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PATH3309 > 18 - Melanoma > Flashcards

18 - Melanoma Flashcards

1
Q

Melanoma

A
  • A malignant tumour derived from melanocytes
  • 3rd most commonly diagnosed cancer in aus
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2
Q

Melanocytes

A

Cells responsible for melanin production

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3
Q

Melanoma risk factors

A
  • Fair complexion
  • UV radiation
  • Large numbers of naevi
  • Family history
  • Previous melanoma
  • Immunosuppression
  • Exposure to harmful chemicals
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4
Q

Clinical features of benign naevus

A
  • Small
  • Well circumscribed
  • Even colourisation
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5
Q

Histological features of benign naevus

A
  • Symmetrical
  • Cells predominantly in nests
  • Round to oval, even nuclei
  • “maturation” as the cells get deeper
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6
Q

Spitz naevus

A
  • Occurs in children and young adults
  • Can be histologically mistaken for melanoma
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7
Q

Blue naevus

A

Appears darker as pigmented cells are in the dermis

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8
Q

Dysplastic naevus

A
  • Larger than benign (>6mm))
  • Irregular borders
  • Variable colouration
  • Some patients develop large numbers of dysplastic naevi (dysplastic naevus syndrome)
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9
Q

Dysplastic naevus syndrome

A

Increased risk of developing melanoma, especially if there is also a family history

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10
Q

Histological features of dysplastic naevus

A
  • Broader and less symmetrical
  • More single cell growth
  • Some larger, darker nuclei
  • Fibrosis in the upper dermis
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11
Q

Melanoma diagnosis

A
  • Asymmetrical
  • Border irregularity
  • Colour variability
  • Diameter (>6mm)
  • Evolving
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12
Q

Microscopic features of melanoma

A
  • Asymmetrical
  • Poorly circumscribed
  • Single cells predominate over nests
  • Very disorganised growth
  • Extension into the upper levels of the epidermis
  • Cytological atypia
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13
Q

Extension into the upper levels of the epidermis

A

Pagetoid spread or “buckshot” scatter

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14
Q

Cytological atypia

A
  • Nuclear enlargement, hyperchromasia, irregularity
  • Prominent nucleoli
  • Mitotic figures
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15
Q

Radial growth phase

A
  • Refers to growth within epidermis (“melanoma in situ”), as well as “microinvasion” into superficial dermis
  • The microinvasive component is limited to single cells and small
    nests
  • Lacks metastatic potential
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16
Q

Vertical growth phase

A
  • Invasive melanoma within the dermis which is expansile
  • Larger than the epidermal nests
  • Mitotic figures
  • Implies a capacity for
    metastatic spread
17
Q

Prognostic indicators of melanoma

A
  • Breslow thickness
  • Clark level of invasion
  • Ulceration
  • Mitotic rate
  • Lymphovascular or perineural invasion
  • Satellite lesions
18
Q

Important mutations in melanoma

A
  • Mutations that activate pro growth signalling pathways
  • Mutations that disrupt cell cycle control genes
  • Mutations that activate telomerase
19
Q

Mutations that activate pro growth signalling pathways

A
  • BRAF
  • NRAS
  • KIT
20
Q

Mutations that disrupts cell control genes

A

CDKN2A

21
Q

Mutations that activate telomerase

A

TERT promoter mutations

22
Q

BRAF

A
  • Serine-threonine kinase
  • Mutations found in 66% of melanomas
  • Most mutations located in highly conserved kinase domain
  • 80% are accounted for by a point mutation leading to V600E substitution
23
Q

BRAF mutations in naevi

A
  • Common in naevi
  • Thus mutation of BRAF and activation of MAPK pathway is important in melanocytic neoplasia
  • But not sufficient for development of melanoma (other mutations required)
24
Q

MAPK

A

The mitogen-activated protein kinase signaling cascade

25
Q

Why do we test for BRAF mutations if not sufficient for melanoma

A
  • Driver mutation
  • Specific BRAF inhibiting drugs have been developed which are selective for the V600E mutation
  • Valuable treatment for metastatic melanoma
  • Testing for the presence of the mutation allows for selection of patients which may benefit from the drug
26
Q

Examples of BRAF inhibiting drugs

A
  • Vemurafenib
  • Dacarbazine
27
Q

RAS mutations in melanoma

A
  • NRAS mutations found in 15% in melanomas
  • HRAS and KRAS mutations are rare
  • KRAS more common in other cancers
28
Q

KIT mutations and melanoma

A
  • Cause increased migration of melanocytes
  • Found in melanomas arising in skin without hair, nails, mucosa, skin with chronic sun exposure
  • BRAF mutations uncommon
  • Incidence increases with age
  • Lentiginous growth pattern
29
Q

CDKN2A

A
  • Located on chromosome 9p21
  • Encodes 2 genes
  • Mutated in up to 40% of familial cases
30
Q

2 genes encoded for by CDKN2A

A
  • p16^INK4a
  • p14^ARF
31
Q

p16^INK4a

A

Inhibits CDK4 and CDK6, reinforcing the ability of RB to block cells in the G1 phase of the cell cycle

32
Q
A
33
Q

p14^ARF

A

Enhances the activity of p53 by inhibiting MDM2, which normally stimulates p53 degradation

34
Q

TERT promotor mutations

A
  • TERT encodes the catalytic subunit of telomerase
  • Mutations in the promoter region of TERT have been identified in approximately 70% of melanomas
  • These mutations increase TERT expression, thus acting as an antidote to senescence
  • The promoter mutations create new binding sites for Ets family transcription factors (which are upregulated by BRAF signalling)
35
Q

Telomerase

A

Enzyme which preserves telomeres and thus protects cells from senescence

36
Q

Hallmarks of cancer displayed by melanomas

A
  • Sustaining proliferative signalling
  • Evading growth suppressors
  • Enabling replicative immortality

PATH3309 (26 decks)

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