This document discusses various types and stages of melanoma and their prognostic factors and treatment approaches. It covers superficial spreading melanoma, nodular melanoma, acral lentigious melanoma, lentigo malignant melanoma, and desmoplastic melanoma. Prognostic factors discussed include tumor thickness, ulceration, mitotic rate, and lymph node involvement. Treatment approaches covered include surgery with safety margins, sentinel lymph node biopsy, adjuvant therapy, isolated limb perfusion/infusion, radiation, chemotherapy, and immunotherapy options. Staging systems like Clark and Breslow are also summarized.

1. Dr. Abhijit Das
3rd year pg
Dept. Of radiotherapy
Ahrcc

2. Superficial
spreading
melanoma
• Most
common
• Assoc. with
sun exposure
Nodular
melanoma
• Worst
prognosis
• 20% of all
cutaneous
melanoma
Acral lentigious
melanoma
• <5% incidence
• Independent of
sun exposure
• d/d: subungual
hematoma/
chronic fungal
infections.
Lentigo
malignant
melanoma
• Chonically
sun damaged
area
• olderpeople
Desmoplastic melanoma:
• Nonpigmented variety
• Negative for melan a/MRT-1 but positive for s100
• Mostly occur in head and neck
• Local recurrence rate is high
• Nodal status is of low incidence

3. • Tumour thickness: higher thickness, stage is upgraded
• Ulceration: ulceration also upstage the disease.
• Gender: female has benefit. (Doubtful).
• Age:< 35 years has higher lncidence of metastasis. But
often nullified by tumor thickness alone.
• Mitotic rate: higher mitotic rate confers poor prognosis.
But still now cut off 1 / sq. Mm is considered.
• Angiolymphatic invasion:, satellitism also poor prognostic
factor.
• Unresolved factor:
1. +Ve deep margin for biopsy
2. Local recurrence
PROGNOSTIC
FACTOR:

4. Uv light and exposure
290-320 mm(UVB)
#Uva (320-360mm)
though sun damages
occur, may have a role
in melanoma
Physical traits.
An single incidence
increases 2nd melanoma
blond or red hair, green
or blue eyes, presence of
multiple (>100)
melanocytic nevi , and
five or more atypical
nevi
DNA damage and cellular senescence
FAILURE TO REPAIR
common risk factors
include dysplastic nevus
syndrome, xeroderma
pigmentosum , and a
family history of
melanoma even without
the known
genetic traits

6. Diagnosis
suspicion Gold standard Newer techniques
for treatment
Asymmetry, Border
irregularities, Colour
heterogeneity, Dynamics,
(dynamics or evolution in
colours, elevation or size>6
mm) (‘ABCD rule’)
• Biopsy(excision)- preffered
• punch
BRAF and NRAS
mutations
The ugly duckling‘concept’
helps to identify melanomas,
because naevi in the same
individual tend to resemble
one another and melanomas
often do notfit the individual’s
naevus
pattern.
• maximum thickness in
millimetres (Breslow),
• information on mitotic rate in
case of a tumour thickness
below 1 mm,
• presence of ulceration,
• presence and extent of
regression and clearance of
the surgical margins
If the tumour is
BRAF-wild type,
testing for NRAS
mutations c-kit
mutation should be
considered
Video dermoscopy
Scope of newer imaging modality is discussed subsequently

8. The Clark method categorizes lesions into
five groups by the level of dermal or subcutis invasion:
level I: confined to the epidermis;
level II: invasion to the papillary dermis;
level III: invasion to the papillary-reticular dermal interface;
level IV: invasion to the reticular dermis
level V: invasion to the subcutaneous tissue.
STAGING
The Breslow system :
lesions by the vertical thickness between
the granular layer of the epidermis and the
deepest part of invasion, measured with
an ocular micrometer.

10. Malignant melanoma
chemotherapy
radiation
surgery

11. Wide excision of primary tumours with safety margins
Recommendation by NCCN guideline
Modifications:
reduced safety margin are acceptable for preservation of
function in acral and facial melanomas and should be carried
out with micrographic surgery.
0.5 cm- 1cm in situ melanomas
1 cm <=1 mm
1-2 cm 1.01mm-2mm
2 cm 2.01-4 mm
2 cm >4 mm

12. Treatment proper WLE with sufficient
margin
Margin??
Trials on margin
WHO
melanoma
programme
trial no 10
612
<=2 mm thickness
1 cm versums 3 to 5 cm
• More local recurrence in 1 cm margin but
clinically insignificant
• But no local recurrence in 1 cm margin in
< 1 mm thick melanoma makes it a
standard.
• though insignificant , but higher
recurrence in >1 mm melanoma becomes
another controversy
French
cooperative
group.
337 PATIENTS
<2 mm thickness
2-5 cm margin
Supports 2 cm margin in 2 mm
thickness, and not requirement of 5 cm
margin
The Swedish
Melanoma
Study Group
989 patients
0.8 t o 2 mm
2- or 5-cm margins

13. INTERGROUP MELANOMA TRIAL
Group
A(468
patients)
Group
B(272
patients)
Randomly assigned to 2 cm
vs. 4 cm margin
Local
recurrence at
first relapse
0.4 vs. 0.9 %
Local
recurrence at
any time
2.1vs.2.6 %
Non random assignment
of 2 cm margin
First recurrence: 3.7%
Overall recurrence: 6.2 %
10 yr disease specific survival rates for
the two groups were 70% and 77% for
2- an d 4-cm margins, respectively
(p = 0.074)
2 cm margin adequate for 1-4 mm thick melanoma
Ulceration and head and neck location are worse prognostic factor(multivariate
analysis)

14. • In past standard practice is elective LN dissection in thicker
melanoma (1 to 4 mm thickness)
 Latest technology : Intraoperative LN mapping /SLNB
(conceptualized by MORTON et al.)
• Isosulphan blue and 99 TC injection increases the sensitivity
(99% vs. 87%)
• Standard evaluation is SLNB its histopathology and IHC(s-100,
melan A, MRT 1, HMB 45)
SLNB

15. T1S (Clinically Melanoma In Situ):
• WLE with a 5 mm margin
• sometimes 1 cm margin is necessary if
cosmetically acceptable.
• If margin close /positive then WLE with wider
margin is accepted.
• No adjuvant therapy or adjuvant investigation is
warranted.

16. Stage I-II
T1a-T2aN0
T2b-T4bN0
Dermatologist/physician
oncologist
Occult
metastasis
1.Physical
exam.(primary site,
satellite nodule
repeat biopsy,
nodal drainage
basins)
With attention to
symptoms like
headache , bone
pain, weight loss, GI
symptoms
investigations?
Controversial.
NCCN GUIDELINE
Clin.stage IA (<0.75 mm thick, no ulceration ,mitoses <1 sq.mm)
Clin. Stage IB(<0.75mmthick, +ulceration, mitoses>1 sq.mm)
Stage II(0.76 mm-1 cm thick + ulceration,mitoses>1 per sq. mm):
Routine imaging not recommended, and MRI ,PET CT ,CT
warranted only for specific signs and symptoms.

17. Clinically T1A
(<1 mm thickness , mitoses =1
per sq. mm, without
ulceration)
• WLE (lesion + skin +
subcutaneous tissue upto
deep muscle fascia) with 1
cm margin,
• primary repair and flap
repair for cosmetic reason.
• Margin should be
measured from margin
from pigmented lesion/
biopsy scar whichever is
more.

18. Clinically
T2A &T2B
melanoma
No signs of
metastatic
disease then
no further
staging
investigation is
recommended
WLE with 1 -2 cm
margin and SLNB
1.To minimize local recurrence 2 cm margin is often practiced.
2.In face and head and neck , where cosmetic reason is present
1-1.5 cm margin may be taken
3. SLNB is mandatory in all cases of tumor depth 1-2 mm thick
4.On the basis of post op H.P, no adjuvant /surgical treatment is
necessary in T2aN0M0 and T2bN0M0 cases.(I,e SLNB is negative)

19. No signs of
metastatic
disease but on
account of high
metastatic
potential
further staging
investigation is
recommend
but yield is
low
Clin. T 3a(2-4 mm
thickness without
ulceration)
&
Clin. T3b(2-4 mm
thickness with
ulceration)
WLE with 1 -2 cm
margin and SLNB
1. SLNB is negative , no further therapy is
necessary(stage IIB)
2. For resected stage IIB-III melanoma adjuvant
therapy with HDI & peg-IFN may be advised

20. T4a (stage IIB), & T4b( with ulceration stage IIC)
(With a metastatic potential and morbidity of 50% in 5
years)
Guided by signs and symptoms and routine serum LDH
Further aggressive staging by CT chest abdomen, pelvis and
MRI of head
WLE with 2 cm margin
(lack of prospective data
But extrapolated data from melanoma with 1-4 mm
thickness since 2 cm margin has lower reccurence)

21. STAGE III (REGIONAL METASTASIS )
SATELLITE NODULES:
ARISING WITHIN 2-5 CM OF
THE SCAR? LESION ARISING
SIMULATNEOUSLY /
SUBSEQUENTLY
LOCAL RECURRENCE:
RECURRENCE AT THE SCAR
SITE/ AT THE EDGE OF
OPAERATIVE SCAR AND FLAP
IN –TRANSIT METS:
ARISING BEYOND 5 CM OF
LESION , BUT NEARER THAN
REGIONAL NODES.
REGIONAL NODES:
NEAREST NODAL BASIN

22. Local recurrence Satellite and in tansit mets
• Following Inadequate resection
• If apparently adequate
resected then it is of very poor
prognosis(5 yr os is 9-11%)
• Poor prognostic factor
• Poor prognostic factor
• Patient usually present with solitary or locally
clustered in transit mets
• More often found with systemic dissemination of
disease.
• Hallmark of ability of metastasize
• Resection and re-resection is
the rule
• Whole scar even upto
underlying fascia removal is
advised
• SNLB is must even if prior SLNB
done (may be positive upto 50
% of cases)
• Recurrent inoperable lesion:
PALLIATIVE RADIOTHERAPY
• Resection with a clear margin (usually with 5-10
mm margin.)
• In case of multiple in transit mets, it is difficult to
perform such operation.
• Due to its frequent reappearence and shorter
time interval between two subsequent in transit
mets, systemic therapy is given
• Radiotherapy after resection
• Supeficial lesion: imquimod, intralesional BCG, il-
2, IFN-ALPHA
• Systemic therapy: anti ctla-4,anti pd-1,anti pdl-1
BRAF &other targated therapy

23. Isolated limb perfusion & infusion
• For local recurrene:
• Melphalan
• TNF- ALPHA
• Unresectable to
resectable lesion.
• May have response
rate 60-90%.
• Others may have
short duration
response
• Very low risk of
limb loss

24. Regional node metastasis
Clinically negative , SLNB + Clinically palpable
Non ulcerated melanoma+1-3
positive SLNB
A palpable node always
represent stage IIIb
>4 involved nodes with
satellite /in transit mets
Poor
prognostica
tion

25. Stage IIIA
Standard recommendation is if there is +ve SLNB, CLND is
recommended(society of surgical oncology& ASCO 2012 joint
guideline)
but
• SLNB is designed to avoid morbidity of CLND.
• It is observed 15% of patients has metastases in CLND specimen, when
one SLNODE is +ve.
• There may be a chance of +ve non sentienl node (one series shows 54%
positive node in non SLN by RT_PCR )
• a recent article on 134 patients shows there is no significant outcome
difference between single +ve SLN and CLND , in regional reccurence.
• Currently one multicenter selective lymphadenectomy trial 2 is ongoing
to search for the answer.
Clinically negative , SLNB +

26. Clinically palpable
Usually CLND is recommended
Overall 25 year survival is 35%
Significant regional control upto 90%
Even if it recur, limited dissection can be done later & grossly
mutilating surgery can be avoided

27. Role of RT in regional nodes:
Though regional nodes may be addressed by therapeutic axillary
inguinal, cervical node dissection, it is observed that:
• extra capsular extension ,
• large lymph nodes (≥3 cm in diameter),
• four or more involved lymph nodes,
• recurrent disease----- there is high chance nodal basin
recurrence
 No prospective data / level 1 evidence regarding definitive
indication and dose fractionation schedule.
 Locoregional control rate is of same range in both high dose
fractionation and conventional schedule
 Supported by TROG96.06(48 Gy delivered in 20 # with 2.4 Gy
/# over 4 weeks),one study by M.D.Anderson, and burmeister
et al. trial always found a significance of improvement in
locoregional control but no overall survival advantage.
 In view of further systemic relapse radiation to local basin is
carefully selected.

28. Stage IV disease
Timing Pattern Prognosis Investigation recommended
 Usually
higher stage
disease are
more prone
to reappear
with distant
mets.
sooner than
lower stage
 Within 2-3
years it
appears
• Regional
nodes(60-
80%)
• Lung and liver
(10% each)
• Skin
• Bone
• GI(small
bowel)
• Adrenal
glands
• Median
survival-12
months
• M1a-15
months
• M1c-6-8
months
• only lung
metastasis has
intermediate
prognosis
• High LDH
highly poor
prognostic
• CT scan CHEST,
ABDOMEN,PELVIS
• MRI brain
• PET CT: Due to warburg effect
melanoma is highly pet avid
(aerobic glycolysis even in
presence of sufficient glucose.).
It can detect upto 5 mm lesion
(exception is uveal melanoma)
• Useful in reresection, detecting
border line nodes or soft tissue
mets.
• Bone scan
• USG
• Regarding histology, always a tissue diagnosis is recommended(either a excicion
biopsy /trucut biopsy)
• IHC(HMB45,melanA, MRT1 S-100)
• BRAf mutation(at position V600K/V600E)-from DNA obtained from melanoma cells-
either by PCR/ by less sensitive sanger sequencing

29. Benefit of surgery is clear
Benefit of surgery is likely

30. Risk and benefit of surgery is to be balanced
Adjuvant therapy in resected stage IV melanoma:
• No standard adjuvant therapy.
• Observation is the current standard
• Experimental drugs:
1. GM-CSF(no benefit), CTL A4 blockade, PD-1 blockade
2. ongoing trials: ECOG 1609-IPILIMUMAB.
3. VEMURAFENIB, DABARAFENIB, TRAMETINIB

31. Treatment of unresectable disease stage IV
Also adjuvant thrapy for stage III
Dacarbazinea (DTIC)
High-dose bolus IL-2
Carboplatin/paclitaxel
Temozolomide (US)
Fotemustine (Europe)

32. ADJUVANT THERAPY
 For patients with Stages III and IV disease, surgery is usually followed with an
additional adjuvant therapy.
CHEMOTHERAPY
 Used as Mono/poly chemotherapy.
 Dacarbazine (DTIC).
 Temozolomide, an oral drug closely resembling DTIC, is FDA-approved for
brain cancers but also used off-label for melanomas that have spread to the
brain or nervous system.
 BOLD & DARTMOUTH regimen
 Another class of drugs, based on a different principle, has come into use more
recently. They are anti- angiogenic, which means that they prevent new blood
vessels from forming. It cut off the blood supply that would nourish the cancer
cells and enable them to grow. Studies are under way with the anti- angiogenic
drug thalidomide, combined with the chemotherapeutic agent, temozolomide.
 Angiostatin and endostatin are two other drugs in this class that have shown
some degree of activity against melanoma in preliminary studies.

33. Use of IFN- alpha
Trials Patient OBSERVATIONS
ECOG
1684
287
>4 MM THICK
MELANOMA
WITH NODAL
BURDEN
a significant
prolongation of relapse-
free survival
(RFS) (5-year actuarial,
37% vs. 26%; p =.002)
and OS (5-year,
46% vs. 37%; p =.02)
The benefit of therapy with
IFN was greatest
among recipients with
palpable regional nodal
metastases or
nodal recurrences
ECOG
1690
high-dose IFN for
1 year or low-
dose IFN for 2
years versus
observation
5-year RFS of 44% and
40% for the high-dose
and low-dose IFN arms,
respectively, compared
with 35% in the
observation arm
For OS, there was no
difference demonstrated for
the three treatment arms
(52%, 53%, and 55% for high-
dose IFN, low-dose IFN, and
observation
ECOG
1694
high-dose IFN
with a
ganglioside GM2
Melanoma
vaccine.
beneficial effects of IFN were seen only in the
patients with stage T4N0 disease and not those with
nodal
disease.
Interferon alfa only to be offered to >1 macroscopically
node positive patients and/or those with tumour > 4mm
deep with adequate performance status and no medical
contraindications. (AJCC T4 or T1-3, N1b or higher, M0)

35. MHC
TCR
T cell
CTLA-4
APC
MHC
TCR
Ipilimumab
T cell
CTLA-4
APC
T-cell activation
MHC
TCR
T cell
APC
CD28
CTLA-4
ctla-47
B7B7
CD28 CD28
1) Co-stimulation via CD28 ligation
transduces T-cell activating signals
Ipilimumab
activated

36. Proportion alive
years
Ipilimumab Plus DTIC Vs. DTIC: OS

38. Trametinib

39. inhibition of BRAF with vemurafenib improves survival in patients with the most
common BRAFV600E mutation and in patients with the less common BRAFV600K mutation
Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K
mutation-positive melanoma (BRIM-3): extended follow-up of a
phase 3, randomised, open-label study
Prof Grant A McArthur, MB BS et al.

40. T is the first in class
MEKi associated with a
significant
improvement of PFS
and OS compared to C
in pts with BRAFV600E/K
mutant MM.
T=trametinib
C=DTIC/paclitaxel

41. Radiation therapy for melanoma
Radiosensitive or radioresistant??
RTOG 83-05
123 PATIENTS
8 GY/# WEEKLY
SUCH 4 #
VS. 2.5GYSUCH 25
#
1. Closed early as interim
evaluation found to be
equally effective
2. Melanoma is a
radiosensitive tumor
No concensus in optimal dose fractionation, but high dose per fractionation is
preffered since systemic therapy can be started early.

42. Indications
Local Recurrence Rates after Surgery
Alone
Demoplastic melanoma 23-48% recurrence rate
Positive margin N/A
Locally recurrent N/A
Breslow ≥ 4 mm and ulceration > 15%
Breslow ≥ 4 mm and satellitosis > 15%
Indications
Regional Recurrence Rates after
Surgery Alone
Extracapsular extension 31-63%
≥ 4 LN 22-63%
LN > 3 cm 42%-80%
Cervical LN 33-50%
recurrent nodal disease N/A
No completion dissection after positive
SLND
20-50%
Adjuvant Irradiation of the Primary Site:
Adjuvant Irradiation of the Regional LN:

43. primary lesion, the
preauricular and Postauricular
lymph nodes (for high facial
and scalp primary tumors),
and the ipsilateral lymph
nodes from levels I through V,
including the ipsilateral
supraclavicular fossa
radiation fields include the axillary lymph
nodes from levels I through III . The
supraclavicular fossa and low cervical lymph
nodes may be included if there is bulky high
axillary disease.

44. pathologically confirmed nodal
disease and always include the entire
surgical scar.
Judgment must be used regarding
elective irradiation of adjacent nodal
regions (i.e., external iliac coverage in
the setting of confirmed inguinal
disease) because of concern about the
increased toxicity associated with
groin irradiation, particularly for obese
patients. Unlike the cervical or axillary
regions, where electrons and flashing
photon fields, respectively, generally
deliver a full dose to the skin, special
attention must be paid to delivering a
full dose to the groin scar

45. Setup, Field Arrangement, and Dose-Fractionation Schedule
Field descriptions dose
cervical disease,
• open neck
position
• usually treated
with two or
three fields,
• depending on
the distance
between the
primary tumor
and the parotid
nodes
• 6- to 9-MeV electron field superiorly can cover
the primary site, and an adjoining 9-MeV electron
field is used to irradiate the parotid and lower
neck nodes.
• The junctions shift (0.5 to 1 cm) after the 2nd &
4th treatments (dose homogeneity).
• A bolus is placed over a line connecting the
lateral canthus and the mastoid tip to spare the
temporal lobe, and an additional piece of
bolus may be placed over the larynx
30 Gy at 6 Gy
per fraction,
twice each
week (Monday
and Thursday
or Tuesday
and Friday)
over 2.5
weeks.
axillary
treatment
supine position
with the treatment
arm akimbo
• anterior and posterior 18-MV photon fields
are used to deliver the dose to the level I, II,
and III axillary lymph nodes
• radiation dose may be prescribed to a volume
such that the isocenter dose may be 3% to 6%
lower than the prescribed dose to ensure that
no volume of tissue receives more than 33 Gy.

46. Field Description dose
Inguinal nodes
• unilateral frog-leg
position, eliminating any
inguinal skin folds
• treatment may be
delivered using a mixed-
beam technique (four
fractions with 16- or
20-MeV electrons and
one fraction with 18-MV
photons)
• if deeper external iliac
lymph node coverage is
required, anterior and
posterior 18-MV photon
fields are used.
• if 18-MV photon
technique is selected, a
tissue-equivalent bolus is
used over the scar, and
the dose is weighted
anteriorly
A dose of 30 Gy is delivered
at 6 Gy per fraction, twice
each week (Monday and
Thursday or Tuesday and
Friday) over 2.5 weeks.
Appropriate reductions are
made to limit the small
bowel dose to 24 Gy.

47. BRAIN METASTASES : most ominous sign
Whole brain RT with or without temozolamide/ fotemustine is keystone to several
trials .
In two study (phase II) cytokine working group has compared RT+/-
temozolmide & RT+/-fotemustine has concluded that though combination
therapy has reduced time to progression , but there is no significant
difference in objective control and OS. Thus should be reserved for
widespread systemic disease with poor PFS/ diffuse foci of lesions not
amenable to SRS.
Overall conclusion:
• All patients with significant cerebral oedema should be managed by
corticosteroids initially
• Patients with single brain mets and low or absent other sites of systemic
disease should undergo resection.
• 1-5 lesion with size below 3 cm and non brainstem location should
undergo SRS followed by observation with serial imaging /
WBRT,(supported by RTOG 9508)
• Poor PFS and widespread systemic disease and low life expectancy should
be treated by WBRT

48. Vertebral metstasis
• Similar like brain mets, if patients with higher life expectancy has 1-
2 vertebral mets, first steroids with surgical decompression and
subsequent PoRT improves the survival.
• If patient has widespread bone mets, with vertebral mets palliative
RT should be considered.
• If failure occurs in patients with limited systemic disease, further
salvage SRS may be a option.

49. Vertebral metstasis
• Similar like brain mets, if patients with higher life
expectancy has 1-2 vertebral mets, first steroids with
surgical decompression and subsequent PoRT improves
the survival.
• If patient has widespread bone mets, with vertebral
mets palliative RT should be considered.
• If failure occurs in patients with limited systemic
disease, further salvage SRS may be a option.

50. Follow up:
• Recurrence usually occur in first 5 year, but 10 year
long recurrence is documented.
• Thus intensive surveillance is not cost effective
Skin exam. & annual surveillance All melanoma patients
Skin self exam. Monthly Patient need to be educated
Every 3-12 months for first 5 yrs and
annually thereafter. (comprehensive
imaging on the basis of specific symptoms)
Clinically stage IA & IIA
Every 3-6 months for first 2 yrs then every
3-12 months for first 3 yrs then annually.
(imaging may be considered)
Stage IIB-IV
Beyond 5 yrs imaging is not recommended
in case of controlled disease