Cancer as a disease: Skin Cancer Flashcards
What are the 3 main layers of the skin
§ There are 3 main layers to the skin – epidermis, dermis and hypodermis (fat layer).
BM separates epidermis from dermis
Muscles found below hypodermis.
Which layer of the skin do most skin cancers arise from
The epidermis
What are the four cell types that make up the epidermis
Keratinocytes
Melanocytes
Merkel cells
Dendritic cells (e.g Langerhans cells).
Summarise the different layers of the epidermis
§ The epidermis is comprised of (superficial à deep):
o Stratum corneum – dead keratinocytes- where they then shed off.
o Stratum lucidum.
o Stratum granulosum.
o Stratum spinosum – dendritic cells.
o Stratum basale – melanocytes, merkel cells, dividing cells - will also see tactile cells (with sensory nerve endings going into the dermis).
Which epidermis cell types are most commonly inflicted in skin cancers
Keratinocytes- mature and differentiate as they go move up form the stratum basale to the stratum corneum- so exposed to UV-Radiation.
Melanocytes- also exposed to UV radiation (they sit on the BM between the epidermis and the dermis).
Describe the keratonicoyte derived skin cancers
Keratinocyte derived
eg basal cell carcinoma (most common)
squamous cell carcinoma
aka Non melanoma skin cancer (NMSC)
Describe the melanocyte derived skin cancers
Melanocyte derived
eg Malignant melanoma
Describe some other types of skin cancer that may arise
Vasculature derived
eg Kaposi’s sarcoma (common in patient’s with AIDS)., angiosarcoma
Lymphocyte derived
eg Mycosis fungoides
Ultimately, what is the cause of skin cancer
Accumulation of genetic mutations —– uncontrolled cell proliferation
Describe the genetic syndromes that can lead to breast cancer
Inherited (genetic) predisposition to developing cancers
Gorlin’s syndrome- tendency to develop BCC- due to defects in the PTCH1 gene
xeroderma pigmentosum- genetic defect in DNA repair- so can't repair DNA damage by UV-Radiation- – increased risk of BCC, SCC and malignant melanoma
Describe how viral infections can cause skin cancers
Viral infections
HHV8 in Kaposi’s sarcoma
HPV in SCC- particuarly in the immunosuppressed.
Describe how UV light can cause skin cancers
Most significant cause- most common cause in patients
BCC, SCC, malignant melanoma
Describe how immunosuppression can cause skin cancers
drugs (immunosuppressants- organ transplants)., HIV, old age, leukaemia
What tool can be used to look at skin lesions more effectively
A dermatoscope (essentially a torch with a magnifying glass).
How will a lesion of malignant melanoma look under a dermatoscope
Irregular borders
Assymetrical
Blue/darkish in the middle/
Describe the epidemiology of malignant melanoma
o Incidence is highest in white people and lowest in blacks (increasing in whites).
o Incidence is highest in the south-west of England.
Describe the appearance of a skin lesion of basal cell carcinoma
§ Has a pearly appearance (pinky, reddish, greyish, glistens) and has dilated vessels (telangiectasia) on the surface
Describe the epidemiology of basal cell carcinoma
§ Epidemiology:
o Incidence is increasing in men and women – due to increasing ages and more exposure
What are the different types of UV radiation (from longest wavelength to the shortest)
UVA- 310-400nm
UVB- 280-310 nm
UVC- 100-280 nm
Describe how the sunlight is essential for life
Essential for photosynthesis (plants)
Infrared spectra provide warmth
Effect on human mood
Stimulates the production of vitamin D in the skin
Describe the difference in properties of the different types of UV radiation in terms of the depths that they penetrate
UV-C -stratosphere (ozone layer)
UV-B- sea level
UV-C- dead sea level
Longer wavelengths can penetrate more.
Which type of UV is most important in skin carcinogenesis
UVB
most important wavelength in skin carcinogenesis
Summarise the key properties of UVA
UVA
100 times more UVA penetrates to the Earth’s surface
major cause of skin ageing (penetrates to the deeper levels of the skin and effects collagen).
contributes to skin carcinogenesis (but UVB more important for skin carcinogenesis)
used therapeutically in PUVA therapy
How does UVB damage DNA
UVB directly induces abnormalities in DNA eg mutations
UVB induces photoproducts (mutations)
Affects pyrimidines ie Cytosine (C) and Thymine (T) bases- cross-linking between bases
The following photoproducts are formed:
cyclobutane pyrimidine dimers eg T=T, T=C, C=C
6-4 pyrimidine pyrimidone photoproducts
How is damage by UV radiation normally repaired
Usually repaired quickly by nucleotide excision repair
Nucleotides removed- then correct ones added with DNA polymerase.
Describe the carcinogenesis of UVA
Also promotes skin carcinogenesis
DNA forming cyclobutane butane pyrimidine dimers but less efficiently than UVB
free radicals which damage DNA and cell membrane
Ultimately, in which 3 gene types does UV radiation cause mutations in
UV damage to DNA leads to mutations in specific genes
cell division
DNA repair
cell cycle arrest
This leads to unregulated cell proliferation
Summarise the repair of UV induced DNA damage
Photoproducts are removed by a process called Nucleotide Excision Repair
Xeroderma pigmentosum
Genetic condition with defective Nucleotide Excision Repair
What are the key features of xermoderma pigmentosum
Increased risk of BCCs, SCCs and melanoma
Photosensitivity and dry skin
Increased freckling
Skin cancers at early age- don’t need much sun exposure to overcome faulty DNA repair process
If suspected- genetically screen all future sibilings
Can be managed with sun avoidance
Summarise the key mutations that can lead to skin cancers
Mutations that stimulate uncontrolled cell proliferation
Eg abolishing control of the normal cell cycle (p53 gene)
Mutations that alter responses to growth stimulating / repressing factors
Mutations that inhibit programmed cell death (apoptosis)
- apoptosis normally occurs to get rid of cells with faulty DNA.
Outline a scheme for photocarcinogensis
UV light (B/A) penetrates into the cell
If this cell has a p53 mutation or an inactivated wild type- then this will lead to skin cancer.
However, in a normal cell, the damage will be repaired
However, sometimes, the damage can be so severe that the cell is unable to repair it- so it undergoes apoptosis.
Summarise the dendritic cells of the skin
Found in the epidermis and the dermis
Called langerhans cells in the epidermis.
Describe the immunomodulatory effects of UV light
UVA and UVB effect the expression of genes involved in skin immunity
Depletes Langerhans cells in the epidermis
Reduced skin immunocompetence and immunosurveillance
Basis for UV phototherapy for eg psoriasis
Further increases the cancer causing potential of sun exposure
Describe UV phototherapy for inflammatoery dermatoses such as Psoriasis
UVA or UVB used
Psoralen UVA/B PUVA/PUVB
Place patient in a light box- dampens down immune response and inflammation
But it will increase your risk of skin cancer.
What happens to the keratinocytes in sun burn
The UV damage leads to keratinocyte apoptosis
The apoptotic cells in UV overexposed skin are called sun burn cells
Describe the consequences of a depletion of langerhan cells
UV light damages cells and causes malignant transformation- Langerhans cells would normally recognise these cells and clear them in the immune response (cell death).
However, if the Langerhans cells have been damaged by UV light, this immune response is lost and you get skin cancer.
Which system is used to categorise people based on their skin type and sensitivity to UV?
Fitzpatrick’s phototypes:
The host response to UV light is determined by genetic influences, especially skin phototype.
State the Fitzpatrick phototypes
1 - Always burns never tans ( ginger)
II - Usually burns, sometimes tans (blond, blue eyes)
III - Sometimes burns, usually tans (brown eyes, olive skin)
IV - Never burns, always tans
V - Moderate constitutive pigmentation - Asian
VI - Marked constitutive pigmentation - Afrocaribean
1 and II more likely to get skin cancers both (non-melanomas and melanomas)
What is the function of melanin and where is it made
Melanin pigmentation is responsible for skin colour
Produced by melanocytes within the basal layer of the epidermis
What does a person’s skin colour depend on
Skin colour depends on the amount and type of melanin produced not the density of melanocytes (which is fairly constant)
Normally one melanocyte for every 5/6 keratinocytes along the basal layer of the epidermis.
Describe the cross-talk between keratinocytes and melanocytes for melanin production
UV light reaching keratinocytes stimulates them to release Melanocyte Stimulating Hormone (MSH) which has a paracrine effect on the melanocytes (who’s digits come into contact with the keratinocytes). This results in the melanosome producing melanin- which travels up the spinous processes of the melanocyte and is taken into the keratinocyte by phagocytosing the tip of the melanocyte
The melanin then wraps around the nucleus to protect it.
How can we stain for melanocytes and melanin
Melanocytes- black
Melanin- brown on H and E stain
What happens to the melanin once it is produced by the melanocytes
It is packaged into melanosomes and it passes along the processes of the melanocytes and is taken up by the keratinocytes
The keratinocytes put the melanosomes around their nuclei, which protects the nuclei from DNA damage
What are the two different types of melanin
Two types of melanin are formed:
Eumelanin – brown or black
Phaeomelanin – yellowish or reddish brown (fair haired people)
Melanin is formed from tryosine via a series of enzymes
Which gene is responsible for the production of melanin
MCR1 gene
>20 gene polymorphisms
Variation in eumelanin : phaeomelanin produced (based on the polymorphism you have)
Explains different hair colour and skin types
Phototypes 2 and 3 will have a more mixed ration of eumelanin: phaeomelanin
Ultimately, what does melanin dictate
Melanin dictates skin sensitivity to UV damage
Outline the production of melanin
Produced by the Golgi and RER of melanocytes:
Tyrosine – DOPA (tyrosinase)
DOPA- dopaquinone (tyrosinase)
Dopaquinone — Eumelanin/Phaeomelanin
Eumelanin/Phaeomelanin – Melanin
Melanocyte secretory function- melanin packaged in melanosomes and transported to the keratinocytes
Keratinocytes take up melanin by melanosome transfer
Which type of skin cancer is the most aggressive
Malignant melanomas- can invade and metastasise
Summarise malignant melanoma
Malignant tumour of melanocytes
Melanocytes become abnormal
Atypical cells and architecture
Caused
by UV exposure
Genetic factors
Risk of metastasis
Describe lentigo maligna (melanoma in situ)
Proliferation of malignant melanocytes within the epidermis (pagetoid spread- move upwards in the epidermis- normally confined to stratum basale)- abnormal melanocytes with abnormal architecture
No risk of metastasis (bound within epidermis)
Treatment is excision and replacement with skin graft.
Describe the features of lentigo maligna
Irregular shape
Light & dark brown colours
Size usually >2.0 cm
Often occur in elderly patients- in sun-exposed areas (e.g face)
What is it the name given to a large area of lentigo maligna that has a smaller area within it that has become invasive
Lentigo maligna melanoma
Describe the features of a superficial spreading malignant melanoma
Lateral proliferation of malignant melanocytes (radial growth phase) pagetoid spread and vertical growth phase (downward growth into the dermis)
Invade basement membrane
Risk of metastasis
Describe the ABCDE rule for the diagnosis of malignant melanomas (particularly superficially spreading MMs)
ABCD rule
Asymmetry Border irregular Colour variation (dark brown-black) Diameter >0.7mm and increasing Erythema
What is it called when a pale area appears in the middle of a melanoma
Area of regression- melanoma been cleared by immune cells- bad- usually means melanoma has invaded deeper and metastasised
Describe the features of a nodular malignant melanoma
Vertical proliferation of malignant melanocytes
(no previous horizontal growth)
Risk of metastasis
Can arise from a mole or can arise de novo
Describe the features of a nodular melanoma arising with a superficial spreading melanoma
Downward proliferation of malignant melanocytes
Following previous horizontal growth
Nodule developing within irregular plaque
Prognosis will become WORSE
Lesion can lose pigmentation (not be fully pigmented)- erythmatous (redden areas)- amelanotic areas
Describe Acral lentiginous melanoma
Melanomas on the soles and palms
May appear as flat pigmented plaques or pigmented lumps
These melanomas are most common in dark skin types
What are non-pigmented melanomas called
Amelanotic melanoma
§ A melanoma where the cancer cells have lost the ability to create melanin.
State the different types of malignant melanomas
Superficial spreading Nodular Lentigo maligna melanoma Acral lentiginous Amelanotic
Summarise the ABCD recognition of melanomas
Asymmetry
Border
Colour
Diameter
What is the prognosis for melanoma based on
Note – Breslow thickness (measured from granular layer to bottom of tumour) states that the deeper the melanoma, the worse the prognosis.
>1- small
1-4- intermediate
>4- large
What are the risk factors for the development of a melanoma
Genetic markers (CDKN2A mutations) Number (>50) and size (>5mm) of melanocytic nevi (moles) Congenital nevi Number of atypical nevi (>5) High socioeconomic status Equatorial latitudes DNA repair defects (xermoderma pigmentosum) Immunosuppression
§ Family history. Intermittent burning exposure. Skin types 1, 2.
§ UV light exposure. Atypical nevus syndrome.
§ Sunburns during childhood. Personal melanoma history.
What is the most important risk factor for the development of melanoma
Sunburn in fair skinned people
What is a keratocanthoma
It is either a benign lesion or a benign version of an SCC
It grows rapidly but then disappears
There is no risk of metastasis
Tends to involute on itself.
Describe squamous cell carcinomas
Malignant tumour of keratinocytes Caused by UV exposure HPV Immunosuppression May occur in scars or scarring processes Risk of metastasis
How can you tell whether an SCC is well differentiated
If the lesion has a keratin horn then it shows that the keratinocytes can still produce keratin and so they are well differentiated
Where do SCCs commonly occur
Lips- smoking
Face
Ears- more protuberant and exposed to sun in Men
Lower legs- more exposed in women
What are BCCs a tumour of
Keratinocytes
Summarise basal cell carcinomas
Malignant tumour arising from basal layer of epidermis (SCCs more superficial) Caused sun exposure Genetics Slow growing Invades tissue, but does not metastasise Common on face
Describe the appearance of BCCs
They are pearly, have a rolled edge and often have arborising telangiectasia
Can be nodular or superficial
Can occur on the eyelids- lose eyelashes- sign of destruction
Describe mycosis fungoides
§ Not a fungal condition – miss-classified.
§ This is a lymphoma that affects the skin-resident T-lymphocytes (cutaneous T cell lymphoma)
§ This can be fatal and has internal organ involvement
Starts as a flat lesion, then plaque, then tumour- dissemination
Looks like psoriasis .
Describe Kaposi’s sarcoma
HIV and HHV8 associated
§ A tumour of the endothelial cells of the lymphatics.
§ Can occur in non-HIV patients and can occur internally
Always caused by HHV8
Describe epidermodysplasia veruciformis
Rare autosomal recessive condition
predisposition to HPV induced warts and SCCs
Can become incredibly keratotic
What is the treatment for many skin cancers based on
Surgery
