Ahmed Zeeneldin

¡ 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

Asymetry, Border irregular, Color variation

¡ 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

¡ CDKN2A¡ CDK4¡ RB1¡ PTEN/MMAC1¡ ras

¡ Cyclin-dependent kinaseinhibitor 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 cutaneousmelanoma§ 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):

النمشة الخبیثة 10%§ Acral lentiginous M (ALM):

¡ Mucosal lentiginous M (MLM): 3% لنمشة المخاطیة ا الخبیثة

¡ 70%¡ Any surface¡ Usually in a navus

¡ Any surface¡ May be amelanotic

¡ sun-exposed areas (eg, hand, neck)

¡ 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§ 1B: T1b, T2A

¡ 2: T2b-T4b§ 2A: T2b-T3A§ 2B: T3B-T4A§ 2C: T4b

Tis T1 T2 T3 T4 M1

No 0 I I/II II II IV

N1 III III III III III IV

N2 III III III III III IV

N3 III III III III III IV

¡ 0: Tis¡ 4: M1¡ 3: LN+§ 3A: T1-4a + N1-2a (AA)§ 3B: T1-4a + N1-2b/c, T1-4b+ N1-2a (AB, AC, BA)§ 3C: T1-4b+ N1b-N2BC (BB, BC)

¡ 1: T1§ 1A: T1a§ 1B: T1b, T2A

¡ 2: T2-T4§ 2A: T2A, T2b-T3A§ 2B: T3B-T4A§ 2C: T4b

5-Y OS (%)10010%30-60

6545-5525-30

90-959095

40-80807050

¡ 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 P

RFS (HR) 1 0.82 0.01

4-y RFS 46% 39%

OS Similar Similar NS

QOL Better Poorfever, chills, stiff or sore muscles, and headaches

AE G3AEG4

102

405

Discontinuation 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).

¡ More RR¡ V: 48% (2 CRs)¡ D: 5%¡ P <0.001

¡ Better PFS¡ Median PFS§ V: 5.3 m§ D: 1.6 M

¡ HR: 0.26¡ P<0.001¡ CROSS OVER¡ Early termination

¡ Better OS ¡ 6 M OS %§ V: 84§ D: 64

¡ Hodi et al., NEJM 2010

¡ Blocks cytotoxicT-lymphocyte associated protein 4 (CTLA-4)¡ Prevents down-

regulation of T-cells

¡ 700 patients with stage III (LN+) or IV M melanoma¡ Randomized to § Ipili+gp100:§ Ipili:§ gp100 vaccine:

MOS:Ipili+gp100: 10 mIpili: 10 mGp100 : 6 mvaccine

HR: 0.66

Ipilimumab: FDA approved

¡ 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