CANCER; Lecture 13, 14, 15 - Epidemiology of Cancer, Breast cancer, Skin cancer Flashcards
Cancer
How many new cases of cancer appear every year?
14 million -> kill approx 8 million people worldwide every year
Cancer
How many people worldwide live with cancer?
33 million - within 5y of diagnosis
Cancer
How many new cases per year of cancer will occur in 2020?
At least 16 million new cases and the number of new cases is expected to rise by 70% in the next 20 years
Cancer
What are the factors of increasing cancer burden?
Mainly due to increasing average life-span, but unhealthy lifestyle is also a major factor -> smoking (29-31%), diet (20-50%), alcohol (4-6%), infection (10-20%), occupation (2-4%), reproductive hormone (10-20%) -> reducing the same RF would lead to substantial reduction of CVD, renal, hepatic disease, diabetes and possibly some neurological diseases
Cancer
What are the 5 main forms of cancer worldwide?
Lung, stomach, liver, colorectal and breast
Cancer
Which major cancers have achieved 5-y survival rates?
In developed world for breast and prostate cancer
Cancer
Which cancers have very little development in the therapeutic progress?
Lung cancer-> little progress achieved in the last 20y
Cancer
Why are migrant studies helpful?
Extent and rate of change are informative of cancer rates in countries -> rapid change in risk following migration implies lifestyle/environment factors act late in carcinogenesis; slow change suggests exposures in early life are most relevant; persistence of rates between generation suggests genetic susceptibility is important in determining risk
Cancer
How does heredity affect types of cancer?
x
Cancer
How does smoking act as a risk factor?
x
Cancer
What are the World cancer research fund’s guidelines for dietary prevention?
x
Cancer
How does a westernised lifestyle relate to cancer?
Cancer
What are the infectious agents that can cause cancers?
Cancer
What is the breast?
Only organ that develops after birth -> during puberty the breast develops into fatty glandular structure; tubular network within the breast that comes together at the nipple
Cancer
Which parts of the breast can get cancer?
Every part of the gland, anatomically and cellularly can have some type of cancer.
Phyllodes tumour - sarcoma in fatty stromal area = very rare and aggressive
Cancer
How is the mammary gland organised?
2 layers of epithelial cells = myoepithelial cells and luminal cells. Layer of myoepithelial cells (some slightly vacuolated) seen just around the luminal cells making contact with the basement -> between tubules you have fatty stromal cells. Luminal cells are the only cell type in gland to express oestrogen receptors, but not all cells express oestrogen receptors (10-15%)
Cancer
What are myoepithelial cells?
Contractile phenotype and will contract when they receive the correct hormonal signals; very important in development of gland, responsible for formation of tubules
Cancer
What is the function of oestrogen in the breast?
Normal response is to stimulate growth; cells with oestrogen receptors don’t grow in response to oestrogen, they act as beacons to produce GF and stimulate growth of nearby cells -> breast cancer has the reversal of this effect, with oestrogen responsive cells directly responding to oestrogen as GF and stimulate own growth
Cancer
How does the cell progress from normal to malignant breast tissue?
- Benign/carcinoma in situ = proliferation of luminal cells but myoepithelium is still around (possible precancerous state);
- lobular carcinoma = tumour has some resemblance of architecture of gland;
- medullary carcinoma = tumour cells don’t look like epithelial cells from the mammary gland -> majority aren’t medullary or lobular so are just called breast carcinoma
Cancer
What are the main histological types of invasive breast cancer?
- Staining tissue samples for oestrogen receptor (ER) to classify breast tumours as ER+/- -> nuclei are stained as ER is TF in nucleus -> over 80% of breast cancers are ER+.
- NB: breast cancer growth is oestrogen-regulated
Cancer
What are the important risk factors for breast cancer?
Early age of onset of menstruation (increase exposure to oestrogens over life time), late age to menopause, age to first full term pregnancy, some contraceptive pills and some HRTs, obesity, diet
Cancer
What is the oestrogen receptor and what occurs when oestrogen binds to it?
Need to dimerise as each half of the dimer will respond to each half of the response element
Cancer
How is the ER present in breast cancer?
x
Cancer
What is the primary treatment of breast cancer?
Surgery -> Lumpectomy (minimal) or mastectomy (radical) and then followed up with radiotherapy and chemotherapy (which can also be carried out by themselves); and endocrine therapy is new(ish)
Cancer
How do we inhibit oestrogen action on breast?
- Ovarian suppression, blocking oestrogen production by enzymatic inhibition and inhibiting oestrogen responses ->
- ovaries are main oestrogen production site in premenopausal women with levels of oestrogen production depending on stage of menstrual cycle (highest at end of follicular phase) and
- post menopausal women make oestrogen through aromatisation of androgens in peripheral tissues
Cancer
What is ovarian ablation and suppression?
Ovarian ablation = eliminates source of oestrogen and can be carried out by surgical oophorectomy, ovarian irradiation BUT there are problems such as morbidity and irreversibility -> so medical ovarian ablation treatments have been produced = LHRH agonist which binds to LHRH receptors in pit. leading to downregulation of receptors and suppression of LH release and inhibition of ovarian function, including oestrogen production
Cancer
What are examples of LHRH agonists?
Goserelin Buserelin Triptorelin Leuprolide
Cancer
What are the main targets of breast cancer treatment in this diagram?
Cancer
What are oestrogens and anti-oestrogens?
Tamoxifen is ER blocker (competitive inhib); negates stimulatory effects of oestrogen causing cells to be held at G1 phase of cell cycle
Cancer
What is tamoxifen?
SERM -> oestrogenic in bone so can protect post menopausal women against osteoporosis and oestrogenic in CVS so can decrease atherosclerosis risk in women;
BUT has been evidence that tamoxifen increases risk of thromboembolic events and it can cause endometrial hyperplasia.
The treatment of choice for metastatic disease in post menopausal patients (1/3 patients respond); few side effects = hot flushes most common
Cancer
What are the main targets and effects of tamoxifen?
x
Cancer
What are some other SERMs that can be used?
Faslodex shows no oestrogen like activity but is effective in controlling oestrogen stimulated growth = pure anti-oestrogen, may offer advantages over tamoxifen by decreasing tumour cell invasion and the stimulation of occult endometrial carcinoma; Raloxifene is an antitumour agent in animals, It is an agonist in bone but has no activity in the breast or uterus, It is used in the treatment of osteoporosis in post-menopausal women
Cancer
How do anti-oestrogens affect breast cancer prevention?
Cancer
What are the types of aromatase inhibitors?
Suicide inhibitors: initially compete with natural substrate for binding to active site, enzyme specifically acts on inhibitor to yield reactive alkylating species, forming covalent bonds at/near active site of enzyme, irreversibly inactivating the enzyme (Exemestane = single dose gives major drop in plasma oestrogens with mild side effects - hot flushes, nausea, fatigue). Competitve inhibitors - bind reversibly to active site of enzyme and prevent product formation, only as long as inhibitor occupies the catalytic site (Anastrozole)
Cancer
What are progestins and what is their involvement in breast cancer?
Progesterone is dominant natural progestin; poor absorption of progesterone is overcome by synthetic derivatives of progestins -> influence both proliferation and differentiation in breast. Used in endo treatment of breast and uterine cancer with antineoplastic properties. Progestin therapy for metastatic breast cancer is a 2nd/3rd line therapy following oestrogen. Main = Megestrol acetate
Cancer
How do we inhibit oestrogen action in the breast?
Significant proportion of patients presenting with breast cancer and all patients with metastatic disease become resistant to endocrine therapy
Cancer
How do we screen for breast cancer?
x
Cancer
What are the types of breast cancer?
x
Cancer
What is the basic patient history of breast cancer?
x
Cancer
Where do postmenopausal women get their oestrogen from?
Conversion of adrenal hormones (androstenedione and conversion catalysed by aromatase enzyme complex (CYP450 heme containing protein and flavoprotein NADPH CYP450 reductase); c=aromatase catalyses 3 steroid hydroxylations in conversion of androstenedione to oestrone, metabolises androstenedione to oestrone sulfate
Cancer
What are the 5 layers of the epidermis?
- Stratum corneum
- Stratum lucidum
- Stratum granulosum
- Stratum spinosum
- Stratum basale
- Karatinocyte basal layer on basement membrane, which proliferate and move up the layers of the epidermis, differentiating and eventually ending up in the stratum corneum (layer of cells with lost nucelus, consisting of keratin)
Cancer
What are the main cell types of epidermis?
Keratinocytes
Melanocytes - sit on the basement membrane and produce melanin
Langerhans cells - APCs found within the epidermis
Merkel cells - involved in sensation
Cancer
What are the 4 types of derived skin cancers?
- Keratinocyte derived:
- Basal cell carcinoma (BCC)
- Squamous cell carcinoma (SCC)
- Collectively known 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
Cancer
What are the examples of causes of skin cancer?
- 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
- SCC
- Malignant melanoma
- Immunosuppression Drugs e.g. azathioprine, cyclosporin, HIV, Old age, Leukaemia
Cancer
What is the incidence of malignant melanoma?
it has been rising in the white population but it has remained relatively stable in other populations
There is also quite a discrepancy in the distribution of melanoma in the UK
Most cases are found on the south west coast where people tend to be in the outdoors more -> occurs mainly on trunk
Cancer
What is the incidence of basal cell carcinoma?
Rising -> due to people living longer, and having more sun exposure. Occurs mainly on face
Cancer
What is UV light?
- 100-280 = UVC, 280-310 = UVB, 310-400 = UVA.
- 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
Cancer
What is the effect of sunlight on life?
Essential for photosynthesis
Infrared spectra provide warmth
Effect on human mood
Stimulates the production of vitamin D in the skin
Cancer
What is UVB and UVA in skin cancer?
- 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 pyrimidone photoproducts
- These are usually repaired quickly by nucleotide excision repair
- UVA can also promote skin carcinogenesis: Forming cyclobutane pyrimidine dimers but less effectively than UVB
- It also generated free radicals, which can damage DNA and the cell membrane
Cancer
How does UV damage lead to skin cancer?
Leads to mutation in: Cell division DNA repair, Cell cycle arrest -> nucleotide excision repair process normally removes photoproducts
Cancer
What is 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
Cancer
Which mutations cause skin 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
Cancer
How does sunburn affect the skin?
- 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.
- 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
Cancer
What are the 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 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
- 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 a 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 cells 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
Cancer
What are the Fitzpatrick phototypes?
- Always burns, never tans
- Usually burns, sometimes tans
- Sometimes burns, usually tans
- Never burns, always tans
- Moderate constitutive pigmentation - Asian
- Marked constitutive pigmentation - Afrocaribean
Cancer
What is 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)
Cancer
What are melanocytes?
- 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
Cancer
What are the 2 types of melanin 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
Cancer
What are malignant melanomas?
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 -> type of skin cancer with highest mortality
Cancer
What is a lentigo melanoma?
- 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
- 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
Cancer
What is a superficial spreading malignant melanoma?
- 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.
- A pale area in the middle of the patch is an area of regression
- The tumour has disappeared either because it has burned itself out or the immune system has got rid of it
- This sounds good but it is actually associated with a higher risk of metastasis
Cancer
How do you diagnose superficial spreading malignant melanoma?
- Asymmetry
- Border irregularity
- Colour variation (dark brown-black)
- Diameter >0.7 mm and increasing
- Erythema
Cancer
What is a nodular malignant melanoma?
- 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
Cancer
What is a nodular melanoma arising within a superficial spreading malignant melanoma?
- 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
Cancer
What are acral lentiginous melanoma?
These are the melanomas that occur on the palms and soles
These might occur in dark skin people
Cancer
What are amelanotic melanoma?
Sometimes melanomas don’t produce pigments so it appears pink
This can also metastasise to the lymph nodes
Cancer
Summarise the types of malignant melanoma and how to classify them?
- Superficial Spreading
- Nodular
- Lentigo Maligna Melanoma
- Acral Lentiginous
- Amelanotic
- Simplified melanoma recognition:
- Asymmetry
- Border
- Colour
- Diameter
Cancer
What is the prognosis of melanomas?
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
Cancer
What are the risk factors for the development of melanoma?
NB: dysplastic nevi are moles that are slightly atypical but not melanomas
Cancer
What is a keratoacanthoma?
Thought to be benign lesion or benign version of a SCC -> grows rapidly but then disappears, with NO risk of metastasis
Cancer
What is a squamous cell carcinoma?
- Malignant tumour of keratinocytes
- caused by UV exposure, HPV, immunosuppression, may occur in scars/scarring process
- risk of metastasis (not as high as melanoma)
- well differentiated can produce a keratin horn
- women tend to get them on legs
Cancer
What is a basal cell carcinoma?
- Malignant tumour from basal layer of epidermis ->
- caused by sun exposure, genetics;
- slow growing, invade tissues but don’t metastasise,
- common on face
Cancer
What are nodular basal cell carcinomas?
Pearly, rolled edge and telangiectasia present (localised collection of distended blood capillary vessels) -> key feature of BCC is arborising telangiectasia
Cancer
What is mycosis fungoides?
Cutaneous T cell lymphoma which specifically affects the skin -> red patches makes it look like psoriasis but biopsy shows atypical lymphocytes, with slow progression over time
Cancer
What is Kaposi’s sarcoma?
Associated with HIV and HHV8 -> tumour of endothelium of lymphatics
Cancer
What is epidermodysplasia veruciformis?
Rare autosomal recessive condition that predisposes to HPV induced warts and SCCs -> extremely keratotic warts on hand and feet
