Lab Diagnostics Exam 2 (Tumor Markers, CSF/Lumbar Puncture)

What are tumor markers?

Proteins, enzymes, isoenzymes, hormones or oncofetal antigens

Produced by cancer cells or by the body in response to cancer and detected in a higher amount than normal (also seen in certain benign conditions)

Where can tumor markers can be found?

Found in the blood, urine, stool, or tissue of some patients with cancer

Is there a "universal" tumor marker that can detect any type of cancer?

NO!

What are some limitations of tumor markers? (4)

1) non-cancerous conditions can cause the levels of certain tumor markers to increase

2) tumor markers have not been identified for every type of cancer

3) generally, not useful to estabish a definitive diagnosis or screening

4) should NOT rely solely on results of a single test

What are tumor markers typically used for? (5)

1) Aid for early detection of the probable presence of cancer (not always)

2) Diagnosis of cancer (not always)

3) Evaluating prognosis

4) Prediction of therapeutic response

5) Monitoring disease and recurrence after treatment

Generally, sensitivity of tumor markers increase at:

Advanced stages of cancer

Why do we usually combine tumor markers with another test to confirm our suspicions of cancer?

Tumor markers are not super specific, some can be involved in multiple types of cancer --> we need other tests to confirm

What is alpha-fetoprotein (AFP)?

Glycoprotein secreted by fetal liver cells and GI tract

Found in high amounts in fetal plasma

What conditions can present with high amounts of alpha-fetoprotein (AFP)?

- During pregnancy

- Primary hepatic cancer (primary hepatocellular carcinoma, hepatoblastoma)

In what benign conditions can we see elevated alpha-fetoprotein?

- Liver cirrhosis

- Viral hepatitis

If AFP is significantly elevated in pregnancy, what can this indicate?

Associated with spinal cord defect/neural tube defects (ex: spina bifida)

What is cancer antigen 125 (CA-125) ?

Glycoprotein derived from coelomic epithelium (found in adult fallopian tubes, endometrium, and endocervix)

What conditions would have elevated cancer antigen 125 (CA-125)?

- 75-80% of pts with ovarian carcinoma

- Adenocarcinoma of the cervix/fallopian tubes

- Benign disorders (endometriosis, PID, ovarian cysts, hepatitis, liver cirrhosis)

What benign conditions can cause elevation of cancer antigen 125 (CA-125)?

- Endometriosis

- Pelvic inflammatory disease (PID)

- Ovarian cysts

- Hepatitis

- Liver cirrhosis

When is screening for cancer antigen 125 recommended?

- In patients with strong family hx of ovarian cancer OR risk factors

- Used for guidance of therapeutic decision + to monitor recurrence

**NOT used as routine screening or for patients with no risk factors

What conditions would have elevated cancer antigen 19-9 (CA 19-9)?

- Pancreatic cancer (70-80% sensitive and specific)

- Gastric cancer

- Colorectal cancer

- Benign conditions (liver cirrhosis, IBD, pancreatitis)

What benign conditions can cause an elevated cancer antigen 19-9? (3)

- Liver cirrhosis

- IBD

- Pancreatitis

What do we use cancer antigen 19-9 results for?

Diagnosis, monitoring response to treatment, and post-tx surveillance of pancreatic cancer

What are cancer antigens 15-3 (CA 15-3) and 27.29 (CA 27.29)?

Glycoproteins most often elevated in pts with breast cancer

When is cancer antigen 15-3 and 27.29 recommended to be tested for?

Monitoring response to therapy

NOT sensitive for early stage breast cancer

What conditions would cause an elevated level of cancer antigen 15-3 and 27.29?

- Breast cancer

- Fibrocystic disease of the breasts

- Another benign and malignant disease of the lung, ovary, pancreas, prostate, colon

- Hepatitis

What is prostate-specific antigen (PSA)?

Glycoprotein produced by normal prostatic lumen

Highly sensitive for prostate cancer

Prostate cancer accounts for ___ in ___ men in the US.

1 in 5

PSA detects only ____% of cancers in screening healthy asymptomatic men?

2%

What are the screening recommendations for PSA?

- USPSTF: men 55-69 should engage in shared decision making with their healthcare provider

- Men over 70 should not be screened!!

What are some risk factors for prostate cancer? (4)

1) Older age

2) African American ethnicity

3) Family hx of prostate cancer (1st degree relatives)

4) BRCA 2 mutations

What two tests are done together to detect prostate cancer if the pt is at high-risk?

PSA + DRE (digital rectal exam)

if DRE is abnormal, then offer PSA screening

What is the normal reference range for PSA?

0-4 ng/mL

What benign conditions could cause elevated PSA? (5)

1) Prostatitis

2) BPH

3) Prostatic trauma

4) Recurrent UTIs

5) After ejaculation

What rise of PSA per year is predictive for prostate cancer?

0.75 ng/mL

If a patient's PSA level is <1, when do we repeat the test?

Every 2-4 years

If a patient's PSA level is 1-3, when do we repeat the test?

1-2 years

PSA level is ____ dependent.

age (the older they get, the higher the PSA level)

What are some interfering factors with PSA test? (5)

1) DRE may increase PSA levels (don't do the same day!)

2) Prostate biopsy may elevate PSA levels

3) Ejaculation within 24 hours of blood testing may elevate prostate levels

4) Recent UTI or prostatitis can cause PSA elevation for up to 6 weeks

5) Meds such as Finasteride (Proscar, Propecia) may decrease PSA levels by about 50%

Meds like Finasteride (Proscar, Propecia) do what to PSA levels?

Decrease them by about 50%

PSA circulates in the blood in what 2 forms?

- Free (fPSA)

- Bound to protein (tPSA)

Which of the two forms of PSA is a high indicator of cancer?

Free PSA

The lower the free PSA%, the higher the risk of prostatic cancer

The _____ the free PSA%, the higher the risk of prostatic cancer.

Lower

If free PSA is < ____%, there is a high likelihood of prostate cancer.

25

Does BPH have more free PSA or bound PSA?

free!! (it's not cancerous)

What are some prostate cancer-specific biomarkers? (4)

1) Prostate cancer gene 3 (PCA3)

2) Human glandular kallirein (hK-2)

3) Prostate-specific membrane antigen (PSMA)

4) Cell cycle inhibitor p27 (Cp27)

What is carcinoembryonic antigen (CEA)?

Glycoprotein that usually disappears in adult life

When would we see elevated carcinoembryonic antigen (CEA)?

- Adenocarcinoma of colorectal carcinoma

- Pancreatic cancer, Gastric cancer, Metastatic disease

- Others: Medullary thyroid carcinoma, Breast, GI, liver, lung, ovarian, pancreatic and prostate cancer

- Benign conditions: smoking, PUD, IBC, UC, pancreatitis, biliary obstruction, liver cirrhosis

What is the normal range for carcinoembryonic antigen (CEA)?

<2.5 ng/mL in non-smokers

<5.0 ng/mL in smokers

What is carcinoembryonic antigen (CEA) used for?

Monitoring of colorectal cancer recurrence or metastasis

Not useful in screening or diagnosing of colon cancer

Levels of CEA over ____ ng/ml are associated with cancer which has already metastasized.

20

What is calcitonin?

Polypeptide hormone secreted by parafollicular cells ("C-cells") of the thyroid

Main action = inhibition of bone resorption and decrease serum calcium

What conditions have elevated calcitonin levels?

- Medullary thyroid cancer

- Bronchogenic carcinoma

- Cancer of the lung, breast, pancreas, GI

- Chronic renal failure, Zollinger-Ellison syndrome (ZES), or pernicious anemia

What are the 4 types of thyroid cancer?

- Papillary

- Follicular

- Anaplastic (high morality)

- Medullary (does not react to tx, needs surgery)

What is serum thyroglobulin (TG)?

Protein precursor of thyroid hormone, is made by both normal thyroid cells and thyroid cancer cells

A tumor marker used in post-tx patients with well-differentiated thyroid cancer post total thyroidectomy (monitor these pts)

What types of thyroid cancer are well-differentiated?

- Papillary

- Follicular

What conditions cause an elevated serum thyroglobulin (TG)?

- Thyroid cancer

- Graves disease

- Hashimoto's thyroiditis

What is chromogranin A (CGA)?

439-amino acid protein released by neuroendocrine cells

Useful to dx neuroendocrine neoplasms (pheochromocytoma, small cell lung carcinoma, medullary thyroid carcinoma)

What two biochemical markers are considered the most useful and first-line tests in disease surveillance of most pts with carcinoid (neuroendocrine) tumors?

CGA and 5-hydroxyindolacetic acid (5-HIAA)

What two genes have an inherited mutation that indicates an increased susceptibility for the development of breast cancer?

BRCA 1 and BRCA 2

More than ____ of women who inherit BRCA 1 or 2 mutations will develop breast cancer by age 50.

1/2

BRCA genes confer an increased risk for which two cancers?

- Breast mainly

- Also ovarian

_____% of patients with BRCA1 gene develop ovarian cancer.

44%

BRCA gene mutations have an ___________ inheritance pattern.

Autosomal dominant

Men with BRCA gene mutation (specifically BRCA 2) are at increased risk for:

Development of breast, prostate, and colon cancer

Who should be tested for BRCA mutations?

- Pt with breast cancer <= 50 years of age with no other family hx

- Pt with breast cancer at any age and family hx of breast cancer and/or ovarian cancer

- Pt with breast cancer at any age and 2 relatives with breast cancer and/or ovarian cancer

- Pt with breast cancer and personal history of ovarian cancer

- Cancer in both breasts in the same woman

- Pts with breast cancer and 1st or 2nd degree relative with BRCA mutation

- Ashkenazi Jewish heritage

- Male with breast cancer at any age

What is human epidermal growth factor receptor 2 (HER-2)?

Oncogene located on chromosome 17q

Associated with worst clinical outcomes for breast cancer (occurs in 25-50% of cases of metastatic breast cancer which show rapid tumor progression, metastasize at a faster rate)

What is beta-subunit of human chorionic gonadotropin (beta-HCG)?

Glycoprotein secreted by placental syncytiotrophoblast cells within alpha and beta subunit

Beta subunit specific to hCG

What conditions causes increased bHCG levels?

- Pregnancy

- Testicular cancer

- Gestational trophoblastic disease (hydatidiform mole/molar pregnancy)

What group of people have a false positive level of beta-HCG?

marijuana smoekrs

If we have a male pt with elevated beta-hCG, what should we suspect?

Testicular cancer

____ and _____ are used to follow treatment in pts with non-seminomatoes germ cell tumor.

AFP and beta-HCG

What are some benign conditions that can cause elevated beta-hCG?

- Pregnancy

- PUD

- Inflammatory intestinal disease

- Liver cirrhosis

What is cerebrospinal fluid?

Clear, colorless fluid formed within the ventricles of the brain

Where is CSF produced? (3 places)

- the choroid plexus (70%)

- ependymal lining of the ventricles

- cerebral subaracnoid space

How much CSF fluid is produced per day?

500 mL

How much CSF fluid is present in the system at any one time?

90-150 mL

Where does reabsorption of CSF take place?

At the arachnoid villi

What is the purpose of CSF?

- Serves as hydraulic shock absorber (keeps brain floating!)

- Regulates intracranial pressure (if absorption is disrupted, can cause increase in ICP)

- Supplies nutrients to the nervous tissue

- Removes waste products

What happens in CSF disease states?

disease can cause elements ordinarily restrained by the BBB to enter the spinal fluid

What are the indications for a lumbar puncture? (4)

1) Suspected CNS infection (viral vs. bacterial vs. fungal)

2) Suspected subarachnoid hemorrhage (looking for RBCs in CSF)

3) Therapeutic reduction of CSF pressure

4) Sampling of CSF for any other reason

- CNS malignancy

- autoimmune disease like MS

- systemic infections: syphilis, TB, lyme

What are the usual community-acquired types of bacterial meningitis? (5)

- Streptococcus pneumonia (~50%)

- Neisseria meningitides (~25%)

- Group B Streptococci (~15%)

- Listeria monocytogenes (~10%)

- Haemophilus influenza type B (<10%)

What are the usual hospital-acquired types of bacterial meningitis? (2)

- Staphylococci

- Aerobic gram negative bacilli

For <3 months, which pathogens tend to cause bacterial meningitis? (4)

- group B streptococci

- E.coli

- Listeria monocytogenes

- aerobic gram-negative bacilli

For 3 months - 18 yrs, which pathogens tend to cause bacterial meningitis? (2)

N. meningitidis + S. pneumoniae

For 18-50 yrs, which pathogens tend to cause bacterial meningitis? (2)

N. meningitidis + S. pneumoniae

For <50 yrs who are immunocompromised, which pathogens tend to cause bacterial meningitis? (4)

- Listeria monocytogenes

- N. meningitidis

- S. pneumoniae

- aerobic gram-negative bacilli

What are contraindications for a lumbar puncture? (6)

1) Local skin infections over proposed puncture site -- ABSOLUTE CI

2) Raised ICP (exception is pseudotumor cerebri)

3) Suspected spinal cord mass or intracranial mass lesion (based on lateralizing neurological findings or papilledema)

4) Uncontrolled bleeding diathesis

5) Spinal column deformities (EX. scoliosis)

6) Lack of patient cooperation

What is the procedure for a lumbar puncture? (8)

1) neuro checks: check lower extremitiy movements, sensations, etc.

2) get LP tray (needles, vials in which to collect CSF, antiseptic material, brushes, syringes for lidocaine, etc.)

3) wipe down area + drape pt over area

4) palpate + mark area (below L2)

5) needle goes in sideways

6) see clear fluid

7) add 3 way cock

8) measure P --> collect in vials

If CSF pressure is >200 mmH2O, how much CSF should you take (maximum!)?

2 mL

What positions should the patient be in to check CSF pressure? (2)

1) fetal position (lateral)

2) leaning over a pillow onto a table

When inserting a lumbar puncture needle, how should the bevel face?

Sideways

How many samples of CSF are usually taken? Why?

4 to differentiate btwn traumatic tap or bleed

What is a traumatic tap?

Damage to blood vessels during lumbar puncture causing RBC to be seen in the CSF sample

Common practice: measure cell counts in 3 consecutive tubes of CSF

- If number of RBCs is relatively constant --> it is assumed that the blood is caused by intracranial hemorrhage

- Falling RBC count is attributed to a traumatic tap

What are some post-lumbar puncture instructions for the patient? (5)

1) Lie prone 4-8 hrs, must remain horizontal

2) Encourage fluids to relieve headache

3) Observe pt for neuro changes

4) The "blood patch" --> small amount of patient's own blood is introduced into the spinal canal at the same tap level to stop spinal headache

5) Monitor puncture site

What does elevated glutimine in CSF indicate?

Elevated in the presence of elevated ammonia --> liver failure

Presence of oligoclonal bands in CSF analysis indicates:

MS

Does absence of oligoclonal bands in CSF analysis rule out MS?

No!!

How will CSF pressure change in...

a) bacterial meningitis

b) viral meningitis

c) fungal (TB) meningitis

a) Bacterial: >30 (significant elevation)

b) Viral: normal or mildly increased

c) Fungal: increased

How will CSF appearance change in...

a) bacterial meningitis

b) viral meningitis

c) fungal (TB) meningitis

a) Bacterial: turbid

b) Viral: clear

c) Fungal: fibrin web

How will CSF proteins change in...

a) bacterial meningitis

b) viral meningitis

c) fungal (TB) meningitis

a) Bacterial: significant increase (100-500)

b) Viral: somewhat increased (30-150)

c) Fungal: 40-150

How will CSF glucose change in...

a) bacterial meningitis

b) viral meningitis

c) fungal (TB) meningitis

a) Bacterial: significant decrease (<40)

b) Viral: slightly decreased (30-70)

c) Fungal: 28-45

How will CSF gram stain change in...

a) bacterial meningitis

b) viral meningitis

c) fungal (TB) meningitis

a) Bacterial: 60-90% positive

b) Viral: normal

c) Fungal: yeast/pseudohyphae

How will CSF glucose-CSF serum ratio change in...

a) bacterial meningitis

b) viral meningitis

c) fungal (TB) meningitis

a) Bacterial: < 0.4

b) Viral: > 0.6

c) Fungal: < 0.4

How will CSF WBC change in...

a) bacterial meningitis

b) viral meningitis

c) fungal (TB) meningitis

c) Bacterial: elevated, 100-2000 (neutrophils/PMN)

b) Viral: elevated, 5-500 (monocytes)

d) Fungal: 20-2,000 (monocytes)