Chemical Pathology JC133: Biochemical Screening For Early Detection Of Diseases

Question 1

Tumour markers

Answer 1

Biomarker found in blood, urine, body tissues
- elevated by presence of **>=1 type of cancer —> detect presence of cancer
- can be produced directly by **tumour / **non-tumour cells as a response to presence of tumour
- many different tumours makers —> each indicative of a particular disease process
- can have **false positive values

Biochemical / Non-biochemical markers:
Biochemical:
- **Elevated in patients with tumour
- Related to **total tumour burden

Non-biochemical markers:
- ***Genetic markers (e.g. Cytogenetics, Plasma nucleic acid (carrying specific mutations / genomic changes))

Question 2

Use of tumour markers

Answer 2

1. ***Screening
   - Prostate cancer
2. Diagnosis
   - HCC: AFP
   - Medullary thyroid cancer: Calcitonin, (Procalcitonin)
3. Determine modality of treatment
4. ***Monitoring disease progression
   - Serial monitoring
   - CA-125: Ovarian cancer
   - CEA: Colon / Lung cancer
   - Thyroglobulin: Differentiated thyroid carcinoma
5. ***Detection of relapse
6. ***Prognostication

Question 3

***Tumour markers available

Answer 3

Prostate: **PSA
Liver: **AFP
Lung: CEA, NSE, ProGRP, CYFRA 21-1
Colon: **CEA
Breast: CA15-3
Ovary: **CA 125, HE4
Pancreas: **CA19.9
Cholangiocarcinoma: **CEA, ***CA19.9
Cervical cancer: SCC
Germ cell: hCG, AFP
Medullary thyroid cancer: Calcitonin, (Procalcitonin)
(Stomach: CEA, CA19.9)

Question 4

Screening for prostate cancer

Answer 4

Very common

PSA (Prostate-specific antigen)
- aka **Human kallikrein 3
- an enzyme: **Serine protease
- complexed with serum anti-proteases: α1-anti-chemotrypsin, α2-macroglobulin

Clinical practice measurement:
- ***p2PSA = [-2]proPSA
—> a type of free PSA
—> better diagnostic power where there is high percentage of % free PSA

Prostate health index (most useful in improving detection rate):
- ***PHI = (p2PSA / Free PSA) x √Total PSA
- 0-20.9: Low risk (8.4%)
- 21-39.9: Moderate risk (21%)
- >=40: High risk (44%)
—> determine need for prostate biopsy to confirm screening results
—> superior to measuring %p2PSA, %free PSA, Total PSA alone for diagnosis of CA prostate
—> fairly expensive (∵ need to measure 3 different forms of PSA)

Serum level:
- <4 ng/ml: negative (Sn: 78%, Sp: 33%) —> 22% false negative
- >10 ng/ml: positive (Sn: 40%, Sp: 90%) —> 10% false positive
- 4-10 ng/ml: troublesome
- NOT a very good test: AUC = 0.58

How to manage 4-10 ng/ml:
Calculate:
- **Density measurement (PSA per ml of prostate —> need to measure prostate volume)
- **Age-related reference interval (e.g. 40-50: 2.5, 50-60: 3.5, 60-70: 4.5, >=70: 6.5)
- ***Velocity / doubling-time over a period of time (>0.75 ng/ml/year)

Measure:
- Free-PSA
- [-2]proPSA (degradation product from Pre-proPSA)
(- Aberrant PSA glycosylation)

Question 5

Screening for Colorectal cancer

Answer 5

Takes 10 years on average to develop from adenomatous polyp to invasive carcinoma

Polyps:
- Adenomatous vs Hyperplastic
- Small vs Large

Screening:
1. Radiological
- Barium enema
- ***CT colonoscopy

2. Biochemical
   - ***Faecal occult blood: Different types
   - Faecal DNA
3. ***Endoscopic
   - Flexible sigmoidoscopy
   - Colonoscopy
   - Capsule endoscopy
4. Combinations

Question 6

***Faecal occult blood tests

Answer 6

1. Guaiac-based
   - detect Heme in Hb
   - Guaiac causes stool sample to change colour (pseudoperoxidase activity of heme in faeces) —> detect **Heme —> oxidising activity —> colour change
   - 2 generations:
   —> Guaiac-based faecal-occult blood tests (gFOBT)
   —> Sensitive guaiac FOBTs
   - need 3 samples (3 faecal samples collected over 3 consecutive days)
   - **false positive: Food / drugs
   - detect **Upper + **Lower GI bleeding but cannot differentiate —> less specific
   - cheap
   - **qualitative
   - not very pleasant
   - dietary precautions: ***Vit C (a reducing agent) >250mg: false negative
2. Faecal Immunochemical tests
   - Ab to detect hidden human blood —> detect **Hb
   - **much more sensitive
   - require **1 sample only
   - Specific for **Lower GI bleeding (∵ Haemoglobin broken down in upper GI tract)
   - more expensive (although overall more cost-effective)
   - quantitative, provide an adjustable cut-off point to adjust sensitivity / specificity
   - increase participation rate
   - no need to change diet (independent on redox reaction —> not affected by reducing / oxidising agents)

Question 7

Advantages and Disadvantages of FOBT

Answer 7

Advantages:
- Potentially examine entire colorectal tract
- **Non-invasive
- **No patient preparation needed
- ***Simple + affordable
- Can be carried out at home
- Most extensively validated screening test for CRC

Disadvantages:
- **Low sensitivity for both adenomas / CRC (40-85%)
- **Low specificity for both adenoma / CRC
- **Ingestion of certain foods (red meats, fruits, vegetables) / medicines (NSAIDs) can yield false-positive results
- Multiple stool samples are necessary
- **Must be performed annually to increase chances of detecting intermittent bleeding

Question 8

Tumour markers in Colorectal cancer

Answer 8

Recommended: CEA
- **Prognosis
- **Surveillance following resection
- ***Monitoring therapy in advanced disease

Faecal occult blood tests: Screening ***>50 yo

DNA test: not recommended at present
- **K-ras (40-60%)
- **APC (~70%)
- ***p53 (40-60%)
- L-DNA
- BAT26
—> more expensive

Question 9

Colorectal screening in HK

Answer 9

FIT (Faecal Immunochemical test)
—> if positive
—> Colonoscopy to find out cause of bleeding