MELANOMA

By : Dr. Aashiq
 INTRODUCTION
 Malignant transformation of melanocyte,the cell
responsible for melanin production.
 Precursor of melanocytes arise in neural crest
migrates to multiple areas in body like skin ,meninges
,mucous membranes ,eyes,upper oesophagus.
 91.2% cutaneous
 5.3 %ocular
 1.3% mucosal and remaining unknown
primary site.
 MOLECULAR BIOLOGY OF
MELANOMA
• Melanoma has significantly have more sequence
variations per mega base of DNA.

• For example, melanomas have 15 times more mutations

per mega base of DNA than colorectal cancer and 4
times more than lung cancer.

• Mutations are cytosine to thymine (C>T) substitutions,

typical of UV radiation– induced thymine dimmers

• Mutations in BRAF, NRAS, and cKit.

cutaneous melanoma Mucosal or uveal melanoma
A carcinogen-induced  BRAF mutations (5% to
cancer with a high mutational 20%)
load,
Dependent on a particular  KIT mutations (5% to 10%)
oncogenic signaling pathway,
the mitogen-activated protein
kinase (MAPK) pathway  Uveal melanomas have
BRAF (50%) or NRAS mutations in the alpha
(20%) subunits of G- protein–
mutations coupled receptors GNAQ
and GNA11
 Driver Mutations in
Melanoma
• Dependent upon driver oncogenic mutations in the MAPK
pathway, with additional genetic alterations in other pathways
leading to
 Uncontrolled cell growth .
 Avoidance of apoptosis.
• Activating mutations in the receptor tyrosine kinase KIT (2%
to 3%), the G-protein neuroblastoma RAS viral oncogene
homolog (NRAS) (15% to 20%), and the serine-threonine
kinase BRAF (40% to 50%).
• Uveal melanomas have a driver mutations in GNAQ and
GNA11, which are the alpha subunits of G-protein–coupled
receptors.
Progression of Melanocytes to Cutaneous
Melanoma
A

B
D
Figure s4.3 (A) A nodule of vertical growth phase melanoma arising from a radial growth phase pigmented macule on the right cheek. (B) Superficial
spreading melanoma, 2.9 mm thick, arising on the temple of a young woman. There Were microscopic satellites, and the patient died
of disease within several years. (C} Superficial spreading melanoma with all the classic features of the ABCD mnemonic
(asymmetry, border irregularity, color variation, and diameter x6 mm}. (D) Large, ulcerated 2.5 mm superficial spreading melanDma
 EPIDEMIOLOGY
• Malignant melanoma is the sixth most common
cancer in US cancer diagnosis.
• This amounts to 4% of new cancer diagnoses and
1.5% of cancer deaths.
• Currently, 1 in 49 men and women will be diagnosed
with melanoma of the skin during their lifetime. Its
incidence is second only to breast cancer for women
from birth to age 39 years.
• Overall 5-year survival rates for melanoma
- 82% in the late 1970s (1975 to 1977) to
- 91% in the more recent era (2002 to 2006).
• Highest per capita incidence of melanoma worldwide is in
Australia

• In nonwhite populations, there is a much higher proportion of

melanomas in acral (subungual, palmar, plantar) and mucosal
locations.

• Ocular and nonacral cutaneous melanomas are 50- to 200-

fold more likely in white populations.

• Gender ratio at diagnosis- 2:1 -male :female, but it depends

on the age group.
 ANATOMIC DISTRIBUTION
• Most common sites in males are on the back and in the head
and neck regions.

• Women, the most common sites are in the lower

extremities, commonly below the knee.
 ETIOLOGY AND RISK
FACTORS
• Ultraviolet Light
Exposure
• UV light exposure as a major etiologic factor in the
development of melanoma.

 UVC radiation is generally absorbed by the ozone layer.

 UVB radiation (290 to 320 nm) is associated with sunburn
and induction of tanning by melanin pigment production
and has etiologic role in melanoma.
 UVA radiation (320 to 400 nm),associated with chronic
sun damage changes.
Physical Traits

 Blond or red hair.

 Green or blue eyes.
 Presence of multiple (>100) melanocytic nevi, and five or
more atypical nevi.
 A prior diagnosis of melanoma is associated with an eight-
fold increased risk of developing a secondary melanoma.
 Familial Predisposition
• 5% of melanomas occur in high-risk families
• Autosomal dominant inheritance with incomplete penetrance.
• The most frequent and highest penetrance melanoma susceptibility gene
is a germline mutation in CDKN2A, a tumor suppressor gene.
• Germline mutation in cyclin-dependent kinase 4.

• Other common risk factors include

 Dysplastic nevus syndrome.
 Xeroderma pigmentosum.
 Family history of melanoma even without the known genetic traits
 Li-Fraumeni syndrome.
 Germline mutations in p53
DIAGNOSIS OF
PRIMARY
MELANOMA
Characteristics of Primary
Melanoma
• Mnemonic ABCD asymmetry,
border irregularity,
color variation, and
diameter >6 mm.

• Melanomas classically are distinguished by their

pigmentation. Melanomas may have shades of brown, black,
blue,red, and white.
• “Ugly duckling” sign: A lesion that stands out as different
from the patient’s other nevi should be evaluated.
• Symptoms like bleeding ,itching,pain and ulceration –
 BIOPSY
• Full-thickness biopsy of the entire lesion, with a narrow (1 to 2 mm)
margin of grossly normal skin.
• This allows assessment of the architecture of the lesion.
• which is critical for differentiation of melanoma from Spitz nevus.
 Melanoma Subtypes: Histologic Growth Patterns

A. Superficial Spreading
Melanoma
B. Nodular Melanoma
C. Acral Lentiginous Melanoma
D. Lentigo Maligna Melanoma
E. Lentiginous Melanoma
F. Desmoplastic Melanoma
 Superficial Spreading Melanoma

• Most common type

• 70% of primary
cutaneous melanomas
• It is typical for the
trunk and extremities.
• Pagetoid growth of
atypical melanocytes in
the epidermis.
• Commonly associated
with sun exposure.
 Nodular Melanoma
• Nodular melanomas lack an
rapid growth phase.
• May be non pigmented
• Commonly are diagnosed when
relatively thick, nodular
melanomas are in
verticalgrowth phase.
• worst prognosis
• 20% of cutaneous melanomas.
 Acral Lentiginous Melanoma
• ALMs account for <5% of
melanomas.
• Site- Acral sites (subungual,
palmar, plantar) and on mucosal
surfaces(anorectal, nasopharyngeal,
female genital tract).
• Independent of UV light exposure.
• More common in African,
Asian, and Hispanic populations
than in fair-skinned whites.
• Prolonged RGP before vertical
growth
• Subungual lesions can be detected
by linear pigment streaks arising
from the base of the nail.
 Lentigo Maligna
•
Melanoma
Older individuals
• Chronically sun-damaged skin
• Commonly on the face
• shades of brown or black
• 10% to 20% of melanomas
• 47% of melanomas of the head and neck
• Extensive RGP that extends for many
years before developing invasion.
• When melanoma is just in situ, this RGP
portion is called lentigo maligna or
Hutchinson freckle, as opposed to LMM.
• LMMs are commonly diagnosed as thin
lesions
 Lentiginous Melanoma
• Its features include diameter ≥1 cm.
• Elongated and irregular rete ridges.
• confluent melanocytic nests and single cells over a broad
area of the dermal/epidermal junction.
• Focal pagetoid spread.
• Cytologic atypia, and possible focal dermal fibrosis.
 Desmoplastic Melanoma
• Uncommon form of melanoma.
• Histologically manifest by dermal melanocytes in a dense
stromal response.
• Usually nonpigmented and usually have lost the melanin
production pathway.
• They usually stain negative for MART-1/MelanA, gp100,
and tyrosinase, stain for S100.
• Most commonly in the head and neck.
 Prognostic Factors for
Primary
Melanomas
• The best predictor of metastatic risk is the depth of invasion,
measured with an ocular micrometer, from the granular
layer of the skin to the base of the primary lesion.

• Other prognostic factor include age, angiolymphatic

invasion,mitotic rate, gender, and body site.
 Depth of Invasion
• Breslow thickness is the depth of invasion measured from
the granular layer of the epidermis to the base of the
lesion.
AJCC Clark level
• level I - melanomas are melanomas in
 T1 lesions are <1 mm thick situ, limited to the epidermis or
 T2 lesions are 1 to 2 mm thick dermal/epidermal junction.
 T3 lesions are 2 to 4 mm thick
 • level II - melanomas invade into the
T4 lesions are >4 mm thick. superficial (papillary) dermis, and
these are usually RGP lesions.

• level III - melanomas fill the

papillary dermis.

• level IV - melanomas invade into

the deep (reticular) dermis and have
significant metastatic risk.

• level V - melanomas are uncommon

and contain invasion into the
subcutaneous fat.
 Ulceration
• Important negative prognostic feature

• T1a, T2a, T3a, and T4a melanomas are nonulcerated, and

T1b, T2b, T3b, and T4b melanomas are ulcerated.
 Patient Gender and Skin
Location

• Incidence of melanoma men > women.

• But in adolescents and young adults it is more common in
women.
• Prognosis is better for women than men.
• Extremities is better than that for patients with truncal or
head- and-neck melanomas
• There is a greater risk of lymph node metastasis in young
patients at the time of SNBx,especially for patients younger
than age 35 years, but the melanoma-associated mortality risk
increases with age for all thickness ranges.
 Growth Pattern
• Overall, nodular melanomas have the worst prognosis,
associated with their diagnosis at a thicker stage.
• Lesser risk is associated with ALM, superficial
spreading melanoma, and LMM, in that order, all
associated with decreasing average Breslow thickness.
• The VGP component appears to be the component of
melanoma that determines metastatic risk.
 Mitotic Rate
• Identified as a negative prognostic feature, especially with
six or more mitoses per square millimeter.

• Other Prognostic Factors

 Angiolymphatic invasion
 microscopic satellites
MANAGEMENT OF A NEWLY
DIAGNOSED CUTANEOUS
MELANOMA (STAGE I–II)
 Complete history and physical examination.
 Biopsy should be done for any suspicious lesions and with a very low
threshold for biopsy.

NCCN Clinical Practice Guidelines in Oncology (NCCN

GuidelinesR)

 Melanoma in situ, No staging radiographs or blood work

 Low-risk thin melanomas (stage IA) recommend imaging “only to
evaluate specific signs or symptoms.”
 Clinical stage I–II, no other imaging is recommended.
 Stage III melanoma chest radiograph (CXR),
computed tomography (CT) scans, or
positron emission tomography (PET)/CT scans, magnetic resonance
imaging (MRI) of the brain,
Wide Local Excision
 SURGICAL STAGING OF
REGIONAL
NODES
• Melanoma may metastasize by lymphatic or
hematogenous routes.
• Usually, lymphatic dissemination presents earlier than
hematogenous dissemination.
• The finding of lymphatic metastases is associated with a
higher risk of systemic disease.
 Intraoperative lymphatic mapping and sentinel lymph
node biopsy
• Vital blue dye (isosulfan blue) intradermally.
• The first node(s) into which these lymphatics
empty.
• Lymphoscintigraphy has been coupled with
the blue dye injection to support
identification of the sentinel node(s), using
handheld probes for detection of γ radiation
emitted by technetium-99 (99Tc).
• up to 1 mCi of 99Tc) and intraoperative
intradermal injection of isosulfan blue dye
(up to 1 ml) a few minutes prior to the
incision.
• Lymphatic mapping and SNBx using both
blue dye and radiocolloid increases sentinel
lymph node identification rates to 99%
 Identify location ofhot Make incision, use Deepen to sentinel node, using
spot(s) gammaprobeto guide dissection tonsils, Cth goad exposure
Figure 94.7 Schematic of a way to iJerti/ ono remove tile sentinel node us eg a handheld gamma can-iere
• Rate of positive nodes increases with increasing tumor
thickness, as would be expected, from <5% for the
thin melanomas that undergo SNBx (e.g., T1b lesions)
to approximately 40% for thick melanomas.
Immunohistochemical detection of isolated
melanoma cells in a sentinel node when stained
for the melanoma marker S100.
MANAGEMENT
 Clinically Localized Melanoma
Melanoma In Situ (Clinical TISN0M0, Stage 0)

• Confined to the epidermis and epidermal/dermal junction.

• Wide excision-Definitive management involves re-excision
with a margin of 5 mm.
• If cosmetically acceptable, obtain a margin of as much as 1
cm, especially if the original biopsy was incomplete.
• SNBx is not indicated.
• No adjuvant therapy is needed if the margins are widely
clear.
• Clinical Follow-Up After Surgical Treatment- annual basis.
Thin Primary Melanoma (Clinical
T1A)
• Melanoma <0.76 mm thick.
• Approximately a 5% risk of subsequent metastasis.
• AJCC- Melanomas are those <1 mm thick, with less than one
mitosis per square millimeter, and without ulceration.
• Stage IA melanomas have a 5-year survival rate of 94%.
• Wide excision with a 1-cm margin (including skin and all
underlying subcutaneous tissue, to the deep muscle fascia)
• Annual follow-up for many years is recommended rather
than frequent follow-up in the first few years.
 Clinical T2A, T2B
Melanomas
• Melanomas 1 to 2 mm thick, with or without ulceration.
• Wide excision with a 1- to 2-cm margin and SNBx.
• SNBx
 Positive, then subsequent management should follow
recommendations given later for stage IIIA melanoma (T2a
with positive SNBx involving one to three nodes) or stage
IIIB melanoma (T2b with positive SNBx involving one to
three nodes).
 Negative, then the patient is considered to have been
pathologically staged as T2aN0M0 (stage IB) or T2bN0M0
(stage IIA), and no additional surgical management is required
and no adjuvent systemic therapy required.
T3A Melanomas (Clinical Stage IIA)

• Melanomas 2 to 4 mm thick, without ulceration, and in the

absence of metastases, these are clinical stage IIA lesions.
• Definitive management includes wide excision with a 2-cm
margin and SNBx .
• SNBx
Negative, then no additional surgical or systemic therapy is
indicated .
Positive, then management for stage IIIA melanoma should be
followed.
 Clinical T3B Melanomas
(Clinical
Stage IIB)
• Melanomas 2 to 4 mm thick with ulceration represent
T3b lesions and thus are clinical stage IIB melanomas.
• Management is wide excision with a 2-cm margin and an
SNBx.
• SNBx
Negative, the summary stage is IIB (T3bN0M0).
patients, no additional surgical therapy is needed. HDI and
pegylated-interferon therapies.
 Thick Melanomas (T4A, T4B, Greater than
4 mm Thick)
• Metastasis and mortality in the range of 50% over 5 to 10
years.
• Ulceration increases this risk
• T4a melanomas are clinical stage IIB, T4b melanomas
are clinical stage IIC.
• Definitive management includes wide excision with at least
a 2-cm margin plus SNBx
• SNBx
Positive- CLND
Negative- adjuvant interferon
 SPECIAL CONSIDERATIONS

Primary Melanomas of the Head and Neck

• Large- diameter lentigo maligna on the face that is not
amenable to surgical resection because of cosmetic results
or comorbid patient conditions
 superficial or Grenz X-rays with local control rates

reported above 90%.

Imiquimod ointment.
•Desmoplastic melanoma,
Adequate margins.If that is not possible,
postoperative adjuvant radiation should be
considered with 2- to 3-cm margins around the
resected lesion.
REGIONALLY METASTATIC MELANOMA
(STAGE III)

Regional metastases are defined as follows:

■ Local recurrence is best defined as
recurrence of melanoma in the scar
from the original excision or at the
edge of the skin graft.
■ Satellites metastases recurrences that
are separate from the scar but within 2
to 5 cm of it are considered satellite
metastases.
■ Regional recurrences beyond 5 cm of
the scar but proximal to regional
nodes are considered in-transit
metastases.
 Management of Local
Recurrence
• Local recurrence is common after a primary lesion is
inadequately excised.
• very poor prognosis.
• Local recurrences were associated with 9% to 11% overall
5- year survival rate, as compared with 86% for those
without local recurrence.
• Management- re-resection of entire scar down to the level of
fascia, Excision with a 1- to 2-cm margin.
 Management of Satellite and In-
Transit Metastases
 Negative prognostic feature, with
clinical outcomes similar to those
observed for Systemic treatments
patients with palpable nodal Anti–cytotoxic T-
metastases. lymphocyte antigen
 Excision with SNBx. (CTLA4),
 Radiation therapy Anti–programmed
 Intralesional therapy with death 1 PD-1
o Interferon-α Anti-PD-L1 antibodies,
o Interleukin(IL)-2 BRAF and other
o bacillus Calmette-Guerin (BCG), targeted inhibitors
o Oncolytic replication competent virus
injections
o Dyes like Rose Bengal
o Diphencyprone,
o Imiquimod,
Isolated Limb Perfusion and Infusion
• Patients with extensive regional recurrences in
an extremity
• melphalan or isolated limb infusion.
 ADJUVANT SYSTEMIC THERAPY
(STAGES IIB, IIC, and III)

• Adjuvant Interferon Therapy

(1)HDI-α for 1 month followed by 1 year of intermediate dosing,
(2)interferon-α at an intermediate dose administered for 1 or 2 years,
(3)interferon-α at a low dose administered for 1 or 3 years, or
(4)pegylated interferon administered for a target period of 5 years
• High-Dose Interferon-�2B
 Induction phase intravenous infusion, 20 million U/m2, for 5
consecutive days every 7 days for 4 weeks .
 Maintenance phase For the subsequent 48 weeks, 10
million U/m2 were administered by subcutaneous injection on
alternate days for a total of three doses every 7 days
• Pegylated Interferon-�
 Biochemotherapy
• Biochemotherapy consisting of

 Dacarbazine 800 mg/m2 on day 1,

 cisplatin 20 mg/m2 on days 1 to 4;
 Vinblastine 1.2 mg/m2 on days 1 to 4;
 IL-2 9 MU/m2 per day continuous intravenous administration
on days 1 to 4;
 interferon 5 MU/m2 per day subcutaneously on days 1 to 4,
8, 10, and 12; and
 granulocyte– colony-stimulating fator 5 ug/kg per day
subcutaneously on days 7 to 16
 Cytotoxic T-Lymphocyte Antigen 4 and PD-1
Blockade

• Ipilimumab is a fully human immunoglobulin G1

monoclonal antibody that blocks CTLA4.

• lambrolizumab anti-PD-1 IgG4 monoclonal antibody MK-

3475.
THANK YOU