Melanoma

Athina Isaakidou M.D., PhD

Consultant Medical Oncologist
German Oncology Center
Overview
• The incidence of melanoma continues to increase dramatically, at an
overall rate of 33% for men and 23% women from 2002 to 2006.
Melanoma is increasing in men more rapidly than any other
malignancy, and in women more rapidly than any other malignancy
except lung cancer
Overview

• Risk factors for melanoma include skin type, personal history of prior
melanoma, multiple clinically atypical moles or dysplastic nevi, a
positive family history of melanoma,5-8 and rarely, inherited genetic
mutations. Genetic counseling could be considered for individuals
with a strong family history of invasive melanoma with or without
pancreatic cancer
• However, melanoma can occur in any ethnic group and also in areas
of the body without substantial sun exposure.
Risk factors
Male sex
• >50 years
• Phenotypic predisposition Atypical moles/dysplastic nevi. Increased mole count (particularly large
nevi).Sun-phenotype/tendency to sunburn. Red hair-blue eyes/Fitzpatrick skin type I/pheomelanin-
predominant phenotype
• Personal medical history/comorbidities Multiple and/or blistering sunburns. Precancer/cancers
especially: ◊ Actinic keratosis/non-melanoma (keratinocyte) skin cancer (eg, basal cell and
squamous cell carcinomas)◊ Childhood cancer Immunosuppression/immune perturbation related
to: ◊ Solid organ transplantation◊ Hematopoietic cell transplantation (HCT) ◊ Human
immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) Rare genodermatoses ◊
Xeroderma pigmentosum
• Genetic predisposition Presence of germline mutations or polymorphisms predisposing to
melanoma (eg, CDKN2a, CDK4, MC1R, BAP1 [especially for uveal melanoma], TERT, MITF, PTEN, and
potential other genes).Family history of cutaneous melanoma (especially if multiple); pancreatic,
renal, and/or breast cancer; astrocytoma; uveal melanoma; and/or mesothelioma
• Melanocytes exist outside of the skin as well, and can give rise to non-
cutaneous melanomas on mucosal membranes, the uveal tract of the
eye, or leptomeninges. Mucosal melanomas most often occur in the
head and neck sinuses and oral cavity, anorectum, vulva, and vagina,
but can arise in any of the mucosal membranes lining the
gastrointestinal and urogenital tracts.
• Mucosal and uveal melanomas differ significantly from cutaneous
melanoma in presentation, genetic profile, staging, response to
treatment, and patterns of progression
Subtypes of cutaneous melanoma
There are four main subtypes of cutaneous melanoma:
• superficial spreading melanoma;
• nodular melanoma;
• lentigo maligna melanoma; and acral lentiginous melanoma (ALM)
• Other subtypes, such as desmoplastic and amelanotic melanoma,
also exist but are rare.
Superficial Spreading Melanoma

• The most common type of melanoma, representing about 70% of all cases.
It begins in the melanocytes and spreads on the surface of the skin
(“superficial”) before it grows deeper and becomes invasive. This type of
melanoma usually appears as a flat or barely raised lesion on the surface of
the skin, often with irregular borders and variations in colour. About half of
these melanomas occur in pre-existing moles; the other half occur in new
lesions.[1] These lesions most commonly appear on the trunks of men, the
legs of women, and the upper back of both sexes. This type of melanoma is
diagnosed most frequently in patients between the ages of 30 and 50.
• It spreads along the top layer of skin—the epidermis—for a period of
months to years before it goes deeper into the skin.
• The darkening in one part of a pre-existing mole or the appearance of a
new mole on unaffected, normal skin.
Nodular melanoma
• Nodular melanoma is the second most common subtype of superficial
spreading melanoma as well as the most aggressive form of the disease. It
accounts for 10% to 15% of all cases of melanoma. Nodular melanoma
usually appears on the trunk, head or neck and is more common in men
than women.
• Unlike other melanomas that tend to grow across the surface of the skin
(like an oil slick spreading), a nodular melanoma invades more deeply
earlier and therefore often presents with a greater depth of invasion when
it is found and biopsied. For this reason, nodular melanomas are more
frequently associated with a poorer prognosis than other melanomas.
• This melanoma usually appears as a blue-black, dome-shaped nodule,
although 5% of the time the lesions are pink or red.
Lentigo maligna melanoma
• This melanoma comes from a pre-existing lentigo, rather than a mole. A
lentigo is a dark, flat or slightly raised, non-cancerous spot on the skin, also
known as a sunspot. Historically, only about 5% of all melanoma cases are
lentigo maligna melanoma.
• This type of melanoma typically takes many years to develop. It is most
often found in elderly adults and on parts of the body that have been
overexposed to the sun, such as the face, ears, arms, chest, and back. The
rate of lentigo malignant melanoma has been steadily increasing over the
last few decades. This increase is thought to be due to the fact that the
development of lentigo malignant melanoma is influenced by chronic sun
exposure.
• Like superficial spreading melanoma, lentigo maligna melanoma usually
grows slowly across the top layer of skin and generally appears as a large,
slightly-raised patch containing differing shades of colour.
Acral Lentiginous Melanoma

• “Acral” comes from the Greek word akron, meaning extremity, and this fourth type of skin
melanoma typically appears on the palms, on the soles, or under the nails. Acral lentiginous
melanoma (ALM) can be difficult to diagnosis and has a lower response rate to available therapies
for cutaneous melanoma, such as immune checkpoint inhibitors, but survival in the metastatic
setting is second only to pure cutaneous melanoma. Less than 5% of all melanomas are ALM, but
it is the most common form of melanoma in people with darker skin and those of Asian descent.
• Like superficial spreading melanoma, ALM grows on the surface of the skin or under the nail bed
before becoming invasive. Because of the misconceptions that melanomas only occur in sun-
exposed areas and that people of colour are not at risk for melanoma, these melanomas can be
discovered later than other types, after they have invaded deeper layers of skin or metastasized.
• When ALM appears on the palm or sole, it looks like a bruise or an elevated, thickened patch—
usually tan, brown, or black, with variations in colour and irregular borders. When ALM occurs
under the fingernail or toenail, it may present as a brown, black, or blue streak in the nail. In
darkly pigmented individuals, it can be completely normal to have darker streaks under the nail
because of the increased amount of melanin that their normal melanocytes produce. However, in
a lightly pigmented person, dark streaks in the nail are very rare, and any streak that cannot be
explained by a trauma must be seriously considered for a biopsy to prove that there is no cancer
under the nail.
Amelanotic melanoma
• Amelanotic melanoma (AM) is a rare type of cutaneous melanoma,
representing about 4% of cases. AM is defined by its lack of colour, or lack
of pigment although a substantial subset of amelanotic melanomas is red
or pink. The subtypes listed above can be amelanotic. Although Amelanotic
melanoma can occur on all body sites, it is more common on chronically
sun-exposed areas.
• AM can progress in a variety of ways. It is often diagnosed at a
later stage than pigmented melanomas.
• AM doesn’t contain melanin, so it does not look like a mole or appear like a
mole. An amelanotic melanoma may be a faint reddish or pinkish colour or
it may have no colour at all; it may an area of skin that simply looks
different from that around it.
Desmoplastic melanoma
• Desmoplastic melanoma (DM) is a rare type of melanoma, representing
less than 4% of cases. It can occur on its own or in conjunction with
another subtype of melanoma. It can be labeled as “pure” or “mixed”
desmoplastic melanoma. Its development is related to chronic UV exposure
and is often found on head and neck, trunk, or extremities of older
individuals.
• DM is challenging because it presents and progresses in a variety of
different ways.
• Desmoplastic melanoma can present in a number of ways, so it’s difficult to
describe what to look for. However, it is often non-pigmented, and it may
present as an amelanotic scar-like or thickened lesion.
Workup
• Patients presenting with a suspicious pigmented lesion optimally
should undergo an excisional biopsy (elliptical, punch or
saucerization), preferably with 1- to 3-mm negative margins
• Excisional biopsy may be inappropriate for certain sites (including the
face, palmar surface of the hand, sole of the foot, ear, distal digit, or
subungual lesions) or for very large lesions. In these instances, a full-
thickness incisional or punch biopsy of the clinically thickest portion
of the lesion is an acceptable option. These procedures should
provide accurate primary tumor microstaging
Workup
• After the diagnosis of cutaneous melanoma has been confirmed,
detailed personal and family history, including any personal history of
prior melanoma or dysplastic nevi, should be obtained. In the physical
examination of patients with invasive melanoma, physicians should
pay special attention to the locoregional area and lymph node
drainage basin(s) of the established melanoma. A complete
dermatologic examination is recommended for all patients with newly
diagnosed melanoma.
Pathology review
• Breslow thickness
• Ulceration status (present or absent)
• Dermal mitotic rate (#/mm2 )
• Assess deep and peripheral margin status
• Microsatellitosis (present or absent)
• Pure desmoplasial if present
• Lymphovascular/ angiolymphatic invasioni
• Neurotropism/perineural invasion
Pathology review
• Mitotic rate is an indicator of tumor proliferation and is measured as
the number of mitoses per mm2
• Mitotic rate greater than or equal to 1 per mm2 was independently
associated with worse disease-specific survival (DSS), especially in
patients with melanoma less than or equal to 1.0 mm thick.14 As
such, mitotic rate has replaced Clark level as a criterion for upstaging
patients with melanomas less than or equal to 1.0 mm in thickness
from IA to IB
Sentinel Lymph Node Biopsy
• SLNB is a minimally invasive staging procedure developed to further
risk stratify patients with clinical stage I-II melanoma according to the
presence or absence of subclinical nodal metastases. Patients with
positive SLNB are at higher risk of recurrence, and might be
candidates for complete lymph node dissection (CLND) and/or
adjuvant systemic therapy
• The correlation between increased primary tumor thickness and SLN
positivity is well established. Due in part to the low probability of
finding a positive sentinel node in patients with thin primary
melanomas (≤1 mm), the utility of SLNB in this population is
controversial
SLN
• In addition to Breslow thickness, other primary lesion characteristics
(eg, Clark level, mitotic rate, ulceration, lymphovascular invasion, VGP,
anatomic site, tumor infiltrating lymphocytes, regression) and patient
characteristics (eg, sex, age) have been assessed for their association
with SLN status in patients with primary melanomas thicker than 1
mm
• SLNB should generally be discussed and offered for patients with
higher risk stage IB (>1 mm thick or 0.76–1.0 mm thick with
ulceration or mitotic rate ≥1 per mm2 ) or stage II melanoma
Staging
In general, cutaneous melanomas are categorized as follows:
• localized disease with no evidence of metastases (stage I–II),
• regional disease (stage III), and
• distant metastatic disease (stage IV)
• Studies have shown that in addition to patient-specific factors of age
and gender, tumorspecific factors of Breslow tumor thickness,
ulceration, and mitotic rate were found to be the three most
important characteristics independently predictive of outcome by
multivariate analysis.
Staging
• Among patients with nodal metastases (stage III), the clinical nodal
status (nonpalpable vs. palpable) and the number of metastatic nodes
are the most important predictors of survival.
• For patients with a positive SLN, prognostic factors include number of
positive nodes, tumor burden in the sentinel node, primary tumor
thickness, mitotic rate and ulceration, and patient age.
• For patients with clinically positive nodes, prognostic factors include
number of positive nodes, extranodal extension, primary tumor
ulceration, and patient age.
Systemic therapy

• In general, immunotherapy and targeted therapy are preferred for

treatment of unresectable or distant metastatic disease
• For patients who are not eligible for any of the recommended
immunotherapy or targeted therapy options (due to progression on
prior therapy, unacceptable toxicity, or comorbidities), cytotoxic
therapy can be considered on a case-by-case basis, and is therefore
considered useful in certain circumstances
• Cytotoxic agents that have been used alone or in combination
include (but are not limited to): dacarbazine, temozolomide,
paclitaxel, albumin-bound paclitaxel, carboplatin/paclitaxel, and
cisplatin/vinblastine/dacarbazine (CVD)