to 10% of the cells in the basal layer of epidermis.Vitamin D metabolites,retinoids,melanocyte-stimulating hormone,isobutylmethylxanthine,diacylglycerol analogues, and UV irradiation all trigger melanogenesis and, in turn, pigmentation.Melanin production is seen in conditions whereAdrenocorticotropic Hormone(ACTH) is elevated, such asCushing's disease. When ultraviolet rays penetrate the skin and damage DNA,thymidine dinucleotide (pTpT) fragments from damagedDNA will trigger melanogenesis

Melanoma

Melanoma is a cancer of melanin producing cells It can arise fromSkinMucosa of oropharynx,nasopharynx,proximal esophagus, anorectum ,female genitaliaEyes-Retina,uveaLeptomeninges(arachnoid,piamater)

NON CUTANEOUS MELANOMASMelanoma in eye can arise from uvea & retina.Treatment : enucleation, photocoagulation, partial resectionMetastasis occurs hematogenously to liver.Although CT show solitary lesions,MRI show hundreds of small lesions. No effective treatment.Mucosal melanomas (oral cavity,anorectum,female genitalia) present as moe advanced disease and have poor prognosis due to occult location

Cutaneous melanoma

EpidemiologyAlthough it accounts for 20cm)Immune compromised conditions: HIV, cyclosporin A therapy, Hodgkins disease40 % of MM form in pre-existing naevus(junctional & compound types, dysplastic naevi)while remaining arises from de-novo skin

NaevusDuring migration of neural crest cells,when melanocytes layer in the epidermis they form a simple mole.Melanocytes that aggregrate in dermis or dermoepidermal junction are called naevus cellsJunctional naevus: deeply pigmented macule or papule.it represents dermo-epidermal proliferation of naevus cells which usually progresses to form a compound naevus. it is premalignantCompound naevus:junctional proliferation of naevus cells with nests and columns in dermis.

Spindle cell naevus:Dense black lesions containing spindle cells and atypical melanocytes at dermo-epidermal junction.High malignant potentialSpitz naevus(juvenile melanoma):Reddish brown nodule. Occurs before puberty.DD-melanoma .Excision biopsy is done if there is doubt in diagnosis.Dysplastic naevus:Irregular proliferation of atypical melanocytes at basal layer of epidermis

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SitesHead & neck -25%Trunk-25%Lower limb-25%Upper limb-11%.

Most Common site :Females-legMales-trunk

Clinical types1)Superficial spreading melanoma2)nodular melanoma3)lentigo maligna melanoma4)acral lentiginuous melanoma5)amelanotic melanoma

Clinical types1)Superficial spreading melanoma-MC type(70 %)-arise from pre existing naevus, after several years of slow change followed by rapid growth-occurs in any part of body-more radial growth-better prognosis

Superficial Spreading Melanoma

2.Nodular melanoma(15%):-more aggressive-Common in younger age group, more common in men-in any part of body-common in mucosal,muco cutaneous region-more vertical growth.-Appear as blue/black papules 1-2cm in diameter-sharply demarcated

Nodular Melanoma

3.lentigo maligna melanoma(5-10%):In sun exposed areas(prolonged intense sun exposure)Slow growing brown macule on face(hutchisons melanotic freckle) ,neck or hands of elderly womenLeast malignant

Lentigo Maligna Melanoma

4.acral lentigious melanoma(2-8%)Soles & palms affectedCommom in carribean ,asian ,hispanic racesFlat ,irregular macule in later life25% are amelanotic and may mimic a fungal infectionPoor prognosis Least common.Subungual melanomas are usually SSM rather than ALM. A classical feature is hutchinsons sign

acral lentigious melanoma

5.Amelanotic melanoma:Worst typeIt presents as pinkish fleshy growth of rapidly progressive tumorThey often arising in GIT and present with obstruction, intususception or as a metastasis from unknown primary

Desmoplastic melanomaMostly found in head and neckHas propensity for perineural infiltrationHigh recurrence rate

Tumor Spread Through lymphatics to regional lymph nodesThrough blood to lungs ,liver,brain,skin,bonesIn-transit or satellite nodules:due to retrograde spread to dermal lymphatics. Seen in skin as a nodule between primary lesion and regional lymph nodes

CLASSIFICATIONSBRESLOWS CLASSIFICATION:Based on thickness of invasion measured by optical micrometerI:4.00mm

PHYSICAL EXAMINATIONTotal body examination

A total-body skin examination is crucial when evaluating a patient with an atypical nevus or a melanoma. The skin examination should be performed on initial evaluation of the patient and during all subsequent visits

Crucial to a good skin examination is a well-lit examining room and a completely disrobed patient.

Serial photography and new techniques, such as epiluminescence microscopy and computerized image analysis, are useful adjuncts.

Epiluminescence microscopy uses a magnifying lens to examine a lesion that has had oil applied.

Computerized image analysis stores images of the lesions and makes them available for comparison over time.

Lymph node examination

If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma may disseminate through the lymphatics, leading to the involvement of regional lymph nodes, and hematogenously, leading to the involvement of any node basin in the body.

Skin examination

During a skin examination, assess the total number of nevi present on the patient's skin. Attempt to differentiate between typical and atypical lesions.

Warning Signs: THE ABCDEs OF MELANOMA

ABCDEA-Asymmetric outlineB-changing irregular BordersC-color changesD-diameter >6mmE-evolution or change over time;elevation

Moles, brown spots and growths on the skin are usually harmlessbut not always.

Anyone who has more than 100 moles is at greater risk for melanoma.

The first signs can appear in one or more atypical moles.

Look for the ABCDE signs of melanoma

B - BORDERThe borders of an early melanoma tend to be uneven. The edges may be scalloped or notched.

C- COLORHaving a variety of colours is another warning signal. A number of different shades of brown, tan or black could appear. A melanoma may also become red, blue or some other colourA ASSYMETRIC OUTLINE

If you draw a line through this mole, the two halves will not match.

D - DIAMETERMelanomas usually are larger in diameter (1/4 inch or 6 mm), but they may sometimes be smaller when first detected.

E - EVOLVINGAny change in size, shape, colour, elevation, or another trait, or any new symptom such as bleeding, itching or crusting points to danger.

DDSuperficial spreading melanomasBenign melanocytic naevi.

Nodular melanomas Vascular tumor (haemangioma)Histiocytoma

Lentingo maligna melanoma Seborrhic keratoses

InvestigationsExcision biopsy of primary lesionFNAC of lymph nodeSentinel lymph node Biopsy For metastasis: USG abdomen, chest x ray, CT brainTumor markers: MELAN-A, S100, HMB45, LDH

AJCC Staging

Treatment GuidelinesEarly stages: wide local excisionMore advanced: wide local excision plus sentinel node biopsy, HILP,chemotherapy, immunotherapyMetastatic:chemotherapy, immunotherapy, targeted therapy

1.)For primary:wide excision with following clearance

If primary area is wide ,then amputation with one joint above is doneIn fingers and toes disarticulation is requiredEnucleation in case of melanoma of eye

MOHS MICROGRAPHIC SURGERY

Mohs Micrographic Surgery is the most effective technique for removing basal cell and squamous cell carcinomas (the two most common skin cancers), is being increasingly used as an alternative to standard excision for certain melanomas.

In this technique, one thin layer of tissue is removed at a time, and as each layer is removed, its margins are studied under the microscope for the presence of cancer cells. If the margins are cancer-free, the surgery is ended.

If not, more tissue is removed, and this procedure is repeated until the margins of the final tissue examined are clear of cancer. Mohs surgery can eliminate the guesswork in the removal of skin cancers and pinpoint the cancers location when it is invisible to the naked eye.

Mohs surgery differs from other techniques since the microscopic examination of all excised tissues during the surgery eliminates the need to estimate how far out or deep the roots of the skin cancer go. This allows the Mohs surgeon to remove all of the cancer cells while sparing as much normal tissue as possible.

In recent years, however, efforts to improve and refine the Mohs surgeons ability to identify melanoma cells have resulted in the development of special stains that highlight these cells. These special stains are known as immunocytochemistry or immunohistochemistry (IHC) stains and use substances that preferentially stick to pigment cells (melanocytes), where melanoma occurs, making them much easier to see with the microscope.

2)For lymph node secondariesClinically palpable node->FNAC->regional block dissectionSLN biopsy done-if there are metastasis in node therapeutic nodal dissection is done.For fixed inoperable nodes chemotherapy

Sentinel lymph node dissectionINDICATIONS:Indicated for tumors between 1 to 4mm thicknessSLND may be considered for melanoma 0.76-1.0 mm in thickness if adverse features (eg, positive deep margins, lymphovascular invasion, age < 40 years, significant vertical growth phase, increased mitotic rate, Clark level IV) are present

The main elements of SLND are as follows:Intradermal injection of a radiotracer around the melanoma lesionTransport to the operative suite and induction of anesthesiaIntradermal injection of about 1 mL of blue dye (isosulfan blue or methylene blue [preferred]) at the site of the lesionMassage of the lesion for 4-5 minutes to enhance lymphatic drainageUse of a handheld gamma probe to identify hot spots (ie, SLNs)Placement of a small incision overlying the hot spot; incisions should be planned to allow for further dissection if this proves necessary

Visual search for blue nodes (guided by blue lymphatics) and use of a handheld gamma probe to identify hot nodes in the fieldRemoval of any nodes with significant radiotracer activity, followed by ex-vivo measurement of their radioactivity countsSending of SLNs (defined as any nodes that are grossly suspicious, harbor blue dye, or have a radioactivity count greater than or equal to 10% of that of the hottest node removed) to pathology for appropriate stainingOnce SLND is complete, wide local excision of the primary melanoma is performed

Treatment of metastatic diseaseThere has not been any effective treatment for advanced metastatic disease Metastatic melanoma has one of the worst survival rate among all cancers with median survival rate of 6-9months.

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3)For loco regional recurrent melanomaHyperthermic Isolated limb perfusion(HILP) is used as a treatment. Isolated limb perfusion has been used to treat extensive or recurrent in-transit metastatic melanoma confined to upper or lower extremity.

Hyperthermic Isolated limb perfusion(HILP)Isolated limb perfusion was first introduced into the clinic by American surgeons from New Orleans in the mid-1950s. The main purpose of the isolated limb perfusion technique is to deliver a very high dose of chemotherapy, at elevated temperature, to tumour sites without causing overwhelming systemic damage. The flow of bloodto and from thelimbis temporarily stopped with atourniquet, and anticancer drugs (Melphalan) are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where themelanomaoccurred.

The temperature is also increased to 42C causing an increased uptake of the drug by the tumor. The combination of high drug dose and high temperature is toxic systemically, thus the isolation of the limb. Blood flow through the limb is typically achieved using an extracorporeal circuit consisting of cannulae, tubing, peristaltic roller pump, heat exchanger, and pressure monitoring/safety devices.

4.)ChemotherapyFor secondaries in lungs, liver,bonesAfter surgery , as a adjuvant therapy.

Drugs used -DTIC (dacarbazine)-melphalan

MelphalanUsual Intravenous Dose: 16 mg/m2The drug is administered as a single infusion over 15 to 20 minutes. Melphalan is administered at two week intervals for four doses, then, after adequate recovery from toxicity, at four week intervals.

Usual Oral Dose: 6 mg once a day. After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks during which time the blood count should be followed carefully. When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted. Response may be very gradual over many months; it is important that repeated courses or continuous therapy be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned too soon

DACARBAZINE:250 mg/m2 IV once a day for 5 days, repeated every 3 weeks.

5)Immunotherapy/biological therapyAlpha interferonInterleukinsSpecific tumor antibodies BCG vaccineINF alphaGM-CSF

6)RadiotheraphyMelanoma is radioresistant tumor.Only for secondaries in brain and bones

7)Targeted therapyActivating definition of molecular subtypes of melanoma and provided potential drug targets.

BRAF are the most frequent mutation in cutaneous melanoma. Approximately 40% to 60%

OncogenicNRASmutation in 15% to 20% of melanomas

c-KITmutation, or increased copy number, is associated with mucosal and acral melanomas (which comprise 6% to 7% of melanomas in Caucasians but are the most common subtype in the Asian population).

CDK4mutations have been described in approximately 4% of melanomas and are also more common in acral and mucosal melanomas.

Targeted therapies that block oncogenic pathways.

BRAF inhibitors (vemurafenib or debrafenib) MEK inhibitors (trametinib) or KIT inhibitors (imatinib)

Drugs that disrupt immunologic checkpoints CTLA-4 (cytotoxic T-lymphocyte antigen 4) : ipilimumab and tremelimumab

PD-1 (programmed death-1) receptor: anivolumab, lambrolizumab also PD-L1 (the ligand for PD-1). Activation of PD-1 receptors by the PD-1 ligand on tumor cells can result in T cell anergy & death.

TAKE HOME POINTSMelanoma arises from any neural crest derived cells.Risk factors-UV exposure,naevus.Warning signs :ABCDEThickness of invasion is most important prognostic factorWide local excision with recommended clearance is mainstay of treatmentSLN biopsy (1-4mm tumors)-if there are metastasis in node ,therapeutic nodal dissection is doneAdvanced MM(worst prognosis)-HILP,chemotherapy(melphalan),immunotherapy,

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