Skin Cancer Flashcards
Outline the main characteristics of skin cancer
Skin Microanatomy
There are 3 main layers to the skin – epidermis, dermis and hypodermis (fat layer).
Basement membrane in between
The epidermis is comprised of (superficial -> deep):
- Stratum corneum – dead keratinocytes.
- Stratum lucidum.
- Stratum granulosum.
- Stratum spinosum – dendritic cells.
- Stratum basale – melanocytes, merkel cells, dividing cells
- The basal layer of keratinocytes is resting on the basement membrane
- The keratinocytes proliferate and as they move up through the layers of the epidermis, they differentiate and eventually end up in the stratum corneum - where they shed - they are also exposed to UV radio and can undergo mutations
- The stratum corneum is a layer of keratinocytes that have lost their nuclei and mainly consist of keratin -‐ it forms the barrier function of the skin
Main cell types of the epidermis:
- Keratinocytes
- Melanocytes -‐ sit on the basement membrane and produce melanin
- Langerhans cells -‐ APCs found within the epidermis
- Merkel cells -‐ involved in sensation
Summarise the types and causes of skin cancer
Types:
- Keratinocyte derived – e.g. BCC (Basal Cell Carcinoma), SCC (Squamous Cell Carcinoma).
- AKA – Non-Melanoma Skin Cancer (NMSC).
- Melanocyte derived – e.g. Malignant melanoma.
- Vasculature derived – e.g. Kaposi’s sarcoma, angiosarcoma.
- Lymphocyte (lymphoma) derived – e.g. Mycosis fungoides (not a fungus).
Causes:
- Genetic syndromes – Gorlin’s syndrome, Xeroderma pigmentosum (=genetic defect in DNA repair) .
- Viral infections – HHV8 (Kaposi’s sarcoma), HPV (SCC).
- UV light – BCC, SCC, malignant melanoma.
- Immunosuppression – drugs, age, HIV, leukaemia.
Melanin
Host Differences and Melanin – most differences are determined by genetic influences (e.g. skin type):
Fitzpatrick phototypes:
- always burns, never tans.
- usually burns, sometimes tans.
- sometimes burns, usually tans.
- never burns, always tans.
- moderate constitutive pigmentation – Asian.
- moderate constitutive pigmentation – Afrocaribean.
Melanin
- Responsible for skin colour
- Produced by melanocytes in the basal layer of the epidermis
- Skin colour depends on the amount and type of melanin produced, NOT the density of melanocytes (which is fairly constant)
- Melanocytes are dendritic and they interdigitate with about 30 or so keratinocytes
- They produce melanin, which is packed into melanosomes
- The melanosomes pass down the processes and are taken up by the keratinocytes
- The keratinocytes put the melanosomes around their nucleus, which protects it from UV damage
- In paler skin types, under the influence of UV light, the keratinocytes will make melanocyte stimulating hormone, which will have a paracrine effect on the melanocytes to make more melanin
Types:
Types – encoded by MCR1 gene has that has >20 polymorphisms and describes the variations in melanin.
- Eumelanin – brown or black.
- Phaeomelanin – yellowish or reddish.
- Tyrosine -> DOPA -> Dopaquinone -> Eumelanin or Phaeomelanin -> melanin
Explain the role of UV light in the pathogenesis of skin cancer and the role of p53 in relation to this
UV light spectrums:
UVA – 310-400nm.
- UVA will reach dead sea level
- 100x more penetrating than UVB.
- Major cause of skin AGEING and contributes to skin carcinogenesis.
- Also forms Cyclobutane pyrimidine dimers but less efficiently than UVB.
- Forms free radicals to damage DNA and cell membranes.
- Used therapeutically in PUVA therapy – treats psoriasis etc.
UVB – 280-310nm.
- Penetrates to ground level.
- Most important in skin carcinogenesis:
- Induces direct abnormalities in skin DNA – e.g. mutations.
- Induces photoproducts – affects PYRIMIDINES (C, T) bases, e.g.:
- Cyclobutane pyrimidine dimers (e.g. T=T, T=C, C=C).
- 6-4 pyrimidine pyrimidone photoproducts.
- Photoproducts are usually repaired quickly by nucleotide excision repair.
UVC – 100-280nm.
- Does not penetrate ozone.
UV and Skin Damage
UV damage to DNA leads to mutations in specific genes:
- Cell division
- DNA repair
- Cell cycle arrest
- Photoproducts are normally removed by a process called nucleotide excision repair
- Xeroderma pigmentosum -‐ genetic condition with defective nucleotide excision repair
- When DNA is not being repaired properly, patients tend to develop cancer at a very young age and at a high frequency
- They will develop BCCs, SCCs and melanomas
- They are also photosensitive and their skin gets very dry
- They sometimes also have ocular and neurological problems
Sunlight has actions including – photosynthesis, warmth from IR, human mood effects, production of VitD.
Summary of Mutations that Cause Cancer:
- Mutations that stimulate uncontrolled cell proliferation
- E.g. abolishing control of the normal cell cycle (p53 gene)
- Mutations that alter responses to growth stimulating/repressing factors
- Mutations that inhibit apoptosis
Sun burn
Sunburn:
- UV leads to keratinocyte apoptosis
- ‘Sun burn’ cells are apoptotic cells in UV overexposed skin
- Apoptosis removes UV damaged cells in the skin which might otherwise become cancer cells
Immunomodulatory effects of UV light:
- UVA and UVB affect the expression of genes involved in skin immunity
- It depletes Langerhans cells in the epidermis
- This causes reduced skin immunocompetence and immunosurveillance
- This is the basis of using UV phototherapy to treat psoriasis -‐ it immunocompromises the skin so the inflammatory condition gets better
- However, this does further increase the cancer causing potential of sun exposure
Photocarcinogenesis
- Overexposure to UV radiation causes DNA damage in the keratinocytes
- It can then get repaired and return to being a normal cell
- If the damage is too severe, it could undergo apoptosis
- If this damage is accompanied by appropriate mutations in other cancer promoting genes, it can lead to skin cancer
- p53 mutations can lead to skin cancer.
- If p53 is intact, the cell damage will lead to expression of the p53 and repair or apoptosis of the cell.
Basal Cell Carcinoma
Basal-Cell Carcinoma
- Has a pearly appearance and has dilated vessels on the surface.
- pale, glistens (shines), pinky - dilates small capillary blood vessels
Epidemiology:
- Incidence is increasing in men and women – due to increasing ages and more exposure.
Basal Cell Carcinoma
- Malignant tumour arising from the basal layer of the epidermis
- Causes:
- Sun exposure
- Genetics
- These are slow growing
- They invade tissues but they do not metastasise
- They are common on the face
Nodular BCC:
- It is pearly, has a rolled edge and there is telangiectasia
- Telangiectasis = a localised collection of distended blood capillary vessels
- A key feature of BCC is arborising telangiectasia -‐ the telangiectasia looks like branches of a tree
Squamous Cell Carcinoma
Keratoacanthoma
- This is thought to be either a benign lesion or a benign version of an SCC
- It grows rapidly but then it disappears
- It has NO risk of metastasis
(1) Squamous Cell Carcinoma
- Malignant tumour of keratinocytes.
- Caused by – UV, HPV, immunosuppression, scarring processes.
- Risk of metastasis - but not as high as in melanoma
- “Horny” descriptors indicate well differentiation and the cell has retained the ability to create keratin.
- Immunosuppression is significant -‐ people who have organ transplants are at high risk of getting SCCs
- This is a well differentiated SCC because it has a keratin horn -‐ it shows that the keratinocytes still have the ability to produce keratin
- Women tend to get SCCs on the lower legs -‐ presumably because they get more sun exposure there
Malignant melanoma
Malignant Melanoma
MM has an irregular margin and is dark-coloured.
Epidemiology:
- Incidence is highest in white people and lowest in blacks.
- Incidence is highest in the south-west of England.
Characteristics:
- (pathological analysis)
- asymetry
- border
- colour
- diameter
Types:
(1) Malignant Melanoma
- Malignant tumour of melanocytes caused by UV exposure and genetic factors.
- Melanocytes become abnormal and have atypical cells and atypical architecture
- There is a risk of metastasis.
(2) Lentigo Meligna (Melanoma in situ):
- Proliferation of malignant melanocytes within the epidermis.
- Normally, the melanocytes are found along the basal layer but here they are distributed throughout the epidermis
- This is considered a premelanoma state
- They normally have an irregular shape and irregular borders with light and dark brown colours
- No risk of metastasis.
Features:
- Irregular shape.
- Light & dark colours.
- Size usually >2.0cm.
Malignant melanoma: descuss types, prognosis, and risk factors
(3) Superficial Spreading Malignant Melanoma
- Lateral proliferation of malignant melanocytes.
- Melanocytes are in epidermis and in dermis (heading outwards: vertical growth phase, heading downwards: horizontal)
- Invasion of the BM and a risk of metastasis.
- Diagnosis rule of MMs – ABCD:
A – Asymmetry.
B – Border irregularity.
C – Colour variation.
D – Diameter >0.7mm and increasing.
(E – Erythema).
4) Nodular Malignant Melanoma
- Vertical proliferation of MMs with no previous horizontal growth.
- Risk of metastasis.
- Usually much darker in appearance.
5) Nodular Melanoma arising within SSMM
- Downward proliferation of MMs following previous horizontal growth.
- Prognosis will become worse.
(6) Acral Lentiginous Melanoma
- A malignant melanoma affecting the palms and soles of the feet.
- Occur in darker skinned people more often than lighter coloured skin people.
(7) Amelanotic Melanoma
* A melanoma where the cancer cells have lost the ability to create melanin.
Note – Breslow thickness (measured from granular layer to bottom of tumour) states that the deeper the melanoma, the worse the prognosis.
Prognosis of Melanoma
- Prognosis of melanoma is determined using Breslow Thickness
- This is the thickness of the tumour from top to bottom, measured in milimetres
- < 1 mm = superficial tumour
- > 1 mm = intermediate or deep tumour
- This will determine how likely the tumour is to metastasise and cause death
Risk Factors for Development of a Melanoma
- Family history.
- Intermittent burning exposure.
- Skin types 1, 2.
- UV light exposure.
- Atypical nevus syndrome.
- Sunburns during childhood.
- Personal melanoma history.
Mycosis Fungoides and Kaposi’s Sarcoma
Mycosis Fungoides
- This is a cutaneous T cell lymphoma -‐ it specifically affects the skin
- affects the skin-resident T-lymphocytes.
- The red patches make it look like psoriasis but if a biopsy is taken, atypical lymphocytes can be seen
- It is usually slowly progressive over decades
- Not a fungal condition – miss-classified.
- This can be fatal and has internal organ involvement.
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.
Epidermodysplasia Verruciformis
Epidermodysplasia Verruciformis
- Rare autosomal condition.
- Gives a predisposition to HPV-induced warts and SCCs.
- Rare autosomal recessive condition that predisposes to HPV induced warts and SCCs
- The pale bits (left image) are the abnormal areas -‐ they will be rough and warty
Note – treatment for many of these skin cancers is still surgical
summarise the role of human papilloma virus in the pathogenesis of squamous cell carcinoma.
