MED2042 WEEK 7 - Biochemical Detection & monitoring of malignancy
Terms
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- What are the strategies against cancer?
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Prevention
- Smoking, abestos
- ? vaccines (e.g. HPV vaccine - cervical CA)
Screening program
- PAP smear
- Mammograms
Treatment
- surgery
- radiotherapy/chemotherapy
- hormones
- ? gene therapy - Ware we winning the battle against cancer?
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Incidence of cancer in males and females has increased.
Mortabilty has decreased in males and females. - What is the most common cancer in Australia?
- Colorectal cancer most common(2001)
- What is the cancer with the highest death rate in Australia?
- Pancreatic cancer (2001)
- What can a tumour be indicated by?
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Signs and Symptoms
- decreased weight, anorexia, mass
General Biochem
- LFTs (cholestatic) Increased Ca2+
Hormones
- ADH, ACTH, PTHrP, hCG
Tissue markers
- PSA, thyroglobulin
Strange protiens
- paraproteins, AFP, CEA, CA125, CA 19-9, CA 15-3
Cell surface marker
- beta2-microglobulin
Enzymes - LD
DNA - BRCA 1 & 2 for breast CA, ras oncogene for colon CA - Why do we measure tumour markers?
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1. Detection early, treatable CA
2. Confirmation diagnosis
3. Staging (classification)
4. Monitoring - response to treatment, recurrence
1,2,3 - limited use
4 - IMPORTANT use - What are features of an ideal tumour marker?
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- High sensitivity - detect early, treatable cancers
- High specificity - no false positive results
- Reflect tumour activity and mass - help guide treatment
- Prevents premature death from cancer
Tumour marker levels correlate reasonably well with tumour volume.
Lack of sufficient sensitivity and specificity limits its use in cancer screening. - What are some tumour marker problems?
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1. Tumours do not always produce markers
2. Sensitivity - poor
- Negative result in people with cancer e.g. CEA only pikes 5% Dukes A colon CA, not for screeening fo cancer
3. Specificity - poor
- positive result in people without cancer e.g. PSA in prostatitis, CA 19-9 in cholestasis
4. False +ve/-ve result due to assay problems - What are some assay problems?
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1. HIGH DOESE HOOK EFFECT - falsely low values
2. HETEROPHILE ANTIBODY INTERFERENCE - falsely high values e.g.heterophile antibody (human antimouse antibody)
3. Values from different labs are not interchangeable - What is PSA?
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Prostate specific antigen
- A glycoprotein (serine protease) secreted by prostatic epithelial cells. Confined to the gland but "leak" into the circulation
- In teh glood, mostly bound to proteins: e.g. alpha-antichymotrypsin
- PSA is tissue specific but not tumour specific
- commonly used reference range - <mg/mL
PRIMARY TUMOUR - Prostate
BENIGN CONDITIONS - Prostatitis (8 weeks), BPH, prostatic trauma, after ejaculation (2d)
DIAGNOSIS - yes
MONITORING TREATMENT - very helpful
FOLLOW-UP AFTER TREATMENT
- 6 monthly x 5y then annually
- any detectable PSA after radical proctectomy indicates recurrence
SCREENING GENERAL POPULATION - controversial
- not recommended in australia - What is the ideal for PSA as a tumour marker? What is teh reality for PSA with BPH?
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Ideal - Cut off at 4ng/mL
Reality - false positives, false negatives, grey area - What are problems with PSA?
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- PSA is neither sensitive or specific (PPV 20-30% at PSA >4ng/mL)
- Follow up procedure invasive
- Treatment has significant complications
- Many people with prostate CA die of other causes
- Despite increase incidence due to introduction of PSA, mortality has not changed - ? Are we detecting clinically less important cases? - What are ways to increase PSA specificity?
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1. Clinical indication - lower threshold for +ve family Hx or abnormal DRE
2. Use age-adjusted reference ranges for different ethnic groups
3. Free PSA/total PSA ratio (fPSA)
4. PSA velocity - >0.75ug/L/year --> high risk for CA
5. PSA density - Against volume of prostate by ultrasound: ug/L/mL - What are some onco-foetal proteins?
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Carcinoembryonic Antigen (CEA)
Alpha foetal protein (AFP)
Beta human chorionic gonadotrophin (beta-hCG) - What is CEA?
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Onco-foetal protein made by normal and malignant epithelial tissues.
PRIMARY TUMOUR - colorectal CA
OTHER TUMOURS - breast, lung, GI epithelium, heat & neck
BENIGN CONDITIONS - usually <20ng/mL; cigarette smoking, most GI conditions, hypothyroidism
FOLLOW-UP AFTER Rx - 2-3 monthy, at least 2y - What are AFP?
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Alpha foetoprotein
- Foetal albumin made by yolk sack and liver
- high in infants and ruing pregnancy
- adults <10ug/mL
- half life ~ 5 days
PRIMARY TUMOURS - hepatoma, germ cell CA (non-seminomatous) - AFP and hepatoma
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- hepatoma is commonly a complication of chronic hepatitis (esp. Hep C)
- AFP > 1000ug/L usually indicate hepatoma
- Current debates on its use in hepatoma screening
- Problems:
> small incrases can be due to early hepatoma or liver deases
> increase in benign conditions (usually <200ug/L): hepatitis, cirrhosis - AFP and germ cell tumours
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- AFP and beta-hCG are important in the treatment of testicular nonseminomatous germ cell tumour
- levels failure to fall after surgery indicate residual disease
- follow up:
> at least 6 repeats in 1st year post op
> then quaterly x 1 year
> less frequent thereafter - Describe Beta-hCG as a tumour marker
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Normally produced by placenta - increased in pregnancy
PRIMARY TUMOUR - nonseminomatous germ cell tumour, gestational trophoblastic disease
OTHER TUMOURS - rarely, GI cancers
BENIGN CONDITIONS - hypogonadal state, marijuana use
FOLLOW-UPAFTER Rx
- For seminomatous germ cell tumour - same as AFP
- For gestational trophoblastic disease - Monthly x 1 year - What are some carbohydrate antigens?
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CA 15-3
CA 19-9
CA 125 - CA 15-3
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- a monoclonal antibody developed to detect glycoprotein found on breast cell epithelium
- same levels in male and females
- no change in pregnancy and lactation
PRIMARY TUMOUR - breast
OTHER TUMOURS - colon, lung, pancreas
BENIGN CONDITIONS - benign breast, liver and kidney disorders, pancreatitis, biliary dis, cirrhosis
MONITORING TREATMENT AND RECURRENCE - helpful
FOLLOW-UP AFTER Rx - 4-6 monthly for recurrence - CA 19-9
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An intracellular adhesion molecule made by pancreatic and biliary cells
PRIMARY TUMOUR - Pancreatic CA, biliary tract CA
OTHER TUMOURS - colon, esophageal and hepatic CA
BENIGN CONDITIONS - usually <1000ng/mL, pancreatitis, biliary dis, cirrhosis
MONITORING TREATMENT AND RECURRENCE: Helpful
FOLLOW-UP AFTER Rx - 2-3 monthly, at least 2 yr - CA 125
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A monoclonal antibody developed to detect glycoprotein found on ovarian epithelial tumour cells
PRIMARY TUMOUR - ovarian CA
OTHER TUMOURS - endometrial, fallopian, breast, lung, GI
BENIGN CONDITIONS - menstruation, pregnancy, fibroids, ovarian cysts, endometriosis, pelvic inflammation, cirrhosis, ascites, and pleural & pericardial effusions
FOLLOW-UP AFTER Rx - 3 monthly, at least 2 years - SUMMARY OF TUMOUR MARKERS
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Tumour markers can provide valuable assistance in management of patients with known malignancy if used appropriately
- Have limited role for cancer screening
> thye do not have sufficient sensitivity or specificity
> low prevalence of the disease in general population
> +ve reulst are far more likely to be false +ve than true +ve
- Tests can be also falsely +ve or -ve due to assay problems - talk to the lab if doubt
- need to monitor levels by the same laboratory