¡ arise from the neural crest¡ migrate to the epidermis, uvea, meninges, and ectodermal mucosa¡ contained within the basal layer of the epidermis, at the junction of the dermis and epidermis¡ produce a protective melanin
¡ Skin § Any § Sun-exposed or unexposed (palm, sole, perineum) § De novo (healthy skin) or in a precursor lesion (navus)¡ Non-cutaneous: § eyes, mucosa, gastrointestinal tract, genitourinary tract, and leptomeninges. § Metastatic melanoma with an unknown primary site may be found in lymph nodes only
¡ Radial (horizontal) in epidermis¡ Vertical in dermis: metastasize
¡ Cyclin-dependent kinase inhibitor 2A¡ Also known as multiple tumor suppressor gene 1 (MTS-1)¡ Most important.¡ On chromosome 9p21¡ Both in sporadic and hereditary melanomas¡ Encodes p14 and p16
¡ Depth of invasion,¡ Presence or absence of ulceration and¡ Nodal status at diagnosis
¡ UVR : most important¡ chemicals and viruses?¡ Greatly elevated risk factors for cutaneous melanoma § Changing mole § Dysplastic nevi in familial melanoma § Greater than 50 nevi, 2 mm or greater in diameter¡ Moderately elevated risk factors for cutaneous melanoma § One family member with melanoma § Previous history of melanoma § Sporadic dysplastic nevi § Congenital nevus
¡ Mechanisms: § suppression of skin immune system, § induction of melanocyte cell division, § free radical production, and § damage of melanocyte DNA¡ Not related to the amount of exposure¡ Highest risk with acute severe exposure¡ Both UVRA (WL 290-320 nm) and UVRB (WL 320-400 nm) are carcinogenic
¡ Skin: § Superficial spreading M (SSM): 70% § Nodular M (NM): 15% § Lentigo maligna M (LMM): 10% اﻟﻨﻤﺸﺔ اﻟﺨﺒﯿﺜﺔ § Acral lentiginous M (ALM):¡ Mucosal lentiginous M (MLM): 3% اﻟﻨﻤﺸﺔ اﻟﻤﺨﺎطﯿﺔ اﻟﺨﺒﯿﺜﺔ
¡ palms, soles, and subungual areas¡ often are mistaken for hematomas¡ extremely aggressive, with rapid progression from the radial to vertical growth phase
¡ mucosal of respiratory, gastrointestinal, and genitourinary tracts¡ conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus¡ more aggressive course than cutaneous M
¡ T (thickness)¡ T1: <=1 mm¡ T2: <= 2 mm¡ T3: <= 4 mm (NOT 3)¡ T4: > 4 mm¡ A: No ulceration¡ B: ulceration
¡ N¡ N1: 1 LN+ [a: micrometastasis (clinically occult), b: macrometastasis (clinically apparent)]¡ N2: 2-3 LN+ [a: micrometastasis b: macrometastasis , c: intransit without LN]¡ N3: >3 (=>4) LN+ or matted LN or intransit+LN¡ M¡ M1a: distant skin, SC, LN with normal LDH¡ M1b: lung mets with normal LDH¡ M1c: other sites or elevated LDH
¡ 0: Tis¡ 4: M1¡ 3: LN+ § 3A: T1-4a + N1-2a § 3B:T1-4a + N1-2b/c, T1-4b+ N1-2a § 3C: T1-4b+ N1-2c¡ 1: T1a-T2a § 1A: T1a Tis T1 T2 T3 T4 M1 § 1B: T1b, T2A No 0 I I/II II II IV¡ 2: T2b-T4b N1 III III III III III IV § 2A: T2b-T3A N2 III III III III III IV § 2B: T3B-T4A N3 III III III III III IV § 2C: T4b
¡ Hx:¡ Examination: § Total skin exam § LNs § Liver and lungs
¡ Laboratory Studies § CBC § Chemistry § LDH¡ Imaging § CXR § CT chest abdomen and pelvis: symptomatic or stage III (LN+), IV (M1) § CT brain : symptomatic or stage IV (M1) § PET in stage stage III (LN+), IV (M1)¡ Procedure: § Biopsy: margin and layers § LND and SLB
¡ IHC stains: § S-100 § HBM-450¡ Ulceration (B)¡ Depth of invasion¡ LN¡ In-transit¡ Mutation analysis: § V600E BRAF mutations by PCR § 40-60% in MM § à vemurafenib
¡ Surgery¡ RT¡ Chemotherapy¡ Biologic therapy: § Cytokines: ▪ INF, ▪ IL-2 § Monoclonal antibodies (MABs): ▪ Ipilimumab (a CTLA-4 blocker) ▪ Anti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) MAB § vaccines and gene therapy: of no proven value
¡ The mainstay of treatment for early stage M¡ Wide local excision + SLNB or elective LND¡ Brain metastatectomy: for acute symptoms
¡ T: § Desmoplastic melanoma with extensive neurotrophism¡ N: § Extracapsular extension § N3 (> 3 involved nodes) § Size >= 3 cm § Cervical > Axillary > Inguinal Location § Recurrent disease after prior complete nodal dissection¡ M: § Brain metastases ▪ Definitive or palliative stereotactic radiosurgery and/or whole brain RT ▪ Adjuvant RT following resection . § Other symptomatic or potentially symptomatic soft tissue and/or bone metastases
¡ Adjuvant § INF in high-risk (T4 or N+)¡ Palliative § V600E BRAF mutations by PCR à vemurafenib § Negative mutations: ▪ Ipilmumab ▪ Chemotherapy: ▪ Single DTIC, temozolamide, paclitaxel ▪ Combinations: - Including DTIC, temozolamide with cisplatin and vinblastin - Paclitaxel, cisplatin/carboplatin
¡ After complete resection¡ In high-risk patients: § Deep lesions (t4 >4 mm deep) § LN+: stage IIIABC § Genetic stratification??¡ high-dose interferon-alfa-2b (IFN) § Regular or § Pegylated (FDA approved in 2011)
¡ FDA approved in high-risk resected MM¡ A pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed § significant increase in relapse-free S (P=0.006) § but not overall survival (P=0.42)¡ Dose: § 20 million U/m2 IV for 5 consecutive d/wk for 4 wk; § then, 10 million U/m2 SC 3 times/wk for 48 wk
Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Eggermont AM et al Lancet. 2008 Jul 12;372(9633):117-26.
¡ 1256 patients with resected stage III melanoma were randomly assigned to § observation (n=629) or § pegylated interferon alfa-2b (n=627) ▪ 6 mug/kg per week for 8 weeks (induction) then ▪ 3 mug/kg per week (maintenance) for an intended duration of 5 years.
Observation Peg_INF PRFS (HR) 1 0.82 0.014-y RFS 46% 39%OS Similar Similar NSQOL Better Poor fever, chills, stiff or sore muscles, and headachesAE G3 10 40AEG4 2 5Discontinuation 31%
¡ V600E BRAF mutation is the most common BRAF mutation.¡ This type of mutation is found in about 8 %of all cancers, including approximately 40-60 % of malignant melanomas.¡ There are other BRAF mutations but they are less common.
¡ TKI that inhibit V600E Mutated BRAF kinase¡ 960 mg orally twice daily¡ Only in positive BRAF V600E mutation on real-time polymerase-chain-reaction assay (Cobas 4800 BRAF V600 Mutation Test, Roche Molecular Systems).
¡ Dacarbazine (DTIC) is the first drug approved. It gives RR 22% with no survival impact¡ DTIC is similar to combinations ; § cislatin – DTIC – vinblastine (CDV) or § cislatin – DTIC – carmustine (Darmouth regimen).¡ Temozolamide § is similar to DTIC (RR 12 vs. 13%) § with easier administration (oral vs. IV).¡ paclitaxel -Carboplatin § gives RR 11-17%. § Less toxicity than DTIC.¡ Adding sorafenib is of No value