Comprehensive overview of Malignant melanoma: staging, diagnosis, risk stratification and treatment

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