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MSC: Disease of major orgns > Tumour Markers > Flashcards

Tumour Markers Flashcards

1
Q

What definition of tumour markers?

A

Measurable analyte produced by a tumour which can help to diagnose the disease, provide prognostic information, identify correct treatment and monitor treatment”

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2
Q

What is the patient pathway in disease?

A
  • Screening
  • Diagnosis
  • Prognosis and Treatment
  • Monitoring therapy
  • Detecting Relapse
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3
Q

What are principles of tumour markers?

A

Relatively low clinical sensitivity

  • Results may be within normal limits in patients with malignancy

Relatively low clinical specificity

  • Results may be increased in patients without cancer

Tumour markers are best used in post-treatment follow-up

Tumour markers require careful interpretation of results

  • Physiological / analytical interferences
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4
Q

How are tumour markers useful for screening?

A
  • Ideal situation would be markers which enable early detection enabling treatment, limited spread and good outcomes
  • Targeted screening in genetic linked disease e.g. BRCA1 and BRCA2 in breast cancer
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5
Q

What is the role of tumour markers in monitoring therapy?

A
  • Most useful role for classical tumour markers
  • Requires quantitative relationship between tumour burden and tumour marker levels
  • Enables assessment of efficacy of treatment
  • Detection of drug/chemo resistance and response
  • Can lead to being classified as in remission (?cured)
  • However, if the tumour marker isn’t raised it can’t be used for monitoring, e.g. some bowel cancers do not have raised CEA levels.
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6
Q

What is the use of tumour markers in monitoring relapse?

A
  • Useful function of tumour markers
  • Debate regarding frequency of measurements in remission = Cost v clinical effectiveness
  • Rate of rise post resection of primary can indicate metastases e.g. CEA, if quick then liver/bone; slower rise brain/soft tissue/skin more likely
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7
Q

What are types of tumour markers?

A
  • General” non specific markers and analytes
  • Functional markers
  • “Classical” tumour markers
  • Haematological malignancies
  • Molecular markers
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8
Q

Where are tumour markers measured?

A
  • Serum/plasma/whole blood
  • Urine and other fluids
  • Faeces
  • Sputum
  • Cell scrapes
  • Tissue
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9
Q

What are general tumour markers?

A
  • Calcium - Hypercalcaemia in malignancy
  • ESR - Inflammation somewhere in body - ?infiltration
  • Sodium - Mineralcorticoid XS – Conn’s
  • LDH - Cellular/tissue damage
  • β2 Microglobulin - Severity and spread of multiple myeloma and some lymphomas and Present in other conditions such as Crohn’s and hepatitis
  • ALP - Bone/Liver metastases
  • Phosphate - PTHrP effect on phosphate excretion
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10
Q

What are examples of functional markers?

A

Pituitary

  • Prolactin
  • ACTH
  • GH
  • TSH

Parathyroid

  • PTH

Adrenal cortex

  • Aldosterone
  • Cortisol

Adrenal Medulla

  • Catecholamines
  • Metabolites

Ovary

  • Oestrogens
  • Testosterone

GI Tract

  • Insulin, glucagon
  • VIP, Gastrin
  • 5HIAA
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11
Q

What are some Gut Hormone Tumours?

A
  • Islet cell tumours of the pancreas
  • Insulinoma
  • Gucagonoma
  • Gastrinoma
  • VIPoma
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12
Q

How can tumour markers be used for monitoring effectiveness of treatment?

A

Pre-treatment level should be high enough for a fall to be monitored - Assay sensitivity

Knowledge of half-life enables response to be monitored by decline in levels

  • No change – tumour marker >50% t0 value
  • Improvement - <50% t0 value
  • Response - <10% t0 value
  • Complete response – tumour marker within RR
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13
Q

What would be the features of an ideal markers for diagnosis?

A

Ideal would be marker with 100% specificity and sensitivity.

  • Sensitivity of test is true positives in disease
  • Specificity is true negatives in health

In reality used in conjunction with other parameters

Most tumour markers are poor for diagnosis

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14
Q

What is the use of tumour markers for prognosis and treatment?

A

If tumour load is related to tumour markers then can be used for survival estimate

  • e.g. HCG and AFP prognostic indicators in testicular teratoma
  • P53, E-cadherin, nm23H1 and MMP-2 used together to predict outcome of node-negative breast cancer

Some receptors used in deciding treatment

  • Most notorious is HER-2 and if patient positive then treated with Herceptin
  • Oestrogen receptors in tumour tissue if positive then may respond to hormone therapy
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15
Q

What are prolactinomas and their treatment?

A
  • Benign tumour of pituitary gland. Most common type pituitary tumour
  • Treatment: Cabergoline, Bromocriptine, Norprolac
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16
Q

What are symptoms of Prolactinomas?

A

Symptoms caused either by

Hyperprolactinaemia

  • In females - amenorrhea, infertility, lactation, loss libido
  • In males, ED, loss libido, infertility
  • Low oestrogen may lead to osteoporosis

Pressure of prolacinoma on surrounding tissues

  • Headaches, vision
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17
Q

What are features and investigations for GH excess?

A
  • 90% of cases of acromegaly are primary. GH excess produced by benign pituitary tumour
  • Few cases by tumours of lungs, pancreas and adrenal
  • Produce GH or GHRH
  • Rarely IGF secreting tumours
  • Single GH measurement not useful. IGF-1 more sensitive
  • Glucose tolerance test: In normal patients GH suppresses, In acromegaly GH remains detectable
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18
Q

What is a medullary thryoid carcinoma?

A
  • First neoplastic manifestation of MEN-2 and significant cause of death
  • Rare tumour of the C cells of the thyroid gland. Multifocal C cell hyperplasia → MTC. Progression from C cell hyperplasia to carcinoma is variable
  • Secretory product of C cell hyperplasia/MTC is calcitonin. High levels are used as a tumour marker
  • Metastasis is common
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19
Q

What are features of thryoid cancer in MEN-2?

A
  • The thyroid cancer in MEN-2 is considerably more aggressive, and develops early in life, than when thyroid cancer develops in non-MEN patients
  • Patients identified with the MEN-2 gene should have their thyroid surgically removed before they are in their mid-teenage years.
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20
Q

What is the function of PTHrP?

A

Shares same N-terminal as PTH. Related in function to PTH:

  • Increase Ca resorption from bone
  • Reduced Ca excretion in urine
  • Reduced renal PO4 re-absorption
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21
Q

How is PTHrP involved in the body and how is it secreted?

A
  • Involved in cell signalling during development. Important physiological roles in growth and development
  • Reportedly secreted by some lung, breast, prostate tumours and in some instances of myeloma. Hypercalcaemia sometimes first sign of malignancy
  • PTHrP measurement can be useful if raised total/ionised Ca, N/L PTH and exclusion of XS Vit D, sarcoid, TB etc
22
Q

What is Conn’s syndrome and the signs of it?

A
  • Primary hyperaldosteronism
  • Although documented as rare, in hypertensive population the occurrence is up to 15%
  • Benign adenoma (one adrenal)
  • Hyperplasia (both adrenal glands)

In Conn’s - aldosterone is high and renin low / undetectable

23
Q

What is a Phaechromocytoma?

A
  • Tumour of Chromaffin cells in the adrenal medulla (unilateral or bilateral)
  • Chromaffin cells produce catecholamines – adrenaline, noradrenaline
  • Ability to suddenly produce large amounts of catecholamines ® rise in blood pressure
24
Q

How do Phaeochromocytoma patients present?

A

Patients present with

  • Headaches
  • Sweating
  • Tachycardia
  • Palpitations, and in rare cases sudden death

Usually presents after MTC in MEN syndromes

Only present in MEN-2A and -2B, not MEN-1

25
Q

What are some epidemiological factors of Phaeochromocytoma?

A
  • 10% Malignant
  • 10% Bilateral
  • Extra-Adrenal (found within nervous tissue outside of the adrenal glands)
  • 10% Children
  • 10% Familial that will have a family member with the same type of tumour
  • Recur (10% or slightly less, will come back 5 to 10 years later)
  • Associated with MEN-2 syndromes
  • Present with a stroke (10% of these tumours are found after the patient has a stroke)
26
Q

What are Carcinoid Tumours?

A

Arise from argentaffin cells located in foregut, midgut and hindgut

  • 66% arise in midgut with appendix being most common, followed by small bowel
  • Predominance of carcinoids in midgut may be incidental following appendectomy

Carcinoid in association with MEN-1 arise in the foregut

Approx 2500 new cases/annum malignant carcinoid (USA). 50% survive >5years

27
Q

Where are carcinoid tumours commonly developed?

A
  • Commonly develop bronchi, stomach, small intestine, appendix and rectum
  • Classification based on embryological origin e.g. foregut, midgut, hindgut
28
Q

What are characteristics of Carcinoid Tumours?

A
  • One of best characteristics of carcinoid tumours is ability to secrete serotonin and the association with carcinoid syndrome
  • Carcinoid tumours have also been found to secrete ACTH, histamine, dopamine, substance P, neurotensin, prostaglandins, and kallikrein
29
Q

What is Carcinoid Syndrome?

A
  • Release of serotonin and other vasoactive substances into the systemic circulation is thought to cause the carcinoid syndrome
  • Manifested by episodic flushing, wheezing, diarrhoea and eventual right-sided valve heart disease (33%)
  • Associated primarily with midgut carcinoid tumors, and occurs almost exclusively in the setting of metastatic, rather then localized disease
  • Occurrence and severity of carcinoid syndrome are directly related to tumour size in an area with direct access to circulation
30
Q

What is the usefulness of 5-HIAA?

A
  • Produced as breakdown product of serotonin. Levels not elevated with other types of tumours
  • Sensitivity 73%, specificity 100%
  • However, the level of 5-HIAA only becomes elevated when carcinoid tumors have metastasized to the liver, making the potential for a cure unrealistic
  • 5-HIAA testing is useful to estimate the extent of disease and survival
  • False-positive test with foods rich in serotonin e.g. Bananas, Walnuts, Plantains, Hickory nuts, Pineapple, Pecans, Kiwi fruit, Avocados
  • Drugs, many that are contained in cough and cold medicines also cause raised 5-HIAA e.g. Acetaminophen (such as Tylenol®)*, Salicylates (aspirin), Guaifenesin (found in some cough medicines), l-dopa (used to treat Parkinson’s disease)
31
Q

What is Chromagranin A?

A
  • Chromogranin A is considered as the best test for detecting carcinoid tumours, and for monitoring their activity. Elevated levels of CgA are found in 80-100% of patients with carcinoid tumors
  • Positive test result does not always indicate carcinoid tumours are present, because CgA levels can also be increased by neuroendocrine tumors. Further testing must be done to make a definitive diagnosis of carcinoid syndrome.
32
Q

What are some classical tumour markers?

A
  • AFP, hCG, S100b, SP1
  • CA125, inhibin A, CA15.3
  • CEA, CA19.9
  • CA211
  • Calcitonin, thyroglobulin
  • Chromogranin A, NSE
  • NMP22
  • PSA
33
Q

What are ACB recommendations for tumour markers?

A
  • Main use is in monitoring of diagnosed cancer patients
  • Laboratories should regularly audit their service to review requesting patterns and use
  • Laboratories should review their requests which they send to referral laboratories
  • Only markers from primary care should be PSA, CA125 and follow up of patient being treated by secondary care
  • Interpret result in view of clinical and laboratory information
  • Lab should provide guidance on re-test limits
34
Q

What are types of testicular cancers?

A

Seminoma ~ 40%

  • ~10% produce hCG
  • ~ 50% produce placental-like ALP at presentation
  • ~ 75% at recurrence
  • LDH may also be raised – non-specific but ?role in monitoring
  • If AFP produced, elements of germ cell tumour are present which changes treatment / management

Non-seminomas ~60%

  • ~90% produce AFP +/- hCG
  • Both of value in determining type, prognosis and therapy
  • Where positive – they are essential for monitoring response, detecting residual tumour and recurrence
35
Q

How is Testicular Cancer monitored?

A

Depending on stage and pathology, recommended that AFP +/- hCG

  • Measured 4-12 times annually (year 1)
  • Twice annually (year 5)
  • Annually thereafter
36
Q

What are malignancies that show a raised AFP?

A

Malignancies with elevated AFP

  • Non seminomatous germ cell tumours of testis, ovary and other sites
  • Hepatocellular carcinoma
  • Hepatoblastoma (children, v rare in adults)

Benign conditions with elevated AFP

  • Hepatitis, cirrhosis, biliary tract obstruction, alcoholic liver disease etc
  • Don’t forget high levels in pregnancy and in first year of life
  • Levels in infants should fall to adult levels by 1 year old
37
Q

What are clinical applications for AFP?

A
  • In combination with hCG for NSGCT
  • Independent prognostic marker for NSGCT

Diagnostic aid for hepatocellular carcinoma (HCC) and hepatoblastoma in patients with cirrhosis and a focal lesion >2cm with arterial hypervascularization

  • AFP >200 ug/L suggestive of HCC
  • nAFP >400 ug/L strongly suggestive of HCC

AFP is not useful for liver mets – CEA is preferable marker

38
Q

What is the purpose of CA125?

A
  • Main application is monitoring treatment
  • Also useful in distinguishing benign from malignant pelvic masses especially in post-menopausal women and if mass already identified
  • Elevated in 80-85% epithelial ovarian cancer but only 50% elevated in early stage (1) cancer
  • Recommended in conjunction with transvaginal ultrasound for early detection in women with hereditary symptoms. At risk population with adjunct tests
39
Q

What is CA125 raised?

A
  • Benign disease: Endometriosis (24%), Benign ovarian tumours (10%), Acute salpingitis (40%), Cirrhosis (67%), Cirrhosis with ascites (100%), Chronic active hepatitis (10%), Acute pancreatitis (32%), Renal failure (15%)
  • Other malignancy: Endometrial cancer(32%), Cervical cancer (25%), Breast cancer (20%), Colorectal cancer (15%), Pancreatic cancer (55%), Lung cancer (30%), Liver cancer (60%), Gastric cancer (30%), Biliary tract cancer (46%)
  • Miscellaneous: Normal pregnancy, Menstruation, Following disruption to the peritoneum (e.g. laparoscopy)
40
Q

What are NICE guidelines for Ovarian Cancer?

A

Recommendations

  • Check CA125 if symptoms suggest ovarian cancer
  • If CA125 > 35 kU/L refer for ultrasound
  • Calculate risk of malignancy index (RMI), if >250 refer to specialist

Symptoms in guidelines include

  • Frequent and persistent (e.g. >12x per month)
  • Abdominal bloating
  • Early satiety
  • Loss of appetite
  • IBS like symptoms

NOT an invitation to screen asymptomatic women!!

41
Q

What are some markers for Breast Cancer?

A

Tissue markers are considered mandatory in all breast Ca patients

  • Oestrogen and progesterone receptors measured to identify those who can be treated with endocrine therapy
  • HER/2 receptors measured to determine those who can be treated with Herceptin

BRCA1

  • Variations of BRCA1 gene lead to increased risk of breast cancer
  • BRCA1 or BRCA2 mutations have up to 60% risk of developing breast cancer by age 90 and increased risk of ovarian cancer
42
Q

What is the action of Herceptin?

A
  • Monoclonal antibody which interferes with HER2/neu receptor
  • HER receptors embedded in cell membrane and regulate growth, survival, adhesion, migration and differentiation
  • In some breast cancers HER2 is over-expressed resulting in overproduction of breast cells via EGF
  • Herceptin binds to HER2 preventing cell overproduction
  • If patient doesn’t have overactive HER2 receptors then herceptin will have no effect – difficult for patients to perceive. If the patient has pre-exisiting heart disease, it can make it worse so to be avoided
43
Q

What is the use of CA15.3 in breast cancer?

A
  • Increased in breast Ca especially with distant mets
  • Sensitivity of 0-36% in early stages
  • Sensitivity of up to 100% in advanced disease
  • Rarely elevated in patients with local breast cancer
  • Major use in post-treatment monitoring
  • Can also be raised in benign and malignant disease of lung, GI and reproductive systems and also in liver disease
44
Q

What is CEA?

A

Glycoprotein, ~60% carbohydrate, MW ~200kDa. CEA and colorectal malignancy

  • ~70% but often not in early stage disease
  • Most useful in post-treatment monitoring
  • Early indicator of recurrence (but not in ~30% of patients)

Also raised in other malignancies such as breast, lung, pancreas etc

Can be raised in benign conditions such as liver disease, obstructive jaundice, Chron’s disease, pancreatitis, renal disease

Can be mildly elevated in ‘healthy’ individuals who smoke

45
Q

How is screening for colorectal cancer designed?

A

All individuals >60 years should be screened

  • 1 in 20 in UK will develop bowel cancer during lifetime
  • 3rd most common cancer in UK and 2nd leading cause of cancer deaths
  • Screening shown to reduce risk of dying from bowel cancer by 16%

Uses faecal occult blood test (FOB)

46
Q

What is the use of CA19.9?

A

Primary malignancy is pancreatic cancer

  • Low sensitivity and specificity limit use in early diagnosis
  • Main use in monitoring treatment

Also known as sialyated Lewis antigen – patients who lack Lewis antigen (blood type protein on RBC ~10% Caucasian population) will not express CA19.9

Can be elevated in:

  • Colorectal, oesophageal and hepatocellular cancers
  • In benign conditions such as pancreatitis, cirrhosis and diseases of bile ducts
47
Q

What is the use of PSA and the causes of it?

A
  • Although prostate CA is considered the only malignancy which leads to elevated PSA, it isn’t completely prostate specific
  • Benign prostate hypertrophy (BPH), UTI, urinary retention, acute and chronic prostatitis can lead to elevated levels
  • Transient elevation can be seen following TURP, prostate biopsy, prostate massage, ejaculation etc
48
Q

What is the main applications of PSA?

A
  • With DRE can aid in diagnosis
  • Prognosis
  • Surveillance following diagnosis
  • Monitoring therapy
49
Q

What are the NICE guidelines for the use of PSA in Prostate cancer?

A
50
Q

How does Total PSA relate to Free PSA?

A

Malignant prostate cells produce more bound PSA

  • oLow level of free in relation to total might indicate cancer
  • oHigh level of free indicates normal prostate, BPH or prostatitis
51
Q

What is CancerSEEK?

A
  • Noninvasive multianalyte test
  • Eight cancer proteins and cancer gene mutations from circulating DNA
  • Uses circulating DNA mutations
  • Median sensitivity 70% (33-98%) - Ovarian, liver, stomach, pancreatic, oesophageal, breast, lung and colorectal
  • Optimistic that eventually will cost <$500

MSC: Disease of major orgns (23 decks)

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