Pathophysiology of melanoma skin cancers (Jackie)
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Most dangerous skin cancer
Malignancy of melanocytes
Found primarily in skin but also ears, eyes, GI tract, oral and genital mucous membranes
Make up 5% of skin cancers but cause 70% of deaths from skin cancer
Melanomas originate from melanocytes, which arise from the neural crest and migrate to the
epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and
produce a protective melanin, are contained within the basal layer of the epidermis, at the junction
of the dermis and epidermis.
Melanomas may develop in or near a previously existing precursor lesion or in healthy-appearing
skin. A malignant melanoma developing in healthy skin is said to arise de novo, without evidence of
a precursor lesion. Many of these melanomas are induced by solar irradiation. The greatest risk of
sun exposure–induced melanoma is associated with acute, intense, and intermittent blistering
sunburns. This risk is different than that of squamous and basal cell skin cancers, which are
associated with prolonged, long-term sun exposure.
Melanocytes
synthesize
melanin using the
enzyme
tyrosinase, and
thus, under
normal
conditions, help
to protect against
UV damage.
Melanoma
induction by UV
radiation is a
multistep
process, involving
both UVB and
UVA.
Melanoma growing first in a
radial growth
phase with little
risk of metastatic
behavior.
This phase is
followed by the
vertical growth
phase with the
capacity for
metastasis.
Tumor
progression likely
is the
consequence of
multiple genetic
events.
SOME of the many Genetics of melanomas
Acquisition of abnormalities at the G1/S checkpoint appears to be the most crucial step in the
genesis and progression of melanoma.
Inactivation of the pRb and p53 pathways at G1/S transition is a fundamental requirement for the
genesis of most human cancers, including melanoma.
P16 has the capacity to control the G1/S transition. By specifically binding to cdk4/6, the p16
proteins inhibit the formation of the cdk4/6/cyclin D enzyme complex, which is required for the
phosphorylation of pRb, ensuring that pRb remains in a complex with the E2F transcription factor
Hypophosphorylated pRb binds to and suppresses E2F transcriptional activity and constrains G1
exit, p16 expression results in cell cycle arrest.
Loss of expression of p16 has been demonstrated in almost 50% of primary melanomas, it has been
observed that loss of p16 expression correlates with increasing tumour thickness, higher mitotic
rate, and increased proliferation rate.
BRAF encodes a serine/threonine kinase downstream of RAS in the MAP kinase (MAPK) pathway.
Mutated BRAF is responsible for the constitutive activation of the MAPK pathway, resulting in high
levels of phosphorylated ERK that promote cell growth and proliferation. BRAF mutations have
been found in approximately 40% to 80% of melanomas and nevi.
The p53 tumour suppressor pathway often is inactivated in cancers; however, alterations of p53
itself rarely are seen in melanomas (0–25%).
Melanoma cells have both radial and vertical growth phases. The radial growth phase encompasses
horizontal growth in the epidermis. These lesions represent early-stage disease and may be curable
with surgical excision. When the lesion enters the vertical growth phase, however, the repertoire of
the many factors that influence tumorigenicity and metastasis changes as the tumour proliferates,
enters the dermis, and acquires the capacity to metastasize.
Tumour progression:
Five stages of malignant transformation and tumor progression in melanocytes have been
suggested: (1) benign melanocytic nevi; (2) atypical nevi; (3) primary malignant melanoma, radial
growth phase; (4) primary malignant melanoma, vertical growth phase; and (5) metastatic
malignant melanoma.
With each successive step of tumorigenesis, a new clone of cells emerges with growth advantages
over the surrounding tissue, resulting in “clonal expansion.” It has been postulated that a critical
step in tumour progression of melanoma may be the transition from radial to vertical growth
phases. The radial growth phase consists of primarily intraepidermal proliferation of melanoma
cells, but also invasion of the papillary dermis by small numbers of cells that have gained a growth
advantage.
Types of melanomas:
1. Superficial spreading melanomas (SSM): 70% of cutaneous melanomas, often arises from a
pigmented dysplastic nevus.
2. Nodular melanomas: 10-15% of melanomas, most symmetrical and uniform, dark brown or
black in colour, radial growth may not be evident  tumour advances quickly to vertical
growth  high risk lesion
3. Lentigo melanoma: found in sun-exposed areas, arise from lentigo maligna precursor lesion
4. Acral lentiginous melanoma: equal frequencies blacks and whites, occur on the palms, soles,
and subungual areas, extremely aggressive and quickly advance to vertical growth phase
5. Mucosal lentiginous melanoma: develop from mucosal epithelium that lines the respiratory,
GI and genitourinary tracts.
Staging
Breslow thickness is defined as the total vertical height of the melanoma, from the very top to the
area of deepest penetration in to the skin. An instrument called an "ocular micrometer" is used to
measure the thickness of the excised tumour.
The Clark level refers to how deep the tumour has penetrated:
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Level I: confined to the epidermis, called "in situ" melanoma; 100% cure rate at this stage
Level II: invasion of the papillary dermis
Level III: filling of the papillary dermis, but no extension in to the reticular dermis
Level IV: invasion of the reticular dermis
Level V: invasion of the deep, subcutaneous tissue
Prognosis
Prognosis of a melanoma lesion can be predicted based on the following: the depth of invasion,
presence or absence of ulceration and to nodal status at diagnosis. Malignant melanomas usually
present at 2 extremes: at one end of the spectrum are patients with small skin lesions that are easily
curable by surgical resection and at the other are patients with widely metastatic disease, in whom
the therapeutic options are limited and prognosis is nil, with a median survival of only 6-9 months.
References:
Abeloff: Abeloff's Clinical Oncology, 4th ed.
Access Medicine: Medical Oncology
http://emedicine.medscape.com/article/280245-overview
Li, W. et al. The role of cell cycle regulatory proteins in the pathogenesis of melanoma. Pathology 38
(4), 297-301.