18.-Misc-Endo-Tumour-Markers.pptx18.-Misc-Endo-Tumour-Markers.pptx18.-Misc-Endo-Tumour-Markers.pptx

18.-Misc-Endo-Tumour-Markers.pptx

1. Pakistan Society Of Chemical Pathologists Distance Learning Programme In Chemical Pathology Lesson No 18 Miscellaneous Endocrine Disorders and Tumour Markers ( Short Name: MEDTM ) By Surg Commodore Aamir Ijaz MCPS, FCPS, FRCP ( Edin ) Professor Of Pathology / Consultant Chemical Pathologist Bahria University Medical & Dental College / PNS SHIFA Karachi 1

2. BCQ s 2

3. Q 1: The most common cause of Cushing Syndrome is: a. Adrnocortical Hyperplasia b. Cushing disease c. Ectopic ACTH secretion d. Iatrogenic e. Pseudo-Cushing Syndrome d. Iatrogenic 3

4. Slides on CUSHING SYNDROME a nd ADDISON DISEASE were Initially Prepared by Dr Mehreen Hassan (PNS SHIFA) 4

5. Cushing’s Syndrome Iatrogenic is most common cause. Other causes are: ACTH dependent: Cushing’s disease (70%) Ectopic ACTH (15%) ACTH independent: Adrenal hyperplasia (10%) Adenoma or carcinoma 5

6. Q 2: A 54 y male is having Cushing Syndrome. His cortisol and other steroid profile is as following: • Serum Cortisol: Increased • Serum DHEAS: Markedly increased • Urinary 17-ketosteroids : Markedly Increased • Serum Aldosterone: Low • Aldosterone precursors : Increased What is the most probable cause of Cushing Syndrome in this patient? a. Adrenocortical Carcinoma b. Adrenal Adenoma c. Bilateral ACTH-independent macronodular hyperplasia d. Ectopic cortisol secretion e. Primary pigmented nodular adrenocortical disease a. Adrenocortical Carcinoma 6

7. Adrenocortical Carcinoma Can present as Hirsutism Characterised by increased metabolites of Cortisol and Aldosterone Increased DHEAS 7

8. Q 3: A 36 y old Registered Nurse is performing night duty for the last 2 years with the habit of going to bed at 0800 h in the morning. She has developed some features suggestive of Cushing Syndrome and referred to you for appropriate investigations. At what time of the day (24 h) you will like to collect her sample : a. Afternoon (1500 h) b. Early evening (1900 h) c. Mid day (1200 h) d. Midnight (0000 h) e. Morning (0900) e. Morning (0900) 8

9. Timing of Cortisol Sampling For Cushing Syndrome (CS) : Late Evening Sample : To see the loss of Diurnal variation i.e. higher cortisol in the evening Exact Time: One hour after usual sleeping time. (True for Serum or Salivary Cortisol timing). For Addison Disease (AD) : Morning sample at 0800 h . 9

10. Q 4: A 32 y pregnant lady has been referred to you for investigation of Cushing Syndrome. As per recent Guidelines which of the following should be the first line tests in this patient ? a. 48-h, 2 mg/d Dexamethasone Suppression test (DST) b. Late evening Salivary cortisol c. Midnight Sleeping Serum Cortisol d. Overnight 1mg DST e. Urinary Free Cortisol e. Urinary Free Cortisol 10

11. Urinary Free Cortisol (UFC) 24 h urine sample is required Better test in Pregnancy and patients on OCP due to increased CBGs in these conditions Should NOT be done in patients with renal impairment In pregnancy Dexamethasone test should NOT be done 11

12. First line Tests for CS Late evening Salivary Cortisol Urinary Free Cortisol (UFC) 1 mg Dexmamethasone Test (DMT) 12

13. Evening Serum cortisol (1 h after sleep) Done for confirmation of CS Can be done in two ways: Sleeping: Difficult to perform but better method Wakening: Also quiteuseful 13

14. Stress Obesity Depression High estrogen state Glucocorticoid resistance syndrome Drugs (phenytoin, phenobarbital etc) Pseudo-Cushing Syndrome 14

15. Low-dose dexamethasone suppression test Oral administration of 0.5 mg dexamethasone every 6h for 2 days Plasma cortisol >5 µg / dl on 3 rd day morning ------ hypercortisolism 15

16. Determination of the Cause of Syndrome Serum ACTH levels Plasma ACTH < 20 p g / ml indicates adrenal tumor High-dose Dexamethasone suppression test Overnight 8 mg test Obtain baseline 0800h plasma cortisol Oral administration of 8 mg dexamethasone at 2300h Obtain plasma cortisol on next morning at 0800h (< 50% of baseline value -------- significant suppression) Two day test Oral administration of 2 mg dexamethasone every 6h for 2 days 16

17. Q 5: The most common cause of Chronic Adrenal Insufficiency Worldwide (including developing countries) is: a. Autoimmune disease b. Drugs c. Fungal Infection d. Malignant Metastasis e. Tuberculosis e. Tuberculosis 17

18. Primary adrenal insufficiency \ Addison’s disease (AD) Inadequate production of glucocorticoids and mineralocorticoids involving destruction of >90% of adrenal cortex Secondary adrenal insufficiency: Inadequate secretion of glucocorticoids caused by pituitary insufficiency Chronic Adrenal insufficiency 18

19. Causes of adrenal insufficiency Causes of AD Idiopathic atrophy (autoimmune adrenalitis ) Granulomatous disease Tuberculosis(more common in our population) Histoplasmosis Sarcoidosis Infectious( Viral(AIDS),fungal, CMV) Neoplastic infiltration Haemochromatosis Amyloidosis Following bilateral adrenalectomy 19

20. Routine investigations: Blood complete picture: Neutropenia Relative lymphocytosis Eosinophilia Mild anaemia Serum electrolytes: Hyperkalaemia Hyponatraemia Hypercalcaemia 20

21. Routine investigations ( contd ) Serum urea - Serum creatinine Plasma glucose Hypoglycemia Acidosis 21

22. Morning Serum Cortisol < 10 Ug /Dl Plasma ACTH Assay > 150 Pg /Ml Dynamic Function Tests ACTH stimulation tests: Short synacthen test Long synacthen test Diagnosis of AD 22

23. Short Synacthen Test Indication : Investigation of adrenal insufficiency Contraindication: Pituitary surgery Principle: To evaluate the ability of adrenal cortex to produce cortisol in response to synthetic ACTH Side effects: Hypersensitivity in rare cases Preparation: No dietary restrictions performed in morning Requirements: Two plain tubes 250 µg synacthen (1 vial) paed dose: 36 µ g/kg body weight 23

24. Short synacthen test - protocol ( contd ) Procedure : mins 3ml blood for cortisol Inj synacthen 250 µ g I/V or I/M 30 mins 3ml blood for cortisol 60 mins 3ml blood for cortisol Interpretation : If post- synacthen cortisol >18 µg / dL or post- synacthen cortisol increases by an increment of 8 µg / dL Primary adrenal insufficiency is ruled out 24

25. Long Synacthen Ttest To differentiate between primary & secondary adrenal insufficiency Prolonged stimulation of adrenal glands by synthetic ACTH improves adrenal response Blood samples drawn: basal cortisol sample, then inj synacthen 250 µg I/M & Cortisol samples at 1,2,4,8 & 24 hrs Gradual rise in cortisol & peak at 24 hrs indicates secondary adrenal insufficiency No response or initial (1hr) response which is not sustained indicates primary adrenal insufficiency Gradual rise in cortisol & peak at 4-8 hrs is normal ACTH assay has reduced the significance of long synacthen test 25

26. Q 6: As per reported natural history of Addison Disease (due to autoimmune etiology) the first Endocrine abnormality is : a. Decreased cortisol response to ACTH b. Decreased morning cortisol c. Increased CRH d. Increased Plasma Renin Activity e. Raised morning ACTH d. Increased Plasma Renin Activity 26

27. Q 7: As a Consultant Chemical Pathologist in a tertiary care hospital, you want to develop a strategy for immediate determination of diagnosis and cause of adrenal insufficiency. Which of the following test you would like to use at the time of patient presentation: a. Estimation of early morning Serum Cortisol b. Estimation of evening Serum Cortisol c. High dose ACTH Stimulation test with 250 µg d. Low dose ACTH Stimulation test with 1µg e. Simultaneous estimation of Serum Cortisol and Plasma ACTH e. Simultaneous estimation of Serum Cortisol and Plasma ACTH 27

28. Q 8: Corticotropin -releasing hormone (CRH) stimulation test is used in various adrenal abnormalities. All of the following are indications of CRH stimulation test EXCEPT: a. As part of inferior petrosal sinus sampling for ACTH-dependent Cushing's syndrome. b. Discriminate between pseudo-Cushing's and Cushing's syndrome. c. Discriminate between Primary and Secondary Adrenal Insufficiency d. Discriminate between Secondary and Tertiary Adrenal Insufficiency e. Discriminate between patients with an ectopic or a pituitary ACTH-secreting tumour . c. Discriminate between Primary and Secondary Adrenal Insufficiency 28

29. Q 9: A 72 y male industrialist is suspected of Acromegaly because of sudden increase in his shoe size and enlargement of fingers. He is not a known case of Diabetes Mellitus or liver disease. He was thoroughly investigated for the diagnosis of Acromegaly and determining the cause of excess Growth Hormone (GH) if present. The results of his investigations showed following results: • IGF-1: 452 ng /ml (ref range: 135-449) • OGTT with GH (by Chemiluminescence method) o GH basal : 0.2 ng /ml o GH level at 2 h : 0.6 ng /ml • Pituitary MRI: Normal What is the most probable diagnosis? a. Equivocal results b. Extra-pancreatic islet tumour c. Extra-Pituitary Acromegaly d. Normal for age e. Pituitary Adenoma c. Extra-Pituitary Acromegaly 29

30. For Detail Account Of GH Disorders Please See PPT Prepared By Dr Shagufta Yousaf 30

31. Diagnosis of Acromegaly in this pt IGF1 is normally decreases in elderly In this patient IGF 1 is markedly increased There is paradoxical rise of GH which is an indication of Acromegaly Normal MRI of pituitary indicates extra-pituitary acrmegaly GHRH Acromegaly can be the final diagnosis 31

32. Q 10: A 39 y female complains of polyuria with 24 h urinary volume more than 4.0 litre which has developed gradually over the last one year. She has been referred to you for ‘Water Deprivation Test’ (WDT) for the diagnosis or exclusion of Diabetes Insipidus (DI). You perform some preliminary tests which show following results: • Serum Sodium : 124 mmol /L (132-142) • Urine osmolality: 118 mOsmol /Kg Now how will you proceed with this patient? Please select the best option: a. Central DI requiring WDT for confirmation b. DI and Psychogenic polydipsia excluded not requiring WDT. c. Nephrogenic DI requiring WDT for confirmation d. No clue of any disorder requiring WDT e. Psychogenic polydipsia requiring WDT for confirmation . e. Psychogenic polydipsia requiring WDT for confirmation. 32

33. For Detail Account Of Diabetes Insipidus Please See PPT Prepared By Dr Shagufta Yousaf 33

34. Q 11: All the following are characteristics of an Ideal Tumour Marker EXCEPT: a. Can be used for evaluating prognosis b. Can be used for prediction of therapeutic response c. Elevated at early stage of the disease d. High levels at the time of diagnosis e. Levels decrease without any treatment e. Levels decrease without any treatment . 34

35. Q 12: A 52 y male who is a known patient of Cirrhosis of liver as a sequale of Hepatitic C. His Alpha Fetoprotein (AFP) has been monitored regualrly and usually remains below 200 ng /ml. A recent report, howevr , shows AFP 545 ng /ml and on repeating the test a simialr values was obtained. What is the most probable cause of rise of AFP in this patient : a. Carcinoma of Colon b. Carcinoma of the pancrease c. Extension in Cirrhosis d. Hepatocellular Carcinoma e. Testicular germ cell tumour d. Hepatocellular Carcinoma . 35

36. Q 13: CA-125 is a time- honoured marker of Carcinoma Ovaries. There are efforts to imporve its efficiency ad diagnostic marker for Stage 1 Ovarian Carcinomas. All of the following are situations when CA-125 can be used as a better marker for the diagnosis of Ovarian Carcinoma EXCEPT : a. In combination with AFP b. In combination with Carcinoembryonic Antigen c. In combination with Human Epididymis Protein d. Serial monitoring of CA 125 e. Use in post-menopausal women a. In combination with AFP . 36

37. Q 14: For the monitoring of Carcinoma Breast several biochemical or circulating tumour markers have been found useful. Which of the following tumour markers have been approved by FDA for the detection of recurrent Breast Carcinoma: a. CA-15-3 b. CA-27.29 c. CA-549 d. Extracellular domain of HER2 (HER 2 ECD) e. Mucinlike Carcinoma Associated Antigen (MCA) b. CA-27.29 . 37

38. Q 15: Research in Oncogene has led to discovery of certain gene which can predict certain cancers with reasonable accuracy. A subset of these Oncogene have been found quite commonly in otherwise healthy women raising the moral and ethical issues of prophylactic surgery. Which of the following oncogenes is a suppressor gene used for inherited prediction of Breast Cancer in a family with the patients of these cancers : a. APC mutation b. BRCA mutation c. Her-2/ neu gene d. N- ras mutation e. VHL Mutation b. BRCA mutation . 38

39. For Detail Account of Tumour Markers Please See PPT Prepared By Drs Anwar Magsi and Fawad Sana 39

40. SAQ s 40

41. Q:16: Diagnosis of Growth Hormone Deficiency in short stature children is one of the most common Endocrine challenges a Chemical Pathologist has to face. As a Consultant Chemical Pathologist you have been instructed by your University Administration to establish an “ Auxology Clinic” i.e. Growth Clinic in the hospital in collaboration with Consultant Paediatricians. Please address following issues in this regard:   Please make a list of essential equipment and charts etc. required for clinical examination of the children referred to this ‘Growth Clinic’ from Primary Care Services .   A major problem in diagnosis of Growth Study is selection of children who have high pre-test likelihood ratio i.e. they have higher chance of testing positive for Growth Hormone Deficiency (GHD). Such screening is essential for a cost effective and efficient “ Auxology Clinic”.   Please make a FIVE line criteria for selecting children to undergo GHD studies. Name the specific tests which are carried out for the diagnosis of GHD without any stimulation . Name the provocative tests which can be used for the confirmation of GHD.   . 41

42. Suggested Answer to Q.16a Please make a list of essential equipment and charts etc. required for clinical examination of the children referred to this ‘Growth Clinic’ from Primary Care Services.  ( Plz see next slide)   42

43. Equipment and Charts for Growth Clinic Weighing machine Vertical stadiometer for children ˃2 years of age Neonanometer for children ˂2years of age Glucometer with strips Refrigerator ( to keep insulin at optimal temperature) WHO growth charts for length for age for girls and boys for less than 2 years age CDC growth charts for height for age for girls and boys for more than 2 years age     43

44. Equipment and Charts for Growth Clinic ( Cont ) Height velocity chart for boys and girls Calculators to calculate midparental height in boys and girls Calculator for calculating CDC height for age percentiles in boys and girls Charts to estimate bone age Syringes (insulin, 5 cc, 10cc, iv canulas ) 25% dextrose, 5% dextrose saline, distilled water Sample collection tubes for serum (growth hormone) and plasma glucose Other emergency drugs in a tray like antiemetic, solucortef , etc.     44

45. Suggested Answer to Q.16b A major problem in diagnosis of Growth Study is selection of children who have high pre-test likelihood ratio i.e. they have higher chance of testing positive for Growth Hormone Deficiency (GHD). Such screening is essential for a cost effective and efficient “ Auxology Clinic”.   Please make a FIVE line criteria for selecting children to undergo GHD studies ( Plz see next slide) 45

46. Selection of Patients for GH Studies Height progressively decline to lower percentile usually < 3 rd percentile Weight increasing with chronological age Reduced Growth velocity Delayed bone age Other systemic cause of short stature / constitutional delay are ruled out e.g. Hypothyroidism, Coeliac Disease etc. 46

47. Suggested Answer to Q.16c Name the specific tests which are carried out for the diagnosis of GHD without any stimulation . IGF 1 IGF BP3 47

48. Suggested Answer to Q.16d Name the provocative tests which can be used for the confirmation of GHD. Exercise Stimulation Test L-Dopa Stimulation Test Arginine Test Insulin Stimulation Test 48

49. Q:17: Use of Prostate Specific Antigen as a marker for screening of Prostatic Cancer has been one of the most controversial topics in cancer management. The levels of Serum PSA from 4.0 to 10 ng /ml present a diagnostic dilemma. Many strategies have been proposed to improve the diagnostic accuracy of PSA for prostatic carcinoma, though there is no consensus about acceptance of these PSA modifications.   Please name the strategies proposed for improvement of diagnostic performance of PSA. Write brief description of THREE of these strategies (not more than two lines for each). ( Plz see next slide)   49

50. Strategies proposed to improve the diagnostic performance of PSA For PSA between 4 -10.0 ng / mL . PSA velocity (change in PSA over time), PSA density (PSA per unit volume of prostate), Free PSA Complexed PSA Age specific reference ranges Race specific reference ranges   50

51. Age specific reference ranges :   PSA level increase with age. 40 to 49 years — 0 to 2.5 ng /mL 50 to 59 years — 0 to 3.5 ng /mL 60 to 69 years — 0 to 4.5 ng /mL 70 to 79 years — 0 to 6.5 ng /mL By lowering the upper limit of reference interval, more cancer will be detected in younger men for whom a potential cure by radical prostatectomy is most beneficial. 51

52. PSA Velocity The rate of PSA increase as a function of time.PSA increases more rapidly in men with prostatic cancer than in healthy men. After establishing a base line concentration of PSA in each patient, the rate of increase of PSA is than calculated. The increase of PSA in health, BPH, and prostatic cancer appears to be different with a highest rate (>0.75µg/L/ yr ) observed in patient with prostatic cancer. The specificity improves to 90%for BPH and sensitivity is 72% for prostatic cancer. 52

53. Prostatic Density :   Divide PSA concentration by the prostatic volume as determined by transrectal ultrasonography. Patient with PSA between 4 a 10µg/L, a negative digital rectal examination result, and elevated PSA density have increased risk of prostate cancer . Adjusting the PSA density cutoff value for total PSA level might improve the test sensitivity. 53

54. Thank You and Best Of Luck 54