Clinical oncology Flashcards
(168 cards)
1
Q
What are the main anti-cancer modalities? (x4)
A
Surgery, radiotherapy, chemotherapy and immunotherapy.
2
Q
What are the types of cytotoxic chemotherapy? (x5) How does chemotherapy work generally?
A
Select rapidly dividing cells by targeting structures (mostly DNA) – given IV and works SYSTEMICALLY, meaning that all rapidly dividing cells are affected. Because chemotherapy cannot target only cancer cells, side effects are common. Alkylating agents. Antimetabolites. Anthracyclines. Vinca alkaloids and taxanes. Topoisomerase inhibitors.
3
Q
What are the most typical side-effects of cytotoxic chemotherapy? (x4)
A
Hair loss, bone marrow suppression (causing anaemia and neutropenia (–> neutropenic sepsis), nausea and vomiting, and tiredness.
4
Q
What approaches can be used to minimise the common side-effects of cytotoxic chemotherapy? (x3)
A
□ HAIR LOSS – scalp cooling. □ BONE MARROW SUPPRESSION – transfusions, platelets, dose reduction and GCSF (stimulates production of granulocytes to combat the effects of neutropenia). □ NAUSEA AND VOMITING – antiemetics.
5
Q
When is chemotherapy administered? (x3)
A
□ Post-operatively: adjuvant. □ Pre-operatively: neoadjuvant. □ As monotherapy or in combination with curative or palliative intent.
6
Q
What is the mechanism of action of alkylating agents in chemotherapy? Disadvantage?
A
Add alkyl groups (CnH2n+1) groups to guanine residues in DNA. This causes cross-linking between DNA strands and prevents the DNA from uncoiling at replication. Therefore, APOPTOSIS is triggered in cells at checkpoints in the cell cycle. DISADVANTAGE: They can also be oncogenic (cause secondary cancer) as they encourage mispairing (remember, mutations can cause cancer).
7
Q
What are pseudo-alkylating agents?
A
Have the same mechanism as alkylating agents but add platinum instead of alkyl groups to guanine residues in DNA. This promotes the same mechanism of cell death.
8
Q
Examples of pseudo-alkylating agents? (x3)
A
Cisplatin, carboplatin and oxaliplatin.
9
Q
Examples of alkylating agents? (x4)
A
Chlorambucil, cyclophosphamide, dacarbazine and temozolomide.
10
Q
What are the side-effects of alkylating (and pseudo-alkylating) agents? (x9)
A
Cause hair loss (though not carboplatin), nephrotoxicity, neurotoxicity, ototoxicity (toxic to ear – only in platinum alkylating agents), nausea, vomiting, diarrhoea, immunosuppression and tiredness.
11
Q
What is the mechanism of action of antimetabolites in chemotherapy?
A
Act as purine or pyrimidine residues, leading to inhibition of DNA synthesis, DNA double strand breaks, and apoptosis is triggered. They can also be folate antagonists, which inhibit dihydrofolate reductase, required to make folic acid, an important building block for all nucleic acids – especially thymine.
12
Q
What examples are there of antimetabolites? (x4)
A
Purine/pyrimidine residues: mercaptopurine, fludarabine and dacarbazine; Folate antagonists: methotrexate.
13
Q
What are the side-effects of anti-metabolites? (x8)
A
Hair loss, bone marrow suppression causing anaemia, neutropenia and thrombocytopenia, increased risk of neutropenic sepsis, nausea, vomiting, diarrhoea, Palmar-plantar erythrodysesthesia (swelling, numbness and skin peeling on palms of hands and feet), fatigue.
14
Q
What is the mechanism of action of anthracyclines in chemotherapy?
A
Inhibit transcription and replication by intercalating (inserting between) nucleotides within DNA/RNA strand. They also block DNA repair (mutagenic) and create DNA and cell membrane damaging free oxygen radicals.
15
Q
Examples of anthracyclines?
A
Doxorubicin and epirubicin.
16
Q
What are the side-effects of anthracyclines? (x7)
A
CARDIAC TOXIICITY (arrythmias, heart failure – probably due to free radicals), alopecia (spot baldness), neutropenia, nausea and vomiting, fatigue, skin changes and red urine (in doxorubicin).
17
Q
What is the mechanism of action of vinca alkaloids and taxanes in chemotherapy?
A
Work by inhibiting assembly (vina alkaloids) or disassembly (taxanes) of mitotic microtubules, causing dividing cells to undergo mitotic arrest.
18
Q
What are the side-effects of vina alkaloids and taxanes? (x6)
A
Nerve damage (peripheral and autonomic neuropathy), hair loss, nausea and vomiting, bone marrow suppression (neutropenia, anaemia etc), arthralgia (joint pain) and allergy.
19
Q
What is the mechanism of action of topoisomerase inhibitors in chemotherapy?
A
Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription, by inducing temporary single strand (topo1) or double strand (topo2) breaks in phosphodiester backbone of DNA. Inhibitors therefore affect binding of the topoisomerase to DNA, and permanent DNA breaks occur as a result.
20
Q
Examples of topoisomerase inhibitors? (x3)
A
Topotecan and irinotecan inhibit topo I; etoposide inhibits topo II.
21
Q
What are the side-effects of topoisomerase inhibitors? (x5)
A
Acute cholinergic type syndrome (diarrhoea, abdominal cramps and diaphoresis (sweating) in IRINOTECAN), hair loss, nausea and vomiting, fatigue and bone marrow suppression.
22
Q
How may cancer cells be resistant to chemotherapy drugs? (x2)
A
□ Enhanced DNA repair mechanisms: cancer cells may use PARP to remove DNA adducts. □ Enhanced pumps on cell surface which efflux chemotherapy drugs through ATP-binding cassette (ABC) transporters – preventing amount that gets into the cell and affects the DNA.
23
Q
What are targeted cancer therapies? Examples? (x4)
A
□ Non-cytotoxic therapies manipulate pathways used by cancers to exercise their functions. Targeting these pathways can disrupt cancer cells and treat cancer. □ They interfering with specific targeted molecules rather than by simply interfering with all rapidly dividing cells. In other words, they are specific (unlike chemotherapy which is systemic). □ Monoclonal antibodies. □ Small molecule inhibitors. □ Anti-sense oligonucleotides. □ RNA interference.
24
Q
Use of targeted therapies in monogenic and complex cancers?
A
In monogenic cancers, you can use targeted therapies to disrupt pathways. In complex cancers, parallel pathways (other pathways used by the cancer) are upregulated, or feedback cascades are activated, so targeted therapies DO NOT work.
25
What are dual kinase inhibitors? However?
These overcome the issues of treating complex cancers with targeted therapies: dual kinase inhibitors prevent feedback cascades. However, they increase toxicities (side-effects).
26
What happens to receptor and signalling mechanisms in some cancers – in relation to signalling cascades? (x3)
□ There is OVER-EXPRESSION OF GROWTH FACTOR RECEPTORS e.g. HER2 in breast cancer, EGFR in breast and colorectal cancers, and PDGFR in glioma (brain cancer). □ There is OVER-EXPRESSION OF LIGANDS e.g. VEGF is overexpressed in prostate, kidney and breast cancer. □ CONSTITUTIVE (LIGAND INDEPENDENT) RECEPTOR ACTIVATION e.g. EGFR in lung cancer and FGFR in head and neck cancers. □ All these mechanisms INCREASE KINASE ACTIVATION and SIGNAL AMPLIFICATION.
27
How do monoclonal antibodies target cancers?
They target the mechanisms of signalling in cells. Monoclonal antibodies work by targeting extracellular receptor components to prevent dimerization, neutralise ligand, or cause internalisation of the receptor. They may also promote an immune response via complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC).
28
How are monoclonal antibodies named? (x4)
□ -momab: derived from mouse antibodies. □ -ximab: chimeric (formed from parts of many animals). □ -zumab: humanised. □ -mumab: fully human.
29
What examples are there of monoclonal antibodies in oncology?
□ BEVACIZUMAB binds and neutralises VEGF ligand in colorectal cancer. □ CETUXIMAB targets EGFR.
30
How do small molecule inhibitors work?
Bind to kinase domain of tyrosine kinase receptors within cytoplasm, to block autophosphorylation and downstream signalling in cells. They also act on intracellular kinases which can affect cell signalling pathways too.
31
Example of small molecule inhibitors?
□ GLIVEC (IMATININB) targets BCR-Abl translocations to treat Chronic myelogenous leukaemia (CML) by targeting ATP binding regions within the kinase domain. □ Erlotinib (targets EGFR). □ Gefitinib (targets EGFR).
32
What are the advantages of targeted therapies in cancer treatment over cytotoxic therapies?
They block CANCER HALLMARKS e.g. VEGF inhibitors block blood flow to tumour (angiogenesis is a hallmark of cancer), and AKT inhibitors block apoptosis resistance mechanisms, WITHOUT the toxicity of cytotoxic agents (i.e. side-effects) – targeted therapies target the cancer; chemotherapy is more systemic and targets just rapidly dividing cells.
33
What are the advantages and disadvantages of monoclonal antibodies? (x4 and x6)
□ ADVANTAGES: specific, cause receptor internalisation, long half-life and can be labelled. □ DISADVANTAGES: risky, expensive, can cause allergies, must be administered IV, and are complex and large – meaning low tumour penetration. Susceptible to RESISTANCE.
34
What are the advantages and disadvantages of small molecule inhibitors? (x4 and x3)
□ ADVANTAGES: oral administration, cheap, small so there is good tissue penetration, can be use don heterogenic tumours (tumours that differ morphologically and phenotypically). □ DISADVANTAGES: short half-life, their targets are more pleiotropic (meaning, their targets affect multiple things) so the effects of the drug can be more wide-ranging leading to unexpected toxicities. Susceptible to RESISTANCE.
35
What are the mechanisms of resistance to targeted therapies? (x4)
□ Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively) □ Intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways) □ Intragenic mutations □ Upregulation of downstream or parallel pathways
36
How may anti-sense oligonucleotides be used in cancer treatments?
Anti-sense oligonucleotides are DNA-like molecule 17-22 nucleotides in length. They are complementary to a target gene – blocking translation of that specific mRNA sequence and recruiting RNase H to cleave the target mRNA.
37
What is the biggest obstacle to developing targeted cancer therapies?
Tumour heterogeneity - different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential.
38
What are the different prefixes to cancer TNM staging?
‘c’ is given from evidence acquired before treatment including biopsy, clinical examination, imaging, surgical exploration; ‘p’ is specific to staging from HISTOPATHOLOGIC examination; ‘y’ is staging given after chemo or radiotherapy. There are other prefixes. For example, ‘pT1, pN0, pM0’.
39
What is performed in breast cancer screening? Appearance?
Mammograms and self-assessment (e.g. women feeling for lumps on their breast). Mammograms use low-energy X-rays to assess the human breast for tumours.
40
If the mammogram screening is positive, what is performed to diagnose breast cancer?
A core biopsy is performed (needle insertion, and a core of breast tissue is removed – like removing cheese from a cheese roll). It is then sent for microscopic analysis in histopathology. A vacuum-assisted biopsy or fine needle aspiration (using local anaesthesia) can also performed depending on the clinician’s concern.
41
What would the macroscopic appearance of cancerous breast tissue be like?
Firm, white area with consistency of a ‘gritty pear’.
42
How is breast cancer classified? (x2)
Classified by histological appearance. Most breast cancer are derived from epithelium lining the DUCTS (ductal carcinoma) or the LOBULES (lobular carcinoma). Lobules produce and store milk, and release them into ducts which converge on the nipple. Can be further classified into in situ (when confined within a particular tissue compartment) or invasive (tumour invaded to surrounding tissue).
43
How is T in TNM staging assessed in breast cancer?
* T1: less than 2cm.
* T2: between 2 and 5cm.
* T3: larger than 5cm.
* (T4: if there is involvement with the chest wall, skin or it is inflammatory breast cancer.)
44
How is N in TNM staging assessed in breast cancer?
• N0: there is no metastasise to regional lymph nodes. • N1: regional lymph node metastasis present – spread to axillary nodes. • N2: tumour spread to an extent between N1 and N3. • N3: tumour spread to more distant or numerous number of nodes – infraclavicular, mammary or supraclavicular nodes.
45
What do lymph nodes look like histopathologically: normal vs. cancerous?
Germinal centres are visible in healthy lymph tissue (indicated by circles) and trabeculae (white ‘bubbles’ – extensions of the fibrous capsule of the lymph node, inside the node). In cancers, these features are not visible, and the node is enlarged.
46
What is the epidemiology of breast cancer? (x3 points)
It is the leading cause of cancer in females, accounting for 1 in 5 deaths among women from cancer. 1 in 9 women in the UK will develop the disease in their lifetime.
47
What are the trends in breast cancer incidence?
Increasing.
48
What are the trends in breast cancer mortality? Reasons for this? (x3)
Falling, despite increased incidence. This is because of early diagnosis, better chemo/radiotherapies, and emergence of hormonal therapies.
49
What is the anatomy of the breast?
Mammary gland is a modified sweat gland with lobes of glandular tissue separated by fibrous septa. Each lobe contains a lactiferous duct that dilates beneath the nipple to form a lactiferous sinus for milk lactation. The acini (alveoli/LOBULES) of the lactiferous ducts produce the milk. The suspensory ligaments (Cooper’s ligaments) are strong fibrous connective tissue.
50
What happens in the development of breast prenatally, pubertally and post-pregnancy?
1. There is no development of the mammary gland prenatally. 2. The main spurt of growth occurs at puberty and is dependent on high levels of oestrogen and progesterone produced in the ovary. 3. Post-pubertal development results in cyclical increases in ductal branching resulting in an extensive fat pad. 4. Pregnancy is characterised by branching and development of secretory acini from the terminal ductal alveoli. 5. Following weaning, the mammary gland regresses to a near pre-pregnancy state through apoptosis.
51
What type of cancer are most breast cancers?
Carcinoma – arising from epithelial cells of the lumen of ducts and lobules of the breast.
52
What is the epithelial structure of breast lactiferous ducts?
There are two epithelial layers: epithelial and myoepithelial cells. Myoepithelial cells are in contact with the basement membrane and have a contractile property – they squeeze the epithelium for the purposes of lactation.
53
What is the pathogenesis of breast tumours? Types of cancer and their incidence?
• Luminal epithelial cells proliferate within the basement membrane (carcinoma in situ and benign), so the luminal space becomes invaded. • They then break through the basement membrane to spread. There are two types: • INFILTRATING LOBULAR CARCINOMA – originate from the lobules/alveoli and retain some morphology of a tubular structure despite the absence of myoepithelial cells. This accounts for 5-15% of breast cancers. • INFILTRATING DUCTAL CARCINOMA – they show no special histological structure, and account for 80% of breast cancers.
54
How are antibodies used in histopathology of breast cancer? Why is this used?
Immunohistochemical staining using antibodies against the Human Oestrogen Receptor (ER) is used to determine whether the cancer has oestrogen receptors. Over 80% are oestrogen-receptor positive – where there are oestrogen receptors, hormonal therapy can help treat the cancer.
55
What is the effect of oestrogen receptor (ER) activation (by oestrogen) in the breast? Mechanism?
1. Oestrogen receptor is a monomeric protein found in cytoplasm, bound to hsp90 protein.
2. The ligand, oestrogen is able to get across cell membranes because it is lipophilic. The oestrogen binds to the ER and the hsp90 protein is removed.
3. ER can now bind to another ER (which is also bound to oestrogen), creating a dimeric receptor.
4. The dimeric receptor-ligand complex moves to the nucleus and binds to specific DNA binding sites called OESTROGEN RESPONSE ELEMENTS (specific sequences before target genes). The complex is a transcription factor.
5. There are changes in gene expression which INCREASE cell proliferation, resulting in breast cancer.
56
What are the gene products of oestrogen receptor activation? (x4)
Progesterone receptor upregulation (sensitise cells to progesterone), Cyclin D1, c-Myc and TGF-alpha (involved in regulation of cell cycle and prevents apoptosis).
57
What are the treatment approaches to breast cancer? (x4)
Surgery, radiation therapy, chemotherapy and endocrine therapy.
58
What is the treatment regime in breast cancer in relation to the treatment approaches listed? (x2 types)
• Surgery is the first-line treatment in cancers. • Chemo/radio/endocrine therapies are used as adjuvants, post-operatively, to remove any other cancer cells (in case of metastases). • Chemo/radio/endocrine therapies are used as neo-adjuvants (when treatment is used before surgery) in a small number of cases, when tumours are large. Aim of the neo-adjuvant therapy is to reduce tumour size so it becomes more operable. This is becoming less common because of early detection.
59
What are the options in surgical treatment of breast cancer? (x2)
Mastectomy (removal or breast) and lumpectomy (surgery to remove tumour and a small amount of normal breast tissue to conserve the breast). During each type of surgery, one or more nearby lymph nodes are also removed to see if caner cells have spread to the lymphatic system.
60
What are the types of endocrine therapies in breast cancer? (x3)
• Ovarian suppression. • Blocking oestrogen production by enzymatic inhibition. • Inhibiting oestrogen responses.
61
How is the breast hormonally controlled? (x3 pathways) !
1. Hypothalamus produces LHRH which acts on the pituitary gland which produces FSH and LH. These stimulate the ovary to produce oestrogen and progesterone. Oestrogen and progesterone act on many tissues, including the breast.
2. Pituitary also produces ACTH which acts on the adrenal glands. The adrenal glands are subsequently stimulated to produce androgens. Androgens (androstenedione and testosterone) from the adrenals can be converted into oestrogens PERIPHERALLY by aromatisation (aromatase). This occurs particularly in fatty tissue – remember, breast is a fatty organ! The hormone produced is ESTRONE (E2), not oestrogen. Adrenal glands can also produce progesterone from ACTH stimulation, which can act on breast tissue.
3. Pituitary gland is stimulated to produce prolactin and growth hormone which can act on breast.
62
What is ovarian ablation? (x3 procedures) In what type of women is this treatment mostly recommended (highlighted in capitals in first bullet points)? Disadvantage of two of these procedures? !
• This is ovarian suppression and used in PRE-MENOPAUSAL women when the ovary is the major source of oestrogen biosynthesis. Procedures include: • SURGICAL OOPHRORECTOMY (removal of ovaries) • OVARIAN IRRADIATION (using radiation to destroy key cells in the ovary that manufacture oestrogen). • However, these procedures are irreversible (this is significant because pre-menopausal women are of child-bearing age – these procedures eliminate the possibility of becoming pregnant). There are now REVERSIBLE ovarian ablation therapies too: • Block production of FSH and LH in the pituitary (and therefore inhibit stimulation of oestrogen and progesterone in the ovaries). This is produced by using an LHRH AGONIST (this seems paradoxical because agonist will increase the stimulation of the pituitary to produce FSH and LH. However, the mechanism is as follows: LHRH agonist binds to LHRH receptors in the pituitary leading to over-production. This results in negative feedback on the pituitary and receptor down-regulation and suppression of LH and FSH release --\> inhibition of ovarian function, including oestrogen production). • When this procedure is stopped, women regain their fertility.
63
What examples are there of LHRH agonists? (x2)
Goserelin and Buserelin.
64
What are agonists and antagonists?
Agonists occupy receptors and activate them; antagonists block receptors and prevent from activation.
65
How are oestrogen responses inhibited?
ANTI-OESTROGENS e.g. Tamoxifen, competitively inhibit oestrogen by binding to ERs (antagonists) – binding ERs blocks stimulation of transcription. Blocking the ER in this way causes the cell to be held at the G1 phase of the cell cycle and prevents oestrogen’s pro-proliferative effects.
66
When is Tamoxifen used? (x2)
Tamoxifen is the endocrine treatment of choice for metastatic disease in post-menopausal women. Tamoxifen also PREVENTS development of breast cancer: NICE recommends that Tamoxifen be used in high-risk groups e.g. where there is family history, for prophylaxis.
67
Why is use of Tamoxifen desirable in post-menopausal women? (x3)
• There are few side-effects, with hot flushes being most common during therapy. • Tamoxifen is a selective oestrogen receptor modulator (SERM). This means that it is an oestrogen antagonist in only CERTAIN TISSUES. • Oestrogen is important in maintaining bone mass, and antioestrogens have the potential therefore, to precipitate premature osteoporosis. Tamoxifen, however, is an antagonist in the breast but an AGONIST in bone and therefore has oestrogenic effect in bone and continues to protect from osteoporosis. • Oestrogen is important in preventing atherosclerosis (lowering LDL and increasing HDL). Antioestrogens have the potential therefore, to precipitate premature osteoporosis. Tamoxifen, however, is an antagonist in the breast but has oestrogenic effects on the CVS and continues to protect from CVD post-menopause.
68
What are the undesirable effects of Tamoxifen? (x4)
• Tamoxifen also has oestrogenic (agonistic) effects that increases risk of thromboembolism. • Promotes endometrial thickening, hyperplasia and uterine fibroids (benign tumour of uterus) long-term. This can lead to endometrial cancer. • Increases cataracts. • Increases vasomotor symptoms such as flush.
69
How is oestrogen production blocked by enzymatic inhibition? In what women is this treatment recommended (highlighted in capitals in first bullet points)? What are the two types of drug? Example of each?
• In POST-MENOPAUSAL women, the major source of oestrogen derives from aromatisation of androgens (androstenedione and testosterone) to ESTRONE in peripheral sites such as fat, liver and muscle. • Blocking aromatase enzyme complex – AROMATASE INHIBITORS – therefore prevents this process. Aromatase consists of a complex containing cytochrome P450 heme containing protein, and the flavoprotein NADPH cytochrome P450 reductase. • Drugs bind to the androgen active site (which contains heme group). There are two types of inhibitor: IRREVERSIBLE (called Type 1), and competitive, REVERSIBLE (called Type 2) inhibitors. • Irreversible: Exomestane; Reversible: Anastrozole. • Inhibitors SUPPRESS PLASMA OESTROGEN LEVELS, so tumours are not stimulated to grow.
70
What is the effect of progesterone on breast cancer?
Progesterone is a NATURAL PROGESTIN. It’s response in breast tissue is complex, but influences both proliferation AND differentiation of breast cells --\> increases risk of cancer.
71
What is progestin therapy in breast cancer? How does it work? Example?
Synthetic PROGESTINS are agonists and mimic progesterone. They overstimulate breast cells, leading to negative feedback and reduced expression of progesterone receptors in breast tissue e.g. Megestrol acetate.
72
What is the problem with endocrine therapy in breast cancer patients?
A significant proportion of patients presenting with breast cancer and, all patients with metastatic disease become resistant to endocrine therapies, even though most cases continue to demonstrate estrogen responses and contain estrogen receptor.
73
How do you tackle endocrine therapy resistance? Note about difference between pre- and post-menopausal women?
When ER-positive cancer patients relapse with metastatic disease/endocrine resistance, you use another endocrine therapy – continue this until you run out of therapies. This obviously becomes more difficult for post-menopausal women whom ovarian ablation treatments do not work.
74
What are the risk factors of breast cancer? (x5)
• Early age of onset of menstruation – means oestrogen exposure start earlier. • Late age of menopause – means extended exposure to oestrogen. • Increased age at first full-term pregnancy. • HRT. • Obesity – there is more fat tissue for peripheral conversion of androgens to oestrogen.
75
What is the effect of oestrogen withdrawal in ER-positive ER-negative breast cancers?
70% of ER-positive cancers respond. 5-10% of ER-negative cancers also respond.
76
What is the incidence of colorectal cancer? (x2 points)
4th most common cancer in the work and second leading cause of cancer death, behind lungs.
77
Where is incidence of colorectal cancer highest?
High in US, Eastern Europe and Australia. Low in Japan, Mexico and Africa.
78
What age is colorectal cancer incidence most common?
Aged between 50 and 80.
79
What are the causes of colorectal cancer? (x4)
• Genetic predisposition. • Dietary factors: high fat, low fibre, high red meats, refined carbohydrates and carcinogens are found in certain foods e.g. meats cooked at high temperatures produce carcinogen heterocyclic amines (HCAs). • Old age. • Smoking.
80
What are the functions of the colon? (x3)
• Extraction of water from faeces (electrolyte balance). • Faecal reservoir (evolutionary advantage). • Bacterial digestion for vitamins such as B and K.
81
What is the mucosal organisation of the colon?
Arranged in CRYPTS OF LIEBERKUHN. Epithelial cells are proliferating and differentiating from the base of the crypt from stem cells. The epithelium contains goblet cells (produces mucins) for lubrication and innate host defence, ECM and endocrine cells. Mesenchymal cells are the support cells which holds everything in place.
82
Colon epithelium is v. proliferative: How do we minimise risk of mutation and cancers? (x3)
Natural loss of the defective cell through the constant turnover of epithelium; DNA monitors; repair enzymes when things do go wrong.
83
What is the screening test used to detect bowel cancer? (x2)
• BLOOD in stool: because colorectal cancers and polyps can bleed. • SIGMOIDOSCOPY: most colorectal cancers are located in the sigmoid colon. NB: colonoscopy is not included in screening, though it is a test.
84
Why may blood in stool not be indicative of colorectal cancer?
Blood can be caused by other causes including haemorrhoids, gastric and duodenal ulcers and inflammatory bowel disease.
85
What is done if the colorectal screening programme comes tests positive?
Full length colonoscopy (in 60-75 year olds) or sigmoidoscopy (in 55-60 year olds).
86
What are bowel polyps?
Bowel polyps are small growths on the inner lining of large intestine (or other hollow spaces).
87
What are the different types of bowel polyp? (x4)
• HYPERPLASTIC (there is no malignant potential). • INFLAMMATORY (polyps associated with inflammatory conditions such as IBD). • NEOPLASTIC (cells have lost normal differentiation and can be benign (adenomatous) or malignant). • HAMARTOMATOUS (tumours that grow at normal rate but contain mucus-filled glands and abundant connective tissue. There is a chance of malignancy. They arise from faulty development).
88
What happens when polyps are identified in patients?
Polyps are resected, tattooed and sent to histopathologists for examination.
89
What is the difference between adenoma and adenocarcinoma?
Adenoma = dysplasia of epithelial tissue i.e. it is a benign neoplasm of mucosal epithelial cells; adenocarcinoma = cancerous.
90
What are the three types of colon adenoma? Histopathology of each? !
* TUBULAR: columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity. There is increased proliferative activity, and reduced differentiation (looks less like original cell). Disorganisation is greater. Tend to be pedunculated.
* VILLOUS: mucinous cells with nuclear enlargement, elongation, multilayering and loss of polarity. Proliferation is exophytic – grows outwards. Rarely, they may have hypersecretory function resulting in excess mucus discharge and hypokalaemia (you lose potassium into the colon). Tend not to be pedunculated.
* TUBULOVILLOUS (both characteristics).
* See photo – left side is tubular, and right side is villous.
91
What does reduced (or poorly) and increased differentiation mean?
Reduced means that cell looks less like original cell.
92
What are the two different shapes for adenoma polyps?
PEDUNCULATED adenoma – has a head, neck and stalk (these are easier to resect); SESSILE adenoma – these are flat and harder to resect.
93
When histopathologists study a polyp, how do they examine polyp and determine cancer? !!!
* Look for disorganised cell organisation – tells us could be adenoma/adenocarcinoma.
* Larger NUCLEO:CYTOPLASMIC ratio, so tissue looks DARKER. This indicates dysplasia (abnormal cell growth/development) which is characteristic of adenoma and adenocarcinoma polyp. Dysplasia rules out inflammatory polyp.
* LARGE polyp = higher risk of malignancy.
* Check for whether it has been completely excised – identified if there is normal mucosa at the base of the excision.
* Staging and grading if bowel cancer is determined.
* Adenoma is classified into TUBULAR (tube-like shape), VILLOUS (velvety or cauliflower-like in appearance) or TUBULOVILLOUS (both characteristics).
94
How is dysplasia in a bowel polyp assessed? What is the criterion for cancer diagnosis?
Polyp is determined as having LOW-GRADE or HIGH-GRADE dysplasia. High grade dysplasia is one of the criterions for bowel cancer diagnosis.
95
What is adenomatous polyposis coli?
Also called APC or FAP occurs from mutation in the 5q21 gene – resulting in loss of epithelial adhesion, so epithelium becomes hyperproliferative and patient develops thousands of polyps.
96
What is the epidemiology of colonic adenomas? In relation to cancer?
25% of adults have adenomas at age 50; 5% become cancers if left.
97
What is the classic genetic progression from colonic adenoma to adenocarcinoma? !!!
1. NORMAL COLON: There are two pathways that begin the genetic predisposition to adenoma-carcinoma development in the colon: (1) mutation in the APC gene (FAP pathway), and (2) microsatellite instability (in MSH2 genes, for example – HNPCC pathway). In these pathways, the mutations are just a ‘first hit’, and therefore don’t manifest into an adenoma; they simply PREDISPOSE cancer.
2. MUCOSA AT RISK: from methylation abnormalities and inactivation of normal alleles – this is the ‘second hit’.
3. ADENOMAS: these develop from protooncogene mutation in K-ras gene and homozygous loss of additional tumour suppressor genes such as p53.
4. ADENOCARCINOMAS: develop after many gene mutations or gross chromosomal alterations.
5. THIS IS THE ADENOMA-CARCINOMA SEQUENCE.
98
What is microsatellite instability?
Microsatellites are areas of the genome where short sequences of DNA are repeated. In microsatellite instability, these repeat sequences are mutated. This is common on colorectal cancer, and results in defective ability to correct mistakes that occur when DNA is copied.
99
What is the clinical presentation of bowel cancer? (x8)
CHANGE IN BOWEL HABIT, BLEEDING, UNEXPLAINED IRON DEFICIENCY ANAEMIA, bloating, cramps, weight loss, fatigue and mucus post-rectally.
100
Where in the colorectum do colorectal cancers present? Percentage incidence in each area? (x4)
• CAECUM/ASCENDING COLON: 22%. • TRANSVERSE COLON: 11%. • DESCENDING COLON: 6%. • RECTOSIGMOID: 55%.
101
Between stage and grade, which is most important in the assessment of cancer prognosis? Why?
Stage – stage assesses spread; grade assesses the tumour.
102
How are cancers staged?
Using TNM staging: T describes size of the primary TUMOUR and whether it has invaded nearby tissue; N describes nearby lymph NODES involved; M describes distant METASTASIS.
103
How is T of the TNM staging system in colon cancer assessed?
* Tx: tumour cannot be assessed.
* T0: no evidence of tumour.
* T1: tumour invades submucosa.
* T2: tumour invades muscularis propria.
* T3: tumour invades through muscularis propria into subserosa.
* T4: tumour directly invades other organs or structures or perforates the visceral peritoneum.
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What is the T-staging for the following sample?
This is difficult. The darker pink is muscularis propria. There is SOME invasion past the muscularis in the middle part of the picture – hence, this is T3.
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What is Duke’s staging in colon cancer?
A classification system for colorectal cancer not used anymore. Replaced by TNM. Ranked from A to C – where A indicates growth limited to mucosa/submucosa, B indicates invasion into/beyond muscularis propria, and C denotes spread to lymph nodes.
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How is N of the TNM staging system in colon cancer assessed?
• Nx: lymph nodes cannot be assessed. • N0: no regional lymph node metastasis. • N1: regional lymph node metastasis present – spread to closest or small number of nodes. • N2: tumour spread to an extent between N1 and N3. • N3: tumour spread to more distant or numerous number of nodes.
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How is the M of the TNM staging system in colon cancer assessed?
M0: no distant metastasis; M1: metastasis to distant organs BEYOND REGIONAL LYMPH NODES.
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What does cancer grading assess?
The degree of differentiation of a cell from its primary appearance. Graded from G1-G4 where G4 implies that the cancer has high grade dysplasia. Remember that when something is ‘well differentiated’, it resembles normal colonic epithelium, and when something is ‘poorly differentiated’, it does not resemble normal colonic epithelium.
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Who is screened for colon cancer? (x1 point + x5 criterion)
• Offered every two years to men and women between the ages of 60 and 74. • Screening is also given to patients if: • Patients have had a previous adenoma. • 1st degree relative affected by colorectal cancer, especially before age of 45. • 2nd affected first degree relative. • Evidence of dominant familial cancer trait including colorectal and uterine cancers. • UC and Crohn’s disease patients.
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What are the layers of human skin?
Look at photo.
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What is the structure of the epidermis?
Made up of four cell types: keratinocytes, melanocytes, Merkel cells (or tactile cells) and dendritic cells. Keratinocytes proliferate in the stratum basale and migrate up and mature: they ascend through the stratum spinosum, granulosum, lucidum and corneum where they flake. Keratinocytes are found closest to the skin surface, so are most susceptible to damage from UV radiation.
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What are the three common skin cancers? Appearance of each?
* BASAL-CELL CARCINOMA: Malignant tumour arising from keratinocytes in the basal layer of epidermis. It is slow-growing and invades tissue but does not metastasise. They are common face, and look pearly (glistens, pink-grey colour) with telangiectasia (dilated blood capillaries).
* SQUAMOUS-CELL SKIN CARCINOMA: from the squamous keratinocytes of the epidermis. Common in sun-exposed areas such as lips, face, ears and women’s legs.
* MALIGNANT MELANOMA: cancer of melanocytes. Looks dark, irregular border and asymmetrical.
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What is Bowen’s Disease?
It is squamous-cell carcinoma IN SITU of the skin – not invaded the basement membrane.
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What are the causes of skin cancer?
• Genetic syndromes such as Gorlin’s syndrome and xeroderma pigmentosum. • Viral infections such as HHV8 (herpes) in Kaposi’s sarcoma and HPV in squamous cell skin carcinomas. • UV light. • Immunosuppression e.g. drugs, HIV and old age.
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What is the incidence of malignant melanoma among different ethnicities?
Incidence has been increasing among white people. Incidence in black, Asian and Hispanics has stayed low.
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What are the types of UV radiation, and what is the nature of our exposure to them?
* UVC (wavelength 100-280nm): blocked by the ozone layer (the stratosphere).
* UVB (280-310nm): reaches earth but does not penetrate beyond sea surface.
* UVA (310-400nm): able to penetrate sea.
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What is the relative contribution of each UV radiation type to skin cancer?
UVB is the most important wavelength in skin carcinogenesis; 100x more UVA reaches the Earth’s surface than UVB but is not the most important contributor to skin carcinogenesis – however, because of its higher presence and deeper penetration, it is the major cause of skin ageing.
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What mutations cause skin cancer?
• Mutations that stimulate UNCONTROLLED CELL PROLIFERATION such as abolishing the control of the normal cell cycle (p53 gene). • Mutations that alter responses to GROWTH stimulating/repressing FACTORS. • Mutations that inhibit APOPTOSIS.
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What is the mechanism of sunburn?
UV leads to keratinocyte cell apoptosis – therefore, sun burnt cells are apoptotic cells in UV overexposed skin. Apoptosis removes UV damaged cells in the skin which might otherwise become cancer cells.
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What is the mechanism of photocarcinogenesis?
Upon exposure to UV light, skin cell accumulates mutations in the cell. The cell either becomes (i) cancerous as a result, (ii) the DNA mutations are repaired, or (iii) damage is too severe that the cell is put into apoptosis.
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What are the immunomodulatory effects of UV light?
There are dendritic cells in the dermis and dendritic cells called Langerhans cells in the epidermis, involved in skin immunity. UVA and UVB effects expression of genes involved in skin immunity and depletes the numbers of these dendritic cells. This leads to immunosuppression and contributes to the development of skin cancer (and is the basis of UV phototherapy for inflammatory skin conditions such as psoriasis).
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What is the role of melanin? Source?
Responsible for skin colour, protects nucleus from damage by UV, and produced from tyrosine by melanocytes. Skin colour does not depend on the number of melanocytes; it depends on the amount and type of melanin produced.
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How is melanin produced and deposited in skin?
There is a baseline exposure of melanin. After UV exposure, keratinocytes send out paracrine messages (Melanocyte-stimulating hormone), stimulating melanocytes to upregulate production of melanin. Melanin is then sent to keratinocytes using the processes of the melanocyte cells and packaged into vesicles called melanosomes. Melanosomes are arranged around the nucleus of keratinocytes to protect from UV-mediated damage to DNA.
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What are the two types of melanin?
Eumelanin (is brown – leading to brown pigmentation), and phaeomelanin (is yellow/red-brown
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What gene controls the production of melanin? Different melanin types?
MCR1 gene – has over 20 polymorphisms that result in variation in eumelanin:phaeomelanin production. Lighter skin/hair people will produce higher proportions of phaeomelanin.
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What are the different types of malignant melanoma? What do they look like? (x7)
* LENTIGO MALIGNA – melanoma in situ; proliferation of melanocytes within the epidermis. They are flat, light and dark brown patches, with irregular edges.
* LENTIGO MALIGNA MELANOMA – where lentigo maligna has invaded local tissue.
* SUPERFICIAL SPREADING MALIGNANT MELANOMA – lateral proliferation of malignant melanocytes that invade basement membrane. There is a risk of metastasise. They look very dark, asymmetrical, and have irregular borders. They are \>0.7mm and associated with erythema (redness of surrounding skin).
* NODULAR MALIGNANT MELANOMA – vertical proliferation of malignant melanocytes. Risk of metastasis. They look very dark and characterised by a lump.
* NODULAR MELANOMA ARISING WITHIN A SUPERFICIAL SPREADING MELANOMA – downward proliferation of malignant melanocytes, following previous horizontal growth. A nodule therefore develops within an irregular plaque, and prognosis will become progressively worse.
* ACRAL LENTIGINOUS MELANOMA – melanoma that appears on the palms of hands or feet.
* AMELANOTIC MELANOMA – where melanoma is non-pigmented.
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How is prognosis of melanoma assessed?
Depth of invasion of the malignant cells: measured from the granular later of the epidermis, to the bottom of the tumour.
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What are the risk factors of melanoma? (x4)
• Family history. • UV radiation. • Sunburn on particularly pale skin. • Skin type I or II (these are pale skin, red/fair coloured hair type-people).
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What is keratoacanthoma?
Type of SCC which grows rapidly and ‘erupts’, then involutes and disappears.
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What are the causes of SCC (squamous cell carcinoma)? (x4)
UV exposure, HPV, Immunosuppression and may occur in scars.
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What does a well-differentiated SCC look like?
A lump on the skin has a ‘horn’ of keratin growing out of the lump. This is because keratinocytes produce their own keratin. Poorly differentiated SCCs will not have an associated keratin ‘horn’.
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What are the causes of basal cell carcinoma? (x2)
Sun exposure and genetics.
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What is Epidermodysplasia veruciformis?
Rare autosomal recessive condition with predisposition to HPV-induced warts and squamous cell carcinomas – condition associated with high risk of skin cancer.
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What is the role of p53 in relation to skin cancer?
p53 is a transcription factor responsible for programmed cell death. It stimulates expression of the Bax gene which initiates this apoptosis pathway. Mutations in p53 results in loss of DNA damage-activated pathway of apoptosis, so mutations are permitted to accumulate in cells and cause skin cancer.
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What is the role of HPV in SCC?
HPV may cause epidermodysplasia verrucifomis which causes the overproduction of keratin in keratinocytes resulting in lesions resembling warts which ultimately transform into SCC.
136
What is leukaemia?
Cancer of the blood involving the BONE MARROW.
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What is the pathophysiology of leukaemia?
Results from a series of mutations in a single lymphoid or myeloid stem cell. These mutations lead to cells showing abnormalities in proliferation, differentiation or survival, leading to steady expansion of the LEUKEMIC CLONE. Disease is characterised by (i) proliferation of leukemic cells (ii) loss of function of normal cells.
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What are myeloid and lymphoid stem cells?
Myeloid and lymphoid stem cells are derived from pluripotential HAEMATOPOIETIC STEM CELLS. Myeloid stem cells give rise to erythroblasts, megakaryocytes, myeloblasts (differentiated into granulocytes) and monoblasts. Lymphoid stem cells give rise to Pre-B and Pro-T lymphocytes.
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What cells can be involved in leukaemia? (x5)
Pluripotential haematopoietic stem cells, myeloid stem cells, lymphoid stem cells, Pre-B lymphocytes and/or Pro-T lymphocytes.
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Why is leukaemia different from other cancers? (x4)
• Most cancers exist as solid tumours. In leukaemia, solid tumours are uncommon: More often, they have leukemic cells replacing normal bone marrow cells and circulating freely in the blood. • Haemopoietic and lymphoid cells behave differently from other body cells: normal haemopoietic stem cells can circulate in the blood and both the stem cells and cells derived from them can enter tissues. • The concepts of invasion and metastasis cannot be applied to leukaemia. • The concepts of benign and malignant cannot be used.
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How is leukaemia classified? (x4)
• Leukaemia that behaves in a ‘benign’ manner are called CHRONIC (means the disease goes on for a long time); OR leukaemia that behaves in a ‘malignant’ manner are called ACUTE (means that, if not treated, the disease is very aggressive). • Depending on the cell of origin, it can also be LYMPHOID (B or T lineage) or MYELOID (can be any combination of granulocytic, monocytic, erythroid or megakaryocytic). • THEREFORE, the following classifications are: Acute lymphoBLASTIC leukaemia (ALL), Acute myeloid leukaemia (AML), Chronic lymphoCYTIC leukaemia (CLL) and Chronic myeloid leukaemia (CML). NB: lymphoblastic and lymphocytic.
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What are the causes of leukaemia? (x4 and x4)
• INHERITED causes include: Down’s syndrome, Chromosomal fragility syndromes, defects in DNA repair and inherited defects of tumour-suppressor genes. • IDENTIFIABLE causes include: Irradiation, Anti-cancer drugs, cigarette smoking and chemicals such as benzene.
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What is the difference between pathophysiology of acute and chronic myeloid leukaemia? !!!
* In AML, cells continue to proliferate but they no longer mature, so there is (i) build-up of the most immature cells in the bone marrow – the MYELOBLASTS or ‘blast cells’; and (ii) a failure of production of normal and functioning end cells such as neutrophils, monocytes, erythrocytes and platelets.
* Platelets may be reduced in AML because of the cancer, but also because some types of AML are associated with DIC, so the platelets are depleted from overuse too.
* In CML, cell kinetics and function are not as seriously affected as in AML. In CML, the cell becomes independent of external signals, there are alterations in the interaction with stroma, and there is reduced apoptosis so that the cell survives longer, and the leukemic clone expands progressively.
* SUMMARY: in AML there is a failure of production of end cells, in CML there is increased production of end cells.
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How do the genetics of acute and chronic myeloid leukaemia differ?
• In AML, the responsible mutations usually affect TRANSCRIPTION FACTORS. Cell behaviour is therefore profoundly disturbed. • In CML, the responsible mutations usually affect a gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus e.g. membrane receptor or cytoplasmic protein. This links to the pathophysiology that has already been mentioned!
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What is the difference between the pathophysiology of acute and chronic lymphoid leukaemia?
• ALL has an increase in very immature cells – lymphoblasts (abnormal, immature cell resembling a large lymphocyte) – with a failure of these to develop into mature T and B cells. • In CLL, the leukemic cells are mature, although T and B cells are abnormal.
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How does leukaemia cause its clinical features? (x10) !!!
* Accumulation of abnormal cells lead to LEUCOCYTOSIS (increased WBC count).
* If there is rapid proliferation of cells within the bones (if leukaemia is acute), then patients can experience BONE PAIN – where cells are produced in the marrow.
* HEPATOMEGALY and SPLENOMEGALY because there are increased number of leukemic cells circulating in the blood and therefore increased number entering tissues --\> causes inflammation. Inflammation common in GUMS too. LYMPHADENOPATHY occurs if the leukaemia is lymphoid.
* THYMIC ENLARGMENT in leukaemia diseases that affect T lymphoid – because thymus is site of T lymphocyte maturation – occurs from accumulation of abnormal cells (seen as an enlarged cardiac shadow in a CXR).
* Increased number of circulating abnormal cells may also cause skin infiltration, leading to PAPULAR LESIONS and LEUKAEMIA CUTIS (see photo).
* Increased breakdown of DNA from dying leukemic cells leads to HYPERURICAEMIA (uric acid) – this can lead to RENAL FAILURE.
* WEIGHT LOSS because increased proliferation requires energy.
* LOW GRADE FEVER and SWEATING from increased metabolic demands from proliferation.
* Increased number of abnormal cells crowds out the normal cells, leading to ANAEMIA, THROMBOCYTOPENIA (manifests as small haemorrhages and bruises across skin) and NEUTROPENIA.
* Loss of IMMUNE FUNCTION from loss of normal T and B cell function – a feature of CLL.
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What is the epidemiology of ALL?
A disease largely of children – incidence is highest between 3 and 4 years.
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What are the risk factors of ALL that arise from epidemiological studies? (x3)
• Delayed exposure to common pathogens in early life – linked to B-lineage ALL. • Small family size. • Working class origin less of risk – possibly because early exposure to pathogens seems to be protective.
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What are the clinical features of ALL? (x6 and x8)
RESULTING FROM ACCCUMULATION OF ABNORMAL CELLS: Bone pain, hepatomegaly, splenomegaly, lymphadenopathy, thymic enlargement, testicular enlargement; RESULTING FROM CROWDING OUT OF NORMAL CELLS: fatigue, lethargy, pallor (pale), breathlessness (caused by anaemia), fever (from neutropenia) and bruising, petechiae and bleeding (from thrombocytopenia).
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What are the haematological features of ALL? (x5)
* LEUCOCYTOSIS from lymphoblasts in the blood – see photo.
* Anaemia (normocytic, because it comes as a result of crowding out of normal cells).
* Neutropenia (low neutrophil count).
* Thrombocytopenia.
* Replacement of normal bone marrow cells with lymphoblasts.
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What are the genetics of ALL? (x4)
• Can occur from a whole range of genetic mechanisms. The mechanism that causes ALL determines the disease phenotype including the prognosis. • HYPERDIPLOIDY (having more than two chromosomes in each pair) is one mechanism: GOOD prognosis. • Chromosomal TRANSLOCATION between Chromosomes 4 and 11: gives rise to a fusion gene (the creation of a novel gene) – POOR prognosis. • Dysregulation of a proto-oncogene, when translocation brings it under the influence of a promoter or enhancer of another gene. • Point mutation in a proto-oncogene.
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How is ALL treated? (x3)
• Supportive therapies such as RBC and platelet infusions, and antibiotics when immune system is compromised. • Systemic chemotherapy. • Intrathecal chemotherapy – injecting into CSF, because systemic chemotherapy techniques are not very good at crossing the BBB and accessing the CSF. Yet, abnormal cells can enter the CSF.
153
What is the epidemiology of prostate cancer? (x2 points)
It has the highest incidence of any cancer in England and is the second largest cause of cancer-related deaths in men after lung cancer.
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What are the clinical features of prostate cancer? (x4)
• Difficulty urinating. • Increased frequency of urination. • Lower back pain (as metastatic prostate cancer commonly spreads to the bones of the abdomen and local lymph nodes). • Blood in the urine.
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What are the causes of prostate cancer? (x2)
• GENETIC: heterogenous. Mostly, the androgen-signalling pathway appears to be disrupted, as well as inactivation of the tumour suppressor gene PTEN. • Infection or inflammation of the prostate.
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What is the role of the prostate?
Provides components of the seminal fluid and is important in fertility.
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What happens to the prostate with age?
There is benign prostatic hyperplasia which can lead to problems with urination as the prostate surrounds to urethra.
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How is prostate cancer examined and investigated? No details needed in this flashcard.
1. DIGITAL RECTAL EXAM to feel for irregularities and enlargement. 2. PSA TESTING from peripheral blood. 3. BIOPSY, called TRUS biopsy. 4. MRI. 5. TREATMENT.
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What is PSA testing for prostate cancer?
PSA (prostate specific antigen) is a component of the seminal fluid and normally, the epithelial cell junctions, the basal cell layer and basement membrane prevent PSA entering the tissue and blood serum. Therefore, any damage to the prostate results in PSA entering the blood.
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What is the problem with PSA testing? (x3)
• PSA can rise in the blood for a number of different reasons such as cancer and infection. A rise in PSA levels in the blood can therefore NOT distinguish between damage due to malignant disease or benign disease. • PSA also rises with age as a result of benign prostatic hyperplasia, so cannot distinguish between disease-causing and age-associated increase in serum PSA. • Once a raised PSA is measured, men will have to undergo invasive biopsy testing – though most with raised PSA don’t have prostate cancer. These FALSE POSITIVES leave otherwise healthy men anxious that they may have cancer until the biopsy has been performed.
161
How is a biopsy used to assess prostate cancer?
Called TRUS biopsy (transrectal ultrasound – as guided with ultrasound). 10 core biopsies are taken of the prostate through the intestinal wall. The prostate is then graded using the GLEASON GRADING SYSTEM.
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What are the risks of biopsy in prostate cancer? (x2)
Infection is likely because you are punching through the intestinal wall which is full of bacteria; leads to blood in urine.
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What are the treatment options for prostate cancer? (x5)
1. DO NOTHING: may be desirable in older patients (whom most commonly get prostate cancer), as there is a possibility that the tumour will remain LATENT for the patient’s lifetime. 2. SURGERY: Radical prostatectomy where prostate is removed. Used when the tumour is LOCALISED. 3. RADIOTHERAPY: there’s two forms – (i) External beam radiotherapy, and (ii) brachytherapy where you implant seeds of radiation into the prostate. 4. HORMONE THERAPY: called ANDROGEN DEPRIVATION THERAPY which is beneficial in metastatic forms of the cancer. The prostate relies on androgens for growth, so depriving prostate of androgens leads to reduction in growth and development of the cancer. 5. CHEMOTHERAPY: used only as a last resort, because most men who are diagnosed with prostate cancer are old, and the side effects tied to chemotherapy are undesirable for these cohorts of patients.
164
What are the disadvantages of radical prostatectomy? (x2)
Can lead to incontinence and impotence in the majority, due to the proximity of the nerves which control these functions to the prostate.
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What are the mechanisms of androgen deprivation therapy?
• Androgens are produced in the testes and stimulated by LH. • (i) Hormone therapy targets LHRH which is released by the hypothalamus and stimulates the pituitary gland. Therefore, a LHRH antagonist can be used to prevent stimulation of the pituitary to produce LH. • (ii) LHRH agonist is used leading to overstimulation of the pituitary and subsequent surge in LH and androgen synthesis and release. Over time, this leads to downregulation of LHRH receptors and LH production ceases. • (iii) ABIRATERONE inhibits an enzyme required for the synthesis of androgens in the testes.
166
What is the problem with treating prostate cancer with LHRH agonists? How is this problem combatted?
Leads to initial surge in the levels of LH and androgen synthesised. This can worsen symptoms of prostate cancer. Therefore, antiandrogens are co-administered.
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What is administered with androgen deprivation therapy? How do they work?
Weak androgens are still produced in the adrenal glands, so anti-androgens are used. These bind to androgen receptors to prevent their activation by androgens.
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What is the disadvantage of androgen deprivation therapy?
In patients on androgen deprivation therapy, many will face relapse after around 13 months. This is because the tumour becomes ANDROGEN-INDEPENDENT and therefore resistant to androgen deprivation therapy. Possible causes of this include that there is amplification of the response to low residual levels of androgen, or weak androgens, or mutations of the androgen receptor causing it to become activated by other ligands such as oestrogens. Androgen-independent tumours are typically more AGGRESSIVE.
