Skin cancers Flashcards
What is melanoma?
Malignant tumour arising from melanocytes
Why is melanoma dangerous?
- Leads to >75% of skin cancer deaths
- Rising incidence rates observed worldwide
What can melanoma arise on?
on mucosal surfaces (e.g. oral, conjunctival, vaginal) and within uveal tract of eye
What are the genetic factors that lead to melanoma?
- Family history (CNKN2A mutations), MC1R variants
- Lightly pigmented skin
- Red hair
- DNA repair defects (e.g. xeroderma pigmentosum)
What are the environmental factors that lead to melanoma?
- Intense intermittent sun exposure
- Chronic sun exposure
- Residence in equatorial latitudes
- Sunbeds
- Immunosuppression
What are the phenotypic causes of melanoma?
- > 100 Melanocytic nevi
2. Atypical melanocytic nevi
What does the MAPK pathway regulate?
regulates cellular proliferation, growth and migration
When are KIT mutations present?
- 30-40% of acral and mucosal melanomas
- also melanomas from chronically sun-exposed skin harbour activating mutations or copy number amplifications of KIT gene
When are activation mutations present?
- NRAS gene (15-20% of melanomas)
- BRAF gene (50-60%) – high in melanomas of skin with intermittent UV exposure, yet low in melanomas of skin with high cumulative UV exposure.
What do BRAF gene mutations do?
BRAF mutations substitution leads to activation of mitogen-activated protein kinase (MAPK) pathway
What else can cause MAPK pathway activation?
Inherited CDKN2A mutations
What is P16 tumour suppressor encoded by?
CDKN2A
What does P16 tumour suppressor bind to?
CDK4/6, p16 prevents formation of cyclin D1-CDK4/6 complex
What does the cyclin D1-CDK4/6 complex phosphorylates?
Rb, inactivating it, leading to E2F release (once released, E2F promotes cell cycle progression)
What is the host response to melanoma?
- CD8+ T-cell recognise melanoma-specific antigens and if activated appropriately, are able to kill tumour cells
- CD4+ helper T-cells and antibodies also play a critical role
- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is natural inhibitor of T-cell activation by removing the costimulatory signal (B7 on APC to CD28 on T-Cell)
How do you treat melanoma?
- Immunotherapy based on CTLA-4 blockade – ipilimumab
2. Also checkpoint inhibitors (PD-1, PDL1)
What is the epidemiology of melanoma?
- Increasing worldwide
- Develops predominantly in Caucasian populations
- Incidence low amongst darkly pigmented populations
- 10-19/100,000 per year in Europe
- 60/100,000 per year in Australia / NZ
What are the subtypes of melanoma?
- Superficial spreading
- Nodular
- Lentigo maligna
- Acral lentiginous
- Unclassifiable
What is the are 60-70% of all melanoma?
- Most common type in fair-skinned individuals
- superficial spreading
Where is melanoma mostly?
seen on trunk of men and legs of women
When do melanoma arise?
•Can arise de novo or in pre-existing nevus
When does regression happen in superficial spreading?
In up to 2/3 of tumours, regression (visible as grey, hypo-or depigmentation), reflecting the interaction of host immune system with tumour
What is the process of superficial spreading?
- After a slow horizontal (radial) growth phaselimited to epidermis
- more rapid vertically oriented growth phase, which presents clinically with development of nodule
What is nodular melanoma?
2nd most common type of melanoma in fair skinned individuals
What are 15-30% of all melanomas?
15-30%
Where does nodular melanoma happen?
- Most commonly trunk, head and neck
* M>F
How does nodular melanoma present?
- Usually present as blue to black, but sometimes pink to red, nodule – may be ulcerated, bleeding
- Develops rapidly
Where does nodular melanoma arise?
- arise as a de novo vertical growth phase without the pre-existing horizontal growth phase
- Tend to present more advanced stage, with poorer prognosis.
What is lentigo maligna?
- Minority of cutaneous melanomas (around 10%) and is >60 years old
- chronically sun-damaged skin, most commonly on the face
How does lentigo maligna progress?
- Slow growing, asymmetric brown to black macule
2. with colour variation and an irregular indented border
When does invasive lentigo maligna melanoma arise?
in a precursor lesion termed lentigo maligna (in situ melanoma) in sun damaged skin)
How many lentigo maligna progress to invasive melanoma?
estimated that 5%
How common is Acral lentiginous?
~5% of all melanomas
When is acral lentiginous diagnosed?
frequently in 7th decade of life
Where does acral lentiginous occur?
palms and soles or in and around the nail apparatus
What is the epidemiolgy of acral lentiginous?
- Incidence similar across all racial and ethnic groups
- As more darkly pigmented Africans and Asians do not typically develop sun-related melanomas, ALM represents disproportionate percentage of melanomas diagnosed in Afro- Caribbean (up to 70%) or Asians (up to 45%)
What early detection of melanoma?
History of change in colour, shape or size of a pigmented skin lesion
What is the public awareness campaign ABCDE for melanoma self detection?
- Asymmetry
- Border irregularity
- Colour variegation
- Diameter greater than 5mm
- E evolving
What is Garbe’s rule?
If a patient is worried about a single skin lesion, do not ignore their suspicion and have a low threshold for performing a biopsy
What are the differential diagnosis of melanoma?
- Basal cell carnoma
- seborrhoeic keratosis
- dermatofibroma
What are poor prognostic features of melanoma?
- Increased Breslow thickness >1mm
- Ulceration
- Age
- Male gender
- Anatomical site – trunk, nhead, neck
- . Lymph node involvement
What is stage 1A melanoma?
10 year survival of >95% whereas thick melanomas >4mm and ulceration pT4b have a 10 year survival rate of 50%
What is breslow thickness?
measurement from granular layer to bottom of tumour
What is dermoscopy?
can improve correct diagnosis of melanoma by nearly 50%
What are the global features of melanoma?
- Asymmetry
- Presence of multiple colours
- Reticular, globular, reticular-globular, homogenous
- Starburst
- Atypical network, streaks, atypical dots or globules, irregular blood vessels, regression structures, blue-white veil
What should you do if you are unsure if it is melanoma?
- Dermoscopic findings should not be considered n isolation
- History and risk factor status are important
- Excise lesion for histological assessment if in any doubt
- “If in doubt, take it out”
What is the management of a melanoma?
- Primary excision
2. Wide excision
What is a primary excision?
- down to subcutaneous fat
- 2mm peripheral margin
What is a wide excision?
- Margin determined by Breslow depth
- 5mm for in situ
- 10mm for =1mm
- Prevents local recurrence or persistent disease
What is the staging of melanoma?
- Pathological
2. TNM
What is the management of melanoma?
Sentinel lymphoma node biopsy
What happens in a sentinel lymphoma node biopsy?
- Lymphatic drainage of finite regions of skin drain specifically to an initial node within a given nodal basin - the ‘sentinel node’
- Represent most likely nodes to contain metastatic disease
What is the imaging of melanoma?
-Stage III, IV
And Stage IIc without SLNB
•PET-CT
•MRI Brain
What is a major prognostic factor in metastic melanoma?
LDH
When is sentinel lymphoma biopsy offered?
- Currently offered for pT1b+
2. Extracapsular spread on lymph node biopsy – needs lymph node dissection
What immunotherapy used in melanoma management?
- CTLA-4 inhibition – unresectable or metastatic BRAF negative melanoma (Ipilimumab)
- PD-L1 (Programmed cell death ligand) inhibitors (Nivolumab)
- Combination immunotherapy not much better than ingle agent in
- Combination immunotherapy leads to 60% response vs 20% monotherapy alone
What is mutated oncogene targeted therapy in melanoma management?
- Combination of aBRAFinhibitor (e.g. encorafenib, vemurafenib, dabrafenib)
- MEK inhibitor (e.g. trametinib)
What is the growth of melanoma superficial spreading?
horizontal growth (asymmetry, border irregualrity and colou variation) (limited to epidermis) then vertical growth (more invasive)
What is the growth of nodular melanoma?
only vertical growth
