clinical oncology 3: skin cancer

Question 1

epidemiology of skin cancer:

Answer 1

• commonest cancer to affect man
• incidence is rising
• main aetiological agent is sunlight

Question 2

what are the important factors for development of skin cancer?

Answer 2

• sunlight
• ionising radiation
• viruses
• tissue scarring

Question 3

what are the most common types of skin cancer?

Answer 3

• basal cell carcinoma (most common, least deadly)
• squamous cell carcinoma
• melanoma (least common, most deadly)

Question 4

what is basal cell carcinoma?

Answer 4

tumours arise from pluripotent stem cells in epidermis

• almost always found on sun-exposed body parts
• locally destructive but rarely metastatic

Question 5

what is squamous cell carcinoma?

Answer 5

tumours arise from basal keratinocytes

• usually tumours of elderly on sun-exposed areas
• often metastatic -> spread to lymph nodes + other organs, particularly lungs
• can arise from other lesions eg solar keratoses

Question 6

what is melanoma?

Answer 6

tumours arise from epidermal melanocytes (or sometimes dermal)

• tumour of young age
• associated with intermittent, intense sun exposure
• unusually found in sun-exposed areas
• associated with systemic immunosuppression
• highly metastatic

Question 7

what are the risk factors for melanoma?

Answer 7

• family history
• presence of dysplastic naevae (abnormal moles) or >50 naevae
• childhood radiotherapy
• higher socioeconomic background (sunny holidays)
• occupational hazards eg ionising radiation of airline pilots
• frequent tanning beds
• other cancer
• transplants
• certain melanocortin-1 receptor variant alleles

Question 8

what are the 4 clinical subtypes of melanoma?

Answer 8

superficial spreading: horizontal growth phase through epidermis followed by vertical invasion

nodular: more aggressive, no horizontal growth phase

lentigo maligna: from precusor lesion of same name

acrolentigenous: start on feet/hands, tent to be due to trauma not sun exposure

Question 9

what are the 4 types of precursor lesion for melanoma?

Answer 9

• junctional / compound-acquired melanocytic naevae
• dysplastic naevae
• dermal naevae
• ginat bathin trunk naevae

Question 10

what are the types of UV light and how do they contribute to skin cancer?

Answer 10

UVA: main cause of skin agein
UVB: can’t penetrate glass -> more important than UVA
UVC: very little penetrates atmosphere so is less relevant even tho is strongest

Question 11

what interactions happen between UVB & DNA?

Answer 11

DNA acts as a chromophore for UVB -> photoproducts eg cyclobutane butane pyrimidine dimers + thymine dimers
- thymine dimers can be repaired via base excision but if damage is irreparable cell apoptoses -> sunburn (mediated by Bax protein)

Question 12

how does UVA damage DNA?

Answer 12

mainly causes indirect DNA damage by formation of xinglet oxygens + free radicals

Question 13

what are Langerhans cells?

Answer 13

specialised dendritic cells that have migrated to superbasilar layer of skin
- recognise tumour-associated antigens on skin -> present to T cells -> mutatnts killed before cancer develops

Question 14

how does Langerhans cell function change with UV exposure?

Answer 14

function decreases proportionally

Question 15

what is the Fitzpatrick classification of skin types?

Answer 15

I: always burns, never tans  
II: usually burns, sometimes tans  
III: sometimes burns, usually tans  
IV: never burns, always tans   
V: moderate constitutive pigmentation   
VI: marked constitutive pigmentation

Question 16

what does melanin do?

Answer 16

responsible for skin pigmentation

• acts as crhomophore for UV light -> absorbs UV -> provides protection for more sensitive layers of skin underneath
• also traps electrons & free radicals

Question 17

how is melanin produced?

Answer 17

from tyrosine via DOPA

Question 18

what are the types of melanin?

Answer 18

eumelanin: black/brown, insoluble, useful
phaeomelanin: yellowish-reddish brown, soluble in alkalis, useless
neuromelanin: present only in the substantia nigra of brain, function unknown
- number of melanocytes relatively constant in everyone so colour is determined by amount & type of melanin

Question 19

what are melanocortins?

Answer 19

group of peptides derived from pro-opiomelanocortin (POMC) MSH (melanocyte stimulating hormone)

• ACTH
• endorphins
• liptrophins

Question 20

what does MCIR do?

Answer 20

highly polymorphic melanocortin-1 receptor

• regulates skin & hair pigmentation phenotype
• promotes a switch from phaeomelanin to eumelanin production -> therefore alleles which don’t work as well are associated with ginger hair and hence skin cancer

Question 21

what are the 2 ways in which tanning occurs?

Answer 21

immediate: UVA -> alteration & redistribution of melanin -> making you look tanned but affording you no extra protection eg tanning booth, first day at beach
delayed: UVB increases production of melanin but effects depend on MCIR variant

Question 22

what is another effect of sun exposure?

Answer 22

epidermal thickening

Question 23

what is an epidermal melanin unit?

Answer 23

each melanocyte is associated with 36 keratinocytes

- melanocytes pass melanosomes via dendrites to keratinocytes -> phagocytose melanosome

Question 24

what is Gorlin’s syndrome?

Answer 24

development of hundreds of basal cell carcinomas on face and trunk age 10-20

• autosomal dominant
• casued by mutation of both alleles of Patched gene -> loss of suppression of Smoothened gene -> production of transcription factor that casues cell proliferation
• Patched & Smoothed gene part of sonic hedgehog pathway

Question 25

what is Xeroderma pigmentosum?

Answer 25

defective base excision repair mechanisms -> very early solar ageing & get BCCs, SCCs & melanomas before age 10 - autosomal/sex-linked recessive - usually death age 10-30

Question 26

what is epidermodysplasia verruciformis?

Answer 26

mild immunodeficiency -> skin gets infected by opportunistic HPV -> thousands of warts beofre age 10 -> develop into SCCs on UV exposure - autosomal recessive - HPV's E6 protein disrupts DNA repair following UV exposure and inactivates p53

Question 27

what is FAMM syndrome?

Answer 27

famial atypical mole/melanoma syndrome - patients have multiple dysplastic naevae -> multiple melanomas - 40-50% have CDKN2A mutation -> less p16 (a cyclin-dependent kinase inhibitor) produced -> cell proliferation

Question 28

which type of skin cancer are transplant patients more likely to get and why?

Answer 28

10x more likely to get SCC than BCC due to EV-causing HPV strains

Question 29

60% of melanomas have a ____ mutation

Answer 29

BRAF mutation - BRAF is part of Raf family of protein kinases in MAPK pathway downstream of Ras - mutation resulst in constitutive activation of BRAF without need for Ras stimulation -> cell proliferation - 90% of mutations are replacement of valine by glutamate at position 600 (BRAF V600E mutation)

Question 30

what is vemurafenib?

Answer 30

small molecule inhibitor selective for BRAV V600E mutants - taken orally - reversible - ATP-competitive

Question 31

how can immunotherapy be used to treat melanoma?

Answer 31

CTLA-4 receptor on T cells is negative regulator, important in self-tolerance to prevent autoimmunity - ipilimumab (IgG mAb to CTLA-4 receptor) removes inhibition -> T cells react better

Question 32

how can skin cancer be prevented?

Answer 32

- sun-block - sun-protective clothing - increasing public awareness of UV exposure dangers -> protective behaviour - increasing public awareness of skin cancer identification -> early diagnosis

Question 33

what does SPF mean?

Answer 33

sun protection factor = time needed in sun with sun-block before skin redness develops after 24h / time needed in sun without sun-block before skin redness develops 24h later