Derm Skin cancer Flashcards
genetic risk factors for melanoma (4)
- family Hx (CDKN2A), MC1R (melanocortin 1 receptor) variants
- lightly pigmented skin
- red hair
- DNA defects (e.g. xeroderma pigmentosum)
Environmental risk factors melanoma (5)
Intense intermittent sun exposure Chronic sun exposure Residence in equatorial latitudes Sunbeds Immunosuppression
What pathway regulates cellular proliferation, growth and migration of melanocytes
(Mitogen- activated protein kinase) MAPK (RAS-RAF-MEK-ERK)
Where are KIT mutations present and how does it occur?
30-40% of acral and mucosal melanomas
also melanomas from chronically sun-exposed skin harbour activating mutations or copy number amplifications of KIT gene.
ACTIVATION MUTATIONS PRESENT IN MELANOMA? (2)
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 does BRAF mutations substitution lead to?
activation of mitogen-activated protein kinase (MAPK) pathway
Inherited CDKN2A mutations also cause MAPK pathway activation
How does P16 - tumour suppressor encoded by CDKN2A - work?
- Binds to CDK4/6, p16 prevents formation of cyclin D1-CDK4/6 complex
- Cyclin D1-CDK4/6 complex phosphorylates Rb, inactivating it, leading to E2F release (once released, E2F promotes cell cycle progression)
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)
Immunotherapy based on CTLA-4 blockade – ipilimumab**
- Also checkpoint inhibitors (PD-1, PDL1)- normally prevent autoimmunity so removing it allows immune system to kill melanoma cells
Melanoma: Subtypes (5)
Superficial spreading Nodular Lentigo maligna Acral lentiginous Unclassifiable
What is the - Most common type of melanoma in fair-skinned individuals
How common is this melanoma?
Superficial Spreading
60-70% of all melanomas
Where is superficial melanoma most frequently seen (different for M and F)
Most frequently seen on trunk of men and legs of women
appearance of superficial spreading melanoma
In up to 2/3 of tumours, regression (visible as grey, hypo-or depigmentation), reflecting the interaction of host immune system with tumour.
After a slow horizontal (radial) growth phase, limited to epidermis, a more rapid vertically oriented growth phase, which presents clinically with development of nodule
incidence M:F of nodular melanoma?
M>F
physical appearance of nodular melanoma?
Usually present as blue to black, but sometimes pink to red, nodule – may be ulcerated, bleeding
Develops rapidly
Mostly affects trunk, head and neck
how does nodular melanoma develop (growth pattern)?
Nodular melanoma is believed to arise as a de novo vertical growth phase without the pre-existing horizontal growth phase
Tend to present more advanced stage, with poorer prognosis.
Melanoma: Lentigo Maligna age group?
> 60 y/o
- Occurs in chronically sun-damaged skin, most commonly on the face
features of growth and appearance of lentigo malina?
Slow growing, asymmetric brown to black macule with colour variation and an irregular indented border.
Melanoma: Acral Lentiginous, commonest age of diagnosis? How common is it?
Diagnosed most frequently in 7th decade of life
Relatively uncommon: ~5% of all melanomas
site of Melanoma: Acral Lentiginous
Typically occurs on palms and soles or in and around the nail apparatus
racial/ethnic incidence of Acral Lentiginous
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%)
public awareness campaign for melanoma
Asymmetry Border irregularity Colour variegation Diameter greater than 5mm Evolving
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
Melanoma: Prognostic Factors
Poor Prognostic features:
- Increased Breslow thickness >1mm
- Ulceration
- Age
- Male gender
- Anatomical site – trunk, nhead, neck
- Lymph node involvement
Stage 1A melanoma have 10 year survival of >95% whereas thick melanomas >4mm and ulceration (pT4b) have a 10 year survival rate of 50%
Melanoma: Investigation
Dermoscopy –can improve correct diagnosis of melanoma by nearly 50%
Dermoscopic findings should not be considered n isolation
History and risk factor status are important
Excise lesion for histological assessment if in any doubt
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
Melanoma: Management
Primary excision down to subcutaneous fat
- 2mm peripheral margin
Wide excision - Margin determined by Breslow depth - 5mm for in situ - 10mm for =1mm Prevents local recurrence or persistent disease
Melanoma: Staging
pathological
TNM
Melanoma: Management
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
Currently offered for pT1b+
Extracapsular spread on lymph node biopsy – needs lymph node dissection
Melanoma: Management, imaging
Stage III, IV
And Stage IIc without SLNB
PET-CT
MRI Brain
what biomarker is a major prognostic factor in metastatic melanoma?
LDH
Melanoma: Management, Unresectable or metastatic
Immunotherapy
CTLA-4 inhibition – unresectable or metastatic BRAF negative melanoma (Ipilimumab)
PD-L1 (Programmed cell death ligand) inhibitors (Nivolumab)
- Combination immunotherapy leads to 60% response vs 20% monotherapy alone
Mutated oncogene targeted therapy
- Combination of aBRAFinhibitor (e.g. encorafenib, vemurafenib, dabrafenib) andMEK inhibitor (e.g. trametinib)
Keratinocyte Dysplasia / Carcinoma: skin colour incidence
Predominantly pale skin types
Keratinocyte Dysplasia / Carcinoma types (3)
Actinic keratoses
- Dysplastic keratinocytes
Bowen’s disease (Squamous cell carcinoma in situ)
Squamous cell carcinoma
- Potential for metastasis/ death
Basal cell carcinoma
- (Virtually) never metastasises - Locally invasive
Basal Cell Carcinoma: sunlight impact?
UV radiation is significant risk factor
p53 mutations are also important – majority are missense mutations that carry a UV signature
how do cells interact in basal cell carcinoma (involves PDGF/r)?
Cross talk between tumour cells and mesenchymal cells of stroma
- Receptors for PDGF are upregulated in Stroma but PDGF is upregulated in tumour cells
what properties do the metalloproteinases and collagenases give basal cell carcinomas?
proteolytic- can degrade pre-existing dermal tissue and facilitate spread of tumour cells
What chromosome loses function in basal cell carcinoma?
chromosome 8q (PTCH gene) (tumor suppressor gene) Receptor for Sonic Hedgehog
- Sonic Hedgehog-Patched signalling pathway
/ SHH signalling is required for growth of established BCCs
Squamous Cell Carcinoma and sun light?
UV radiation is significant risk factor
how does Squamous Cell Carcinoma develop?
through addition of genetic alterations – alterations in p53 are most common (CDKN2A important too):
- 1st p53 mutation: Resistance to UV induced apoptosis and colonial expansion (epidermal p53 clone)
- 2nd p53 mutation: Additional mutation- selection for growth advantage (SC dysplasia)
- Additional genetic mutation: progression of neoplastic clone and genomic instability (SCC in situ)
- Tumour progression: Additional genetic alteration and acquisition if invasive properties (Invasive SCC)
- Tumour progression: Additional genetic mutation and acquisition of metastatic capacity (Metastasis of SCC)
NOTCH1 or NOTCH2 (Wnt / β-catenin signalling) also plays role
