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Concept of screening

  • Population screening is the systemic application of suitable screening test:
    • To identify individuals at risk of a specific condition to warrant intervention
    • Undertaken among asymptomatic individuals
    • Organised process of call and recall to regular screening
    • An aid to early detection and follow up during treatment
    • Different to
      • Dealing with symptomatic patients and
      • Individual case finding in asymptomatic patients with certain risk factors

Criteria

  • Condition
    • Important health problem
    • Recognisable latent and early symptomatic stage
    • Known natural history
  • The test
    • Simple, safe, valid
    • Acceptable
    • Defined cutoff levels (e.g. PSA in the middle --> not defined; can be caused by prostatitis, BPH; every male over 80 will have PSA+; so do it opportunistically)
      • BPH --> prostatic occlusion --> hydronephrosis --> kidney failure, then prostate cancer with metastasis to the back.
      • Combine PSA with DRE to determine size as well as PSA (high both --> cancer, size high, PSA low --> BPH, intermediate could be prostatitis)
      • Best diagnosis for prostate cancer is DRE
  • Treatment
    • Effective with better outcome
    • Availability of facilities
    • Agreed policy of who should start treatment
  • Outcome
    • Improved morbidity, mortality and quality of life
    • Cost effective

Aim

The aim of this practical class is to introduce students to the role of screening in the prevention and management of common diseases.

Learning Objectives

  • 1. Describe the types of screening investigations that might assist in prevention or early intervention in disorders such as diabetes mellitus, atherosclerosis, breast cancer, colorectal cancer and prostate cancer.
  • 2. Discuss the attributes of an effective screening test, in terms of costs versus benefits.
  • Activities
  • In this class, students will divided into 4 groups and assigned one case each. They will complete two tasks per case within 30 min and present their findings to the group. These be discussed by the entire group and the tutors in the second hour of the class.

Criteria for Population Screening Tests

The condition:

  • should be an important health problem
  • should have a recognisable latent or early symptomatic stage
  • the natural history of the condition, including development from latent to declared disease, should be adequately understood

The test:

  • should be simple, safe, precise and validated
  • should be acceptable to the target population
  • the distribution of test values in the target population should be known and a suitable cut-off level defined and agreed

Treatment:

  • there should be an effective treatment for patients identified, with evidence that early treatment leads to better outcomes
  • there should be an agreed policy on who should be treated and how
  • facilities for diagnosis and treatment should be available

Outcome:

  • there should be evidence of improved mortality, morbidity or quality of life as a result of screening and that the benefits of screening outweigh any harm
  • the cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole

Case 1 Colorectal carcinoma

  • 846.25 Colorectal carcinoma and adenomas
    • This is basically a hardcore revision of AEA scenario 2.
  • Read the Museum catalogue history and description associated with the specimen listed above, and then complete the following tasks:

Task 1

  • Is there a population screening test currently recommended for colorectal carcinoma? If so, who should be screened, and how frequently? Justify your answer based on the criteria for screening, and identify groups at increased risk of developing this disease. (Refer to www.cancerscreening.gov.au for help)
    • Yes, FOBT at ages 50, 55, 60, 65 years
    • You get a kit in the mail, poo on the plate, test for occult blood, post it back
    • Do the test 3 times
    • Look for oxidised haem group (RBCs are lysed by this stage)
    • Haem is detected by a histochemical colour change reaction
      • If you look for any Hb, the person can't eat meat before the test. Therefore the new histochemical test is only to human Hb, so the test won't be invalidated
  • Colon cancer as a health problem
    • Deaths due to colon cancer in Australia every year is 4000; which is the 3rd most common cancer death
    • 12000 Australians are diagnosed with CRC every year
      • Primarily between 50-70 years, unless you have FAP or Lynch syndrome/heritable cases
      • If you are in general population, you need FOBT every 5 years
      • If you are in a high risk group, you need a colonoscopy every 2 years

National bowel cancer screening

  • Commenced mid-2006
  • Initially FOBTs offered to Australians turning 55 or 65 or those who participated in pilot study.
  • Extended to all Australians over 50 with average risk and indigenous Australians over 45
  • Test conducted at home and mailed in for analysis
  • Every 12-24 months
  • FOBT reduces mortality by 15-33%; incidence by 20%

Task 2

  • What is the evidence that colorectal adenomas are the precursors of colorectal adenocarcinomas in the vast majority of cases? What complications of colorectal adenocarcinoma might occur? Is there any evidence that early intervention following screening might help to prevent these complications, thereby reducing mortality from this disease?

Proof that adenoma --> carcinoma

  • People with more polyps have higher rates of carcinoma
  • Distribution of polyps and carcinoma is the same
  • Where you find polyps you will find adenocarcinoma (distribution is the same, not in the small intestine)
  • Adenoma progress into adenocarcinoma. If you remove polyps you reduce subsequent malignancy
  • Adenomas and adenocarcinomas share the same mutations
  • Link to read:

Stages of adenocarcinoma

APC beta catenin pathway

  1. mucosa at risk: hyperplastic, highly proliferating, has a single mutation in APC tumour suppressor gene (need 2 alleles to mutate for it to become redundant)
    • for a protooncogene you only need one mutation
  2. early adenoma: methylation of the second allele (second hit)
  3. late adenoma (carcinoma in situ): environmental, nutritional etc causing further proliferation. Results in k-Ras overexpression (oncogene)
  4. p53 deletion - tumour suppressor gene in chromosome 18 - results in carcinoma
  • with every change there is accumulation of mutation (higher percentage of k-ras mutation as you go down these steps)

Distribution of colon cancers

Distribution of colon cancers

Right sided:

  • Caecum/ascending colon: 25%; iron deficiency anaemia; intestinal obstruction (near terminal ileum), occult bleeding --> anaemia
    • Ulcerating, sessile carcinomas

Left sided:

  • Transverse colon--> descending colon: 25%
  • Sigmoid colon (25%): Tenesmus, abdo discomfort, mucoid diarrhea, polypoid lesions (because the bowel pushes the lesion down and down).
  • Rectal cancer (25%) has annular cancer around the whole wall, rectum becomes smaller
  • Most important prognostic indicator is stage which is based on it passing through the muscularis mucosa
    • Duke classification is used here (see phase 1 notes)
  • Specimen is in the exam
  • features to note about specimen:
    • caecum with nearby appendix, ileocecal valve and terminal ileum
    • large adenocarcinoma, distal to which are multiple adenomatous polyps

Case 2

1290.17 283.12 Abdominal aortic aneurysm

Lipid management guideline

www.heartfoundation.org.au Check every 12 months. Up to negotiation

  • Known CHD
  • Other manifestations of ATH disease
    • PAD: peripheral arterial disease
    • CVD
    • AA aneurysm
  • DM
  • Chronic RF or renal transplant
  • ATSI
  • Familial combined hyperlipidemia
  • Familial hypercholesterolemia
  • Others with lower absolute risk (10-15% risk) in the next 5 years
    • LDL > 4mMol, cholesterol > 6mMol and other two or more risk factors
      • HDL < 1
      • HT
      • Overweight
      • Smoking
      • IGT or IFG
      • Microalbuminaemia
      • >45 years
  • Annual screening of total cholesterol
    • TGs
    • LDL
    • HDL
  • All adults should receive ongoing risk assessment and preventative and lifestyle advice within a general practice


  • In pathology:
    • TC increases, LDL increases, TG increases, HDL decreases
    • Reverse this by exercising and diet
  • Framingham Heart Study
    • For anly level of LDLC, HDLC is inversely related to CVD
    • You can reverse atherosclerosis by removing risk factors
  • Scandinavian Simvastatin Survival Study (4S)
    • Secondary prevention
    • LDLC reduced by 38%
    • 30% decreased death rate

Atherosclerosis risk factors

See this here.

Description of the path

  • AAA below the renal arteries: infrarenal area (area with a lot of turbulence)
    • Atherosclerosis started by endothelial injury, causing increased permeability, increase access to lipids that become toxic to the endothelium, phagocytosed by macrophages, oxidised and deposited. This causes endothelial thickening.
    • Area of bifurcation in large artery is a good starting point for ATH
  • Aneurysm has happened as a consequence of ATH
  • Superimposed thrombus due to Virchow's triad
    • Under thrombus is intimal thickening, smooth muscle proliferation and collagen deposition
  • Above the AAA are uncomplicated plaques, 1-2cm, usually raised, creating turbulence
  • Large fusiform appearance
  • Higher risk of rupture, and then you die in 10 minutes


Read the Museum catalogue histories and descriptions associated with the specimens listed above, and then complete the following tasks:

Definitions

  • Arteriosclerosis is hardening of any blood vessels
    • Arteriolosclerosis is thickening of small/medium arteries; media e.g. a) hyaline arteriolosclerosis in diabetics (due to hypertension causing conversion of collagen into hyaline amorphous body) b) hyperplastic
    • Atherosclerosis usually affects medium/large arteries
      • Disease of the intima, media atrophies, causing aneurysm
    • Monckeberg's arteriosclerosis - rare, calcific

Look at the pathology glossary

Complications of atherosclerosis

  • Locations:
    1. Aorta --> ruptures, dead; or aneurysm, pulsating mass; lower limb pain (ischaemia; intermittent claudication); back pain (compress vertebra + nerves); throw of emboli to infarct in lower limb (gangrene)
    2. Coronary arteries --> critical narrowing is 50-70%, causing stable angina (on exertion), >70% is unstable angina (preinfarct). Complicated ATH plaque: A) superimposed thrombus (acute plaque change) or B) haemorrhage into a plaque.
    3. Carotid arteries
    4. Cerebral arteries (MCA)
    5. Popliteal arteries
  • Normal stable plaque is covered by fibrous plaque and is nonthrombotic. Unless it ruptures or bleeds (complicated plaque) it is safe
  • Arteriolosclerosis can rupture (malignant hypertension) but cannot cause aneurysm

Task 1

Is there a population screening test currently recommended for hypercholesterolaemia (a major predisposing factor for atherosclerosis)? If so, who should be screened, and how frequently? Justify your answer based on the criteria for screening, and identify groups at increased risk of developing hypercholesterolaemia. (Refer to the Lipid Management Guidelines, MJA, 2001, Volume 175; National Heart Foundation of Australia; www.heartfoundation.com.au for help)

  • There is no population based screening, but there is targeted screening based on risk factors

Task 2

What are the proposed pathogenetic mechanisms by which hypercholesterolaemia can lead to atherosclerosis? How may atherosclerosis lead to abdominal aortic aneurysms? What other complications of atherosclerosis might occur? Is there any evidence that early intervention following screening might help to prevent these complications, thereby reducing mortality from this disease?

  • Aorta, coronary arteries, internal carotid, popliteal artery are commonest sites for atherosceloris
  • Aorta >5cm is likely to lead to rupture

Case 3 Breast carcinoma

Task 1

Is there a population screening test currently recommended for breast carcinoma? If so, who should be screened, and how frequently? Justify your answer based on the criteria for screening, and identify groups at increased risk of developing this disease. Refer to BreastScreen Australia Program (National Breast Cancer Centre)for help

BreastScreen

  • <40 years: not recommended
    • Ultrasound if indicated
  • 40-49 years: eligible for free 2 years screening but with reduced accuracy
  • 50-69 years: recommended for free 2 yearly screening
  • >70 years: eligible but not targeted by the program
  • Limitation of mammogram
    • 15% false negatives; 15% false positive; needs a trained eye, improving due to better technicians. Stellate structures, microcalcifications. Calcifications in the breast are common, but you're looking for the stellate radiating structure.
    • Can be painful
  • Benefits
    • Screening 10000 women aged 50-69 years will prevent 10-20 deaths over 10 years
    • 40-50 years 5-7 deaths
    • 5 year survival is up to 45%
  • US mortality rate from breast cancer for women aged 30-79; 1975 (48.3/10000), 2000 (38.0/100000)
  • 350.20 Breast carcinoma
    • Read the Museum catalogue history and description associated with the specimen listed above, and then complete the following tasks:

Pathology of breast carcinoma

See AEB/Lectures/Breast carcinoma

  • Sagittal section of the breast with excised lymph node
  • Solid, rock hard mass, retracted nipple, peau d'orange, tethered to skin
  • Most common location of breast cancer is the upper outer quadrant (50% of BCs), 20% are central, upper inner is 10%, lower outer is 10% and lower inner is 10%
    • Therefore we look at axillary lymph nodes in most cases, mamillary LNs in other cases
    • For some reason it's also common that we have lymph node involvement in supraclavicular nodes
  • Once you see something on a mammogram, fine needle aspiration, guided by ultrasound
  • After cytological study from FNA, do excision (e.g. axillary clearance or sentinel biopsy)
    • Inject blue dye into cancer, see where the dye goes.
  • The size of the malignancy is an important prognostic marker and determines excision
  • Prognostic indicators:
    • How many lymph nodes
    • Size of mass; <1mm is good. >5mm is bad.
    • Distant metastasis (liver, bone, brain, blood, suprarenal glands)
    • Tethering
    • Type (ductal carcinoma has poorer prognosis than tubular, columnar, cribriform, papillary, inflammatory)
    • Hormone receptor positive is good because of treatment; for targeted treatment (estrogen receptor); but also this means it's less differentiated so it is low-grade.
      • Her2 good for treatment, bad for prognostic (because of proto-oncogene)
    • BRCA gene (FH and bilateral involvement)
    • Very old or very young (worse ones in young people)
    • Degree of differentiation (e.g. polyploidy, aneuploidy=uneven divisions)
    • Clear margins (i.e. tumour completely cleared)
    • Lymphovascular invasion
  • Cancer Location
    • 40% located between 9-12 o'clock
    • 25% around nipple
    • If in 3-6 o'clock then drains to parasternal, retrosternal nodes

Task 2

How might adenocarcinoma of the breast progress if it is not found at an early stage? Is there any evidence that early intervention following screening might help to prevent these complications, thereby reducing mortality from this disease? What are the main prognostic indicators in this disease?

Case 4

733.30 388.5

Type 2 DM

  • Is this a major health problem?
    • Yes; increasing incidence and prevalence in Australia (ATSI, Indian): 12%
    • High health burden and costly
  • Latent and early symptomatic stage?
    • Yes: many people not known to have DM-2 meet the criteria for this disease, ie there is a detectable preclinical period but length is uncertain (don't know how long from a little bit of insulin resistance to DM-2)
    • Targeted screening is best - we don't know how long from when it starts to when it becomes full-blown DM
    • Estimated to be 10-12 years, screening will detect 5-6 years before clinical diagnosis
  • Natural history of the disease?
    • Clinical diagnosis to development of complications is known
    • Transition from latent to clinical disease is not clear, ie not all individual IFG or IT develop DM
    • Obesity --> Insulin resistance --> Insulin produced in huge amounts -->Pancreatic islet exhaustion (fibrotic/amyloid/hyaline pancreas) --> hyperglycaemia.
    • Normal person --> Preclinical (Predisease = do not meet diagnostic criteria but are at increased risk; Predetection = meet diagnosis criteria but not tested) --> Clinical

Tests

  • Reference range of plasma glucose is 70-120 mg/dL (3.9 to 5.5 mmol/L)
  • These screening tests
    • FBG > 120 mg/dL (impaired fasting glucose IFG)
    • Abnormal 2h glucose tolerance (>200 mg/dL) (impaired glucose tolerance IGT)
    • HBA1c > 6.4%
  • Diagnosis
    • IFG in more than one occasion
    • Clinical symptoms (polydipsia, polyphagia, polyuria) and FG>200mg/dL
    • IGT in more than one occasion

Who gets screeened

Group 1

  • ATSI aged 35+
  • Pacific islander / indian subcontinent/chinese origin 35+
  • People 45+ who have either or both bmi 30+ and hypertension
  • All people with clinical CVD
  • Women with PCO who are obese
  • People with IGT or IFG (12 monthly screening)
  • NHRMC 3 yearly
  • RACGP 12 months

Group 2

  • People 55+
  • People 45+ who have a first degree relative with T2DM
  • Women with history of GD
  • NHMRC does not recommend screening
  • RACGP recommend 3 yearly screening in these groups


Complications of Diabetes Mellitus

  • Cardiovascular disease
  • Renal failure
    • Glomerosclerosis, pylonephritis, UTI, atherosclerosis of renal a.
  • Blindness eg. retinopathy, glaucoma
  • KNIVES: Kidney, neuropathy, infection (gangrene), vessels (CVD), eyes (blindness/retinopathy) , skin (PVD)


  • Pyelonephritis and papillary necrosis
    • Glandular kidney, fibrosis, atrophy, abscesses, sclerosis, inflammation, thickening of blood vessels
  • Diabetic foot ulcer
    • Amputation


  • Pathology of diabetes
    • Hyperglycaemia causes advanced glycosylation endproducts (AGE), they're received by rAGE. rAGEs activate macrophages, which cause proliferation, fibrosis
      • --> arteriolosclerosis (in blood vessels) and --> failure of glomeruli (in kidney)
      • rAGEs occupy the action of inflammatory cells, lowering innate defense, so you are less able to fight infection
      • --> hypertension with arteriolosclerosis
    • Hyperglycaemia causes accumulation of LDL --> atherosclerosis, which also caused by hypertension above
  • High insulin --> glucose is stored in cells that can't metabolise glucose. Then it is stored as polylol (sorbitol --> ____ reductase) --> fructose
    • G6-phosphatase is slow, so sorbitol accumulates. This is an insoluble material. You create a hyperosmolar environment which causes cell swelling and lysis
      • Insulin independent tissue include retinal pericytes, vascular cells and kidney cells. Then these cells lyse causing worse problems.

Read the Museum catalogue histories and descriptions associated with the specimens listed above, and then complete the following tasks:

Task 1

Is there a population screening test currently recommended for type 2 diabetes mellitus? If so, who should be screened, and how frequently? Justify your answer based on the criteria for screening, and identify groups at increased risk of developing type 2 diabetes mellitus. Task 2 Why might people with long-standing diabetes mellitus be at risk for developing the complications shown in specimens 733.30 and 388.5? What other long-term complications of diabetes mellitus might also occur? Is there any evidence that early intervention following screening might help to prevent or delay these complications?

Homework Tasks

Case 5 Prostate carcinoma

  • 1469.20 Prostate carcinoma and vertebral metastases
  • Read the Museum catalogue history and description associated with the specimen listed above, and then complete the following tasks:

Task 1

Why is measurement of serum prostate-specific antigen (PSA) alone NOT currently recommended as a population screening test for prostate carcinoma? Justify your answer based on the criteria for screening. What other test(s) used in combination with serum PSA might help to increase the sensitivity and specificity for detection of early prostate carcinoma?

Task 2

What complication of prostate carcinoma is shown in specimen 1469.20? Which investigation(s) might have been useful in detecting this complication? Is there evidence that this complication could have been prevented by diagnosis and treatment of early stage prostate cancer?

External links