MALIGNANT MELANOMA Rebecca Hopkins Karnesh Patel

Malignant Melanoma Introduction Introduction Epidemiology Epidemiology Types Types Invasion and Metastasis Invasion and Metastasis Risk Factors Risk Factors Diagnosis and Staging Diagnosis and Staging Treatment and Prevention Treatment and Prevention

Skin: Epidermis - Melanocytes Melanocytes: Melanocytes: –In stratum basale –Pale halo of cytoplasm –Neural crest –Produce melanin and pass it on to nearby keratinocytes –Melanin covers nuclei of nearby keratinocytes –Skin colour depends on melanocytes activity, rather than the number present

Epidemiology Trent (1999) IncidenceMortality MaleFemaleMaleFemale Number Crude Rate Per 100, Age Standardised Rate Per 100,

Epidemiology Age Specific Incidence Rates Trent 1999, Trent Cancer Registry

Types Superficial spreading MM (SSMM) Superficial spreading MM (SSMM) Lentigo maligna melanoma(LMM) Lentigo maligna melanoma(LMM) Nodular MM (NMM) Nodular MM (NMM) Acral lentiginous MM (ALMM) Acral lentiginous MM (ALMM)

Superficial Spreading Malignant Melanoma 70% of all melanomas 70% of all melanomas Raised irregular margin Raised irregular margin Unevenly pigmented Unevenly pigmented Becomes nodular on invasion, which is common Becomes nodular on invasion, which is common Cells spread between epidermal ridges via dermal papillae unlike benign lesions Cells spread between epidermal ridges via dermal papillae unlike benign lesions Early detection leads to 95% 5 year survival rate Early detection leads to 95% 5 year survival rate

Superficial Spreading Malignant Melanoma

Lentigo Maligna Melanoma Initially lentigo maligna (Hutchinsons freckle) Initially lentigo maligna (Hutchinsons freckle) 10% of all melanomas 10% of all melanomas Chronic sun-exposure to skin Chronic sun-exposure to skin Starts flat and pigmented, becoming nodular on invasion Starts flat and pigmented, becoming nodular on invasion Colour tan to black, areas of blue and red Colour tan to black, areas of blue and red Uneven, sunken margin Uneven, sunken margin Late presentation makes it difficult to excise Late presentation makes it difficult to excise

Lentigo Maligna Melanoma

Nodular Malignant Melanoma 10-15% of all melanomas 10-15% of all melanomas Raised and nodular Raised and nodular Occasional ulceration Occasional ulceration Pigmentation is generally heavy, though occasionally there is no pigmentation - Amelanotic malignant melanoma Pigmentation is generally heavy, though occasionally there is no pigmentation - Amelanotic malignant melanoma NMM infiltrates the epidermis fast NMM infiltrates the epidermis fast Tumour cells either epitheliod or spindle cell Tumour cells either epitheliod or spindle cell Mitotic figures in the dermis component of lesions confirm malignancy Mitotic figures in the dermis component of lesions confirm malignancy

Nodular Malignant Melanoma

Acral Lentiginous Malignant Melanoma Palmar plantar mucosal melanoma Palmar plantar mucosal melanoma Common in Asian and African populations Common in Asian and African populations 3 - 5% of all melanomas 3 - 5% of all melanomas Initially flat with hazy margins and pigmentation Initially flat with hazy margins and pigmentation Eventually becomes raised and nodular Eventually becomes raised and nodular ALMM grows vertically and metastasises early ALMM grows vertically and metastasises early Epidermis appears hyperplasic, with atypical melanocytes present on the basal aspect. Epidermis appears hyperplasic, with atypical melanocytes present on the basal aspect. Mitotic figures commonly seen Mitotic figures commonly seen

Acral Lentiginous Malignant Melanoma

Invasion And Metastasis Late presentation is associated with worse prognosis Late presentation is associated with worse prognosis Late signs of invasion: Late signs of invasion: Bleeding, ulceration and pain Metastasis can occur via lymphatics or haematogenous Metastasis can occur via lymphatics or haematogenous Initially regional lymph nodes Initially regional lymph nodes Distant metastases : Distant metastases : LIVER, LUNG, BONE, BRAIN LIVER, LUNG, BONE, BRAIN

Risk Factors Ultraviolet light (UVA, sun lamps, UVB) Ultraviolet light (UVA, sun lamps, UVB) Skin type I Skin type I Chemicals: Chemicals: mercury, lead, coal, tar, aniline dye derivatives Radiation: Radiation: X rays, g rays, radiotherapy Xeroderma pigmentosum Xeroderma pigmentosum Increased numbers of naevi Increased numbers of naevi Positive family history Positive family history Human papillomavirus (HPV) Human papillomavirus (HPV)

Ultraviolet Light UVB causes: UVB causes: –Melanogenesis –Immediate skin pigmentation by melanin precursor photo-oxidation –Epidermal thickening via keratinocyte proliferation –Promotes vitamin D synthesis UVA used in sun lamps by around 10-20% of the UK population UVA used in sun lamps by around 10-20% of the UK population Evidence of increased risk of MM in subjects with dark hair and/or females Evidence of increased risk of MM in subjects with dark hair and/or females

Diagnosis History History Examination using total dermatoscopic score (ABCD) Examination using total dermatoscopic score (ABCD) Skin biopsy: Skin biopsy: Shave, punch, incisional/excisional Lymph node biopsy: Lymph node biopsy: Fine needle aspiration, surgical excision

Staging Tumour, Node, Metastasis Tumour, Node, Metastasis Clarks staging (anatomic extent) Clarks staging (anatomic extent) Breslows thickness (vertical depth) Breslows thickness (vertical depth) American Joint Committee on Cancer (modified TNM) American Joint Committee on Cancer (modified TNM) Clinical Clinical

Clarks Staging LevelDescription I Lesions only involve epidermis II Invasion of papillary dermis, has not reached papillary-reticular dermal interface III Invasion fills and expands papillary dermis, but reticular dermis is not penetrated IV Reticular dermis penetrated, but subcutaneous tissue is not V Subcutaneous tissue invaded via reticular dermis

Breslows Thickness TNM Staging 0.75 mm or lesspT1, N0, M mm to 1.50 mmpT2, N0, M mm to 4.0 mmpT3, N0, M0 4.0 mm and greater pT4, N0, M0 pT, N1, M0 pT, N2, M0 pT, N, M1

Clinical Staging StageDescription I (Local) aPrimary lesion alone b Primary and satellites in a 5 cm radius of the primary tumour c Local recurrence in a 5 cm radius of a resected primary tumour d Metastases found more than 5 cm from a primary site, but in the primary lymphatic drainage area IIRegional nodal disease IIIDisseminated disease

Treatment Surgical resection of tumour Surgical resection of tumour MOHS technique MOHS technique Lymph node dissection Lymph node dissection Chemotherapy Chemotherapy Radiotherapy Radiotherapy Immunotherapy Immunotherapy

Surgical Excision At this point in time, the only major effective therapy for malignant melanoma At this point in time, the only major effective therapy for malignant melanoma Excision margins are important Excision margins are important Breslow Thickness Excision Margin Recommended 0.75 mm or less 1 cm 0.76 to 4.0 mm 2 cm 4.0 mm and greater 3 to 5 cm

MOHS Technique Surgeon removes tumour using a microscope to map histology Surgeon removes tumour using a microscope to map histology Stop excision when histology is once again normal Stop excision when histology is once again normal This spares as much skin as possible This spares as much skin as possible

Lymph Node Dissection When node known to contain metastases (therapeutic) When node known to contain metastases (therapeutic) When no evidence of palpable masses (immediate) When no evidence of palpable masses (immediate) Lymphoscintigraphy can help to identify drainage of a node Lymphoscintigraphy can help to identify drainage of a node

Chemotherapy Topical or systemic Topical or systemic 5-fluorouracil, doxorubicin, or cisplatin 5-fluorouracil, doxorubicin, or cisplatin Can delay tumour spread, and can sometimes relieve symptoms Can delay tumour spread, and can sometimes relieve symptoms Cannot cure metastatic melanoma Cannot cure metastatic melanoma Side effects include immunodeficiency Side effects include immunodeficiency

Radiotherapy Use high-energy beams to give a less intense superficial dose, thereby sparing the surrounding skin, as melanoma is invariably deep Use high-energy beams to give a less intense superficial dose, thereby sparing the surrounding skin, as melanoma is invariably deep Teletherapy (external source) can provide long-term local control and effective palliation in melanoma Teletherapy (external source) can provide long-term local control and effective palliation in melanoma Used as an adjuvant Used as an adjuvant

Immunotherapy Manipulation of the hosts own immune response towards tumour cells Manipulation of the hosts own immune response towards tumour cells Ideas include: Ideas include: Immunomodulatory cytokines, autologous/allogeneic immunocompetent cells, monoclonal antibodies, tumour vaccines and interferon

Immunotherapy Non-specific stimulants: Non-specific stimulants: BCG, Corynebacterium parvum, levimasole Interferon a can help make melanoma cells more susceptible to immunologic effector mechanisms Interferon a can help make melanoma cells more susceptible to immunologic effector mechanisms Results comparable to drugs like dacarbazine Results comparable to drugs like dacarbazine Interferon a-2b gives a 24% improvement in 5YSR, and is as cost-effective in high risk patients as other interventions Interferon a-2b gives a 24% improvement in 5YSR, and is as cost-effective in high risk patients as other interventions

Immunotherapy Vaccines: Vaccines: –Viral oncosylates to increase antigenicity –Gangliosides to increase antibody production

Cost Per Patient Clinical Stage Approximate Cost Based On Current Exchange Rates I£ II£2, III£27, IV£28,272.97

Prevention Reduce risk factor exposure: Reduce risk factor exposure: Awareness (TV, leaflets, billboards) Awareness (TV, leaflets, billboards) Covering up (sunscreen, sunglasses, clothes) Covering up (sunscreen, sunglasses, clothes) Avoidance (less time in sun) Avoidance (less time in sun) Screening (possibly feasible) Screening (possibly feasible)