Melanoma arises from neural crest cells that migrate and produce the pigment melanin. It can present in skin or mucosal surfaces and commonly spreads from radial to vertical growth phases as it invades deeper tissues. Treatment depends on tumor stage and characteristics as well as mutation status, and may involve surgery, radiation, immunotherapy, targeted therapy, or chemotherapy.

1. Ahmed Zeeneldin

3. ¡ 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

4. Asymetry, Border irregular, Color variation

6. ¡ 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

7. ¡ Radial (horizontal) in epidermis
¡ Vertical in dermis: metastasize

8. ¡ CDKN2A
¡ CDK4
¡ RB1
¡ PTEN/MMAC1
¡ ras

9. ¡ 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

10. ¡ Depth of invasion,
¡ Presence or absence of ulceration and
¡ Nodal status at diagnosis

11. ¡ 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

13. ¡ 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

14. ¡ 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

15. ¡ 70%
¡ Any surface
¡ Usually in a navus

16. ¡ Any surface
¡ May be amelanotic

17. ¡ sun-exposed areas (eg, hand,
neck)

18. ¡ palms, soles, and subungual areas
¡ often are mistaken for hematomas
¡ extremely aggressive, with rapid progression
from the radial to vertical growth phase

19. ¡ mucosal of respiratory, gastrointestinal, and
genitourinary tracts
¡ conjunctiva, oral cavity, esophagus, vagina,
female urethra, penis, and anus
¡ more aggressive course than cutaneous M

20. ¡ T (thickness)
¡ T1: <=1 mm
¡ T2: <= 2 mm
¡ T3: <= 4 mm (NOT 3)
¡ T4: > 4 mm
¡ A: No ulceration
¡ B: ulceration

21. ¡ 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

22. ¡ 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

23. 5-Y OS (%)
¡ 0: Tis 100
¡ 4: M1 10%
¡ 3: LN+ 30-60
§ 3A: T1-4a + N1-2a (AA) 65
§ 3B: T1-4a + N1-2b/c, T1-4b+ N1-2a (AB, AC, BA) 45-55
§ 3C: T1-4b+ N1b-N2BC (BB, BC) 25-30
¡ 1: T1 90-95
§ 1A: T1a 90
§ 1B: T1b, T2A 95
¡ 2: T2-T4 40-80
§ 2A: T2A, T2b-T3A 80
§ 2B: T3B-T4A 70
§ 2C: T4b 50

24. ¡ Hx:
¡ Examination:
§ Total skin exam
§ LNs
§ Liver and lungs

25. ¡ 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

26. ¡ 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

27. ¡ 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

28. ¡ The mainstay of treatment for early stage M
¡ Wide local excision + SLNB or elective LND
¡ Brain metastatectomy: for acute symptoms

29. ¡ 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

30. ¡ 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

31. ¡ 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)

32. ¡ 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

33. 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.

34. ¡ 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.

35. Observation Peg_INF P
RFS (HR) 1 0.82 0.01
4-y RFS 46% 39%
OS Similar Similar NS
QOL Better Poor
fever, chills, stiff or
sore muscles, and
headaches
AE G3 10 40
AEG4 2 5
Discontinuation 31%

37. ¡ 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.

38. ¡ 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).

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

40. ¡ Better PFS
¡ Median PFS
§ V: 5.3 m
§ D: 1.6 M
¡ HR: 0.26
¡ P<0.001
¡ CROSS OVER
¡ Early termination

41. ¡ Better OS
¡ 6 M OS %
§ V: 84
§ D: 64

43. ¡ Hodi et al., NEJM 2010
¡ Blocks cytotoxic
T-lymphocyte
associated
protein 4 (CTLA-
4)
¡ Prevents down-
regulation of T-
cells

44. ¡ 700 patients with stage III (LN+) or IV M
melanoma
¡ Randomized to
§ Ipili+gp100:
§ Ipili:
§ gp100 vaccine:

45. MOS:
Ipili+gp100: 10 m
Ipili: 10 m
Gp100 : 6m
vaccine
HR: 0.66
Ipilimumab: FDA
approved

46. ¡ 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