15. Cancer as a disease - skin cancer

Question 1

Name the 5 layers of the epidermis.

Answer 1

Come Lets Get Sun Burn

• Stratum Corneum
• Stratum Lucidum
• Stratum Granulosum
• Stratum Spinosum
• Stratum Basale
• 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
  
  • ​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

Question 2

Name the types of skin cancer.

Answer 2

• Keratinocyte derived:
  
  • ​Basal cell carcinoma (BCC)
  • Squamous cell carcinoma (SCC)
  • Collectively know as non-melanoma skin cancer (NMSC)
• Melanocyte derived:
  
  • ​Malignant melanoma
• Vasculature derived:
  
  • ​Kaposi’s sarcoma - arises from the endothelium of the lymphatics
  • Angiosarcoma - arises from the endothelium of blood vessels
• Lymphocyte derived:
  
  • ​Mycosis fungoides - lymphoma that is specific to the skin

Question 3

Name causes of skin cancer.

Answer 3

• Genetic Syndromes
  
  • ​Gorlin’s Syndrome
    
    • ​Autosomal dominant condition where the individual has a defect in the PTCH gene
    • They have a germline mutation in this gene so only require one more mutation to develop BCC
    • RESULT: these patients have multiple BCCs throughout their lives.
  • Xeroderma pigmentosum
    
    • Rare condition caused by a mutation in a gene involved in DNA repair
    • Nucleotide excision repair is faulty in these patients, so they go on to develop multiple skin cancers
• Viral Infections
  
  • ​HHV8 (human herpes virus 8) in Kaposi’s Sarcoma
  • HPV in SCC
• UV light
  
  • ​BCC (been rising)
  • SCC
  • Malignant Melanoma (rising in white population)
• Immunosuppression
  
  • ​Drugs e.g. azathioprine, cyclosporin
  • HIV
  • Old age
  • Leukaemia

Question 4

Describe the types of UV light and their relevance in cancer.

Answer 4

• UVC doesn’t penetrate the stratosphere so isn’t relevant to us on the earth surface
• UVB will reach sea level
• UVA will reach dead sea level
• UVB is more significant for skin cancer development but the dose of UVB that reaches the earth surface is much lower than UVA
• UVA also has an effect on skin cancer development but to a much lesser extent than UVB
• UVA is the major cause of skin ageing
• UVA is used therapeutically to treat psoriasis with PUVA therapy

Question 5

Explain the effect of UVB and UVA.

Answer 5

• UVB directly induces abnormalities in DNA e.g. mutations
• UVB induces the formation of photoproducts(mutations) Particularly affects the pyrimidines(cytosine and thymine) - causes cross-linking
  
  • Cyclobutane pyrimidine dimers (e.g. T=T, T=C and C=C)
  • 6-4 pyrimidine pyrimidine photoproducts
• These are usually repaired quickly by nucleotide excision repair
• UVA can also promote skin carcinogenesis:
  
  • 100 times more penetrative to the Earth’s surface.
  • Major cause of skin ageing
  • Contributes to skin carcinogenesis
  • Forming cyclobutane pyrimidine dimers but less effectively than UVB
  • It also generated free radicals, which can damage DNA and the cell membrane

Question 6

What is the link between UV and skin damage?

Answer 6

• 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

Question 7

What happens in a sun burn?

Answer 7

• 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

Question 8

Explain the immunomodulatory effects of UV light.

Answer 8

• UVA and UVB affect the expression of genes involved in skin immunity
  
  • It depletes Langerhans cells in the epidermis
• This causes reduction immunocompetence and immunosurveillance
• This is the basis of using UV phototherapy to treat psoriasis - it immunocompromises the skin to the inflammatory condition gets better
• However, this does further increase the cancer causing potential of sun exposure
• Mechanism by which UV therapy increases the risk of skin cancer:
  
  • UV can act on keratinocytes and cause DNA damage that could lead to it becoming malignant cell
  • If the Langerhans cells are working properly, they will induce an immune response and cause cell death in the damaged cell
  • If the Langerhans cell have been depleted as a result of UV phototherapy, they will be unable to knock out the damaged cells and this could promote the development of cancer

Question 9

Describe the Fitzpatrick Phototypes.

Answer 9

1. Always burns, never tans
2. Usually burns, sometimes tans
3. Sometimes burns, usually tans
4. Never burns, always tans
5. Moderate constitutive pigmentation - Asian
6. Marked constitutive pigmentation - Afrocaribean

Question 10

What is the function of melanocytes?

Answer 10

• Melanocytes produce melanin 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

Question 11

What are the types of melanin?

Answer 11

• TWO types of melanin are formed:
  
  • Eumelanin- brown/black
  • Phaeomelanin- yellowish or reddish-brown
• Melanin is formed from tyrosine via the action of many enzymes
• Red heads have more phaeomelanin- this doesn’t effectively protect against sun exposure
• The relative amounts of melanin produced is regulated by the MCR1 gene
• There are >20 gene polymorphisms in this gene
• The polymorphism determines the eumelanin: phaeomelanin produced and the quantities
• Melanin dictates skin sensitivity to UV damage

Question 12

Describe melignant melanomas.

Answer 12

• Malignant tumour of melanocytes
• Melanocytes become abnormal and have atypical cells and atypical architecture
• It can be caused by:
  
  • UV exposure
  • Genetic factors
• Risk of metastasis
• This is the type of skin cancer with the highest mortality

Question 13

Describe lentigo maligna (melanoma in situ)

Answer 13

• 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 has no risk of metastasis at this stage (as it hasn’t reached the basement
• PICTURE: This is considered a premelanoma state
  
  • They normally have an irregular shape and irregular borders with light and dark brown colours
  • Usually > 2.0 cm
• Sometimes you can have a large area of lentigo maligna and then you can develop an area within it that becomes invasive - this is lentigo maligna melanoma

Question 14

Describe superficial spreading malignant melanomas.

Answer 14

• Lateral proliferation of malignant melanocytes
• They invade the basement membrane
• It is invasive and it grows outwards
• This has a risk of metastasis because the melanoma is below the basement membrane
• Diagnosis of superficial spreading malignant melanoma:
• ABCDE
  
  • Asymmetry
  • Border irregularity
  • Colour variation (dark brown-black)
  • Diameter >0.7 mm and increasing
  • Erythema
• PICTURE:
  
  • Pale area in the middle - area of regression
  • The tumour has disappeared either because it has burned itself out or the immune system has got rid of it - usually associated with a higher risk of metastasis.

Question 15

Describe nodular malignant melanomas.

Answer 15

• VERTICAL proliferation of malignant melanocytes
• There is no previous horizontal growth
• As it is growing downwards, there is a high risk of metastasis
• These can originate from pre-existing moles or they can originate de novo

Question 16

Describe Nodular melanoma arising within a superficial spreading malignant melanoma.

Answer 16

• This is a downward proliferation of malignant melanocytes that is following previous horizontal growth
• If there is a nodule growing within an irregular plaque, the prognosis will become WORSE
• Sometimes these melanomas have areas of erythema
• This is usually when the tumour has lost the ability to produce melanin so instead it begins to look erythematous

Question 17

Describe the picture.

Answer 17

• Acral Lentiginous Melanoma
• These are the melanomas that occur on the palms and soles
• These might occur in dark skin people

Question 18

Describe the picture.

Answer 18

Amelanotic Melanoma

Sometimes melanomas don’t produce pigments so it appears pink

This has also metastasised to the lymph nodes (arrow)

Question 19

Summarise the types of malignant melanomas

Answer 19

• Superficial Spreading
• Nodular
• Lentigo Maligna Melanoma
• Acral Lentiginous
• Amelanotic
• Simplified melanoma recognition:
  
  • Asymmetry
  • Border
  • Colour
  • Diameter

Question 20

Describe the prognosis of melanoma.

Answer 20

• 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

Question 21

What are the risk factors for the development of melanoma

Answer 21

Question 22

Describe the picture.

Answer 22

• 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

Question 23

Describe squamous cell carcinomas (Causes, risk, areas affected)

Answer 23

• Malignant tumour of keratinocytes
• Caused by:
  
  • UV exposure
  • HPV
  • Immunosuppression
  • May occur in scars or scarring processes
• Risk of metastasis- but not as high as in melanoma
• Immunosuppression is significant - people who have organ transplants are at high risk of getting SCCs
• PICTURE:
  
  • 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
• Often occurs on the lips – smoking is a risk factor
• On ears in men – specially on sticking out ears
• Also on genital regions

Question 24

Describe Basal cell carcinomas (causes, risks, areas affected)

Answer 24

• 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
• PICTURE:
  
  • It is pearly, it has a rolled edge and there is telangiectasia (a localised collection of distended blood capillary vessels)
  • A key feature of BCC is arborising telangiectasia - looks like branches of a tree

Question 25

Describe the picture

Answer 25

• Mycosis Fungoides
• This is a cutaneous T cell lymphoma- it specifically affects the skin
• The red patches make it look like psoriasis but if a biopsy is taken, atypical lymphocytes can be seen
• It is usually slowly progressiveover decades
• Light treatment, chemotherapy or radiotherapy = treatment

Question 26

Describe the picture

Answer 26

• Kaposi’s Sarcoma
• HIV and HHV8 associated
• It is a tumour of the endothelium of the LYMPHATICS

Question 27

describe the picture.

Answer 27

• Epidermodysplasia Verruciformis
• 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
• Sometimes these patients can develop abnormal warts on their hands and feet that become extremely keratotic (right image)