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Transcript of and The Hidden Tumor - ilmar.org.il · CA-125 in males and PSA in females: Use of TM for follow-up...
and The Hidden TumorOrly & Mira Barak
Tumor Markers DiaSorin 9.11.2010
CASE A
Female,74 years oldClinical findings:
Acute symptoms:Stomach ache,
Increased liver size and tenderness
Laboratory findings:,
Fullness
Weight loss-7kg in 2 months
Laboratory findings:
Cholestatic tests impairment and
Additional health status:
increased LDH
Imaging findings:Additional health status:asthma
diabetes
Imaging findings
Infiltrated liver with metastatic patterndiabetes
hypertension
hypothyroidismyp y
Is there any need for tumor markers?
Case ACase A TUMOR MARKERS
CASE Bmale 87 years oldmale,87 years old
Acute symptoms:W k
TUMOR MARKERS
Weakness
Burning on urination
Weight loss 15kg in last Weight loss-15kg in last year
Additional health Additional health status:dyslipidemia y p m
hypothyroidism
Is there any need for tumor markers?
CASE CMale 73years old TUMOR MARKERSMale,73years old
Acute symptoms:Shortness of breath after a long flight with diagnosis of PE and DVT
Additional health status:Hypertension
Hyperparathyroidism
BPH with PSA 10ng/ml
Colon polypectomy
Is there any need for tumor markers?
and The Hidden Tumor
T k t d t t d ?Tumor markers- to do or not to do?
Intermediate summaryIntermediate summary k f l lCase A: tumor markers for tumor localization?
Case B: tumor markers as screen method to ruleout malignancy?out malignancy?
Case C: tumor markers as a diagnosis mean in a Case C: tumor markers as a diagnosis mean in a monitored patient with additional suspicion of paraneoplastic involvement (hypercoagulation)?paraneoplastic involvement (hypercoagulation)?
History…..
1846-Bence Jonce
1940 id h h t1940-acid phosphatase
1963 AFP1963-AFP
1965-CEA1965-CEA
1980-CA125 PSA1980 CA125, PSA
1980-oncogenes and tumor suppressor genesn g n n um r uppr r g n
2001-microarray,mass spectrophotometry, bioinformaticsy p p y
• Hormones (hCG; calcitonin; gastrin; prolactin)
• Enzymes (acid phosphatase; alkaline phosphatase; PSA)
• Proteins & Glycoproteins (CA 125; CA 15.3; CA 19.9)
• Oncofetal antigens (CEA, AFP)
• Receptors (ER, PR, EGFR)
O (R M bl b )• Oncogenes (Ras; Myc; abl-bcr)
• Tumor suppressor genes (BRCA1; p53; Rb)
TM are usually glycoproteins found in blood or excretions,
indicating the presence, course and prognosis of a neoplastic
process
TM are not tissue or tumor specificTM are not tissue or tumor specific
TM are produced by benign and malignant tissue: the
difference is only quantitative
TM levels are dependent on synthesis secretion release TM levels are dependent on synthesis, secretion, release,
clearance of the molecule as well as are dependent on tumor
size metastases and angiogenesissize, metastases and angiogenesis
TM are not tissue or tumor specific
TM are produced by benign and malignant tissue:
the difference is only quantitativeTumor Markers Cancers What else?
y q
AFP (Alpha-fetoprotein)
Liver, germ cell cancers of ovaries or testes
Also elevated during pregnancy, cirrhosis
CA 15-3 Breast and others including Also elevated in benign CA 15 3 Breast and others including lung and ovaries
Also elevated in benign breast conditions;
CA 19-9 Pancreatic, sometimes l t l d bil d t
Also elevated in pancreatitis d i fl t b l colorectal and bile ducts and inflammatory bowel
diseaseCA 125 ovarian Also elevated with
endometriosis, some other diseases and benign conditions; pregnancy,
iascites
CEA (Carcino- Colorectal, lung, breast, Elevated in other conditions (embryonic antigen)
gthyroid, pancreatic, liver, cervix, and bladder
such as hepatitis, COPD, colitis, pancreatitis and in cigarette smokers
There are no TM “normal levels”-the cut-off value is determined in 95% of
הערות לסמני סרטן כפי שמופיעות באוטולאב cut off value is determined in 95% of
blood donors and patients with benign diseases of similar origin.
CEA ) ng/ml (:
5.5 מהבריאים פחות מ- 95ב- %
CA 15 3)U/ml(:
The cut-off values are irrelevant in cancer patients: the single relevant value is the level of TM obtained
CA 15-3)U/ml(: 30 מהנבדקים פחות מ- 95%ב-
CA 125 ) U/ml (:
35value is the level of TM obtained מהבריאים פחות מ-95%ב- during monitoring of the patient in the same lab with the same kit, since the TM kinetics is more important than its
CA19-9 ) U/ml (:
39 מהנבדקים פחות מ- 99ב- %
E E ( )/ lTM kinetics is more important than its absolute value. The kinetics of the TM can differentiate between a benign and malignant process.
ALPHA FETO PROTEIN (AFP)) ng/ml(: 7 מהבריאים פחות מ- 95%ב-
PSA :
מ95%ב קטן 4nמהנבדקים m gn n p .
An increase in the TM level within the reference range may be very
4 מהנבדקים קטן מ-95%ב- הערכת סיכון אישי 2.5מעל
:FPSA
reference rangeלשקול עם מדדים נוספים may be very significant.
ק
הערות כלליות לכל אחד מהסמנים
אינו שולל או מאמת ממאירותללבמעקב השווה לערך קודם
T k ili di (TMUGS)Tumor marker utility grading system (TMUGS)
explanationLevel of pfuse
no clinical use- do not use routinely0 y
There is a clinical correlation- in research- do not use routinely -+/
There is clinical correlation-unknown if the TM use has any additional value or can influence mode of therapy- do not use
ti l
+
routinelyThere is additional specific information, but it should be used only together with other diagnostic means for getting clinical
+2y g g f g g
significance-use routinely only in specific casesIndependent diagnostic tool for routine clinical use+3
Retrospective study on 8253 patientsRetrospective study on 8253 patientsWhen TM are used?Which TM are used?Wh t th t ?What was the outcome?
Follow-up
Clinical suspicion
Appropriate TM? Guidelines?Guidelines?
NACB: Tumor Markers 2009The National Academy of Clinical BiochemistryThe National Academy of Clinical Biochemistry
Laboratory Medicine Practice Guidelines
Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Draft Guidelines - Second Posting
“Although in certain circumstances tumor markers may aid in diagnosis, speculative measurement of panel of tumor markers
(“fishing”) should be discouraged”( f g ) g
• TM usually have a “mean lead time” of 3-12 months in i t th di ti comparison to other diagnostic means
E h TM h ifi i i t• Each TM has a specific in-vivo t1/2
Th l l f h TM i i fl d b i d i i • The level of the TM is influenced by its production in benign diseases and by adjacent tissues.
• The TM level is influenced also by individual factors, circadian rhythm hormones hemodynamic and circadian rhythm, hormones, hemodynamic and iatrogenic factors.
• TM levels are influenced by the sample preparationand the kits used. and the kits used.
M l d iMean lead timetreatmenttreatment
(TM)
CT- CT- CT- CT+
1 2 3 4 5 6 7months
TT1/2TREATMENT
1000 <T1/2 <1/2
(TM)
100
( )
10
TIME
TM ki iTM kineticsTREATMENT INCREASE
DECRESEDECREASE +/-INCREASE
(TM)
NO CHANGE
(TM)
NO CHANGE
TIME
Follow-up by TMTM courseClinical course
between two t sts f d
Increase by >25%Malignancytests performed within 1 month
progression
Decrease not Decrease by >50%Partial remission Decrease not caused by production
Decrease by >50%Partial remission
production cessation or necrosis
Not defined by TM
Complete remission
Biological variation and total errorg
Total error%Precision%Intraindividual marker Total error%P<0.05
Precision%Intraindividual cv%
marker
21 84 79 3CEA 21.84.79.3CEA
23.36.813.6CA 125
17.52.95.7CA 15-3
18.55.110.1MCA
44.312.324.5CA 19-9 44.312.324.5CA 19 9
9.03.05.9β2MG
30.07.014.0PSA
TM standardizationl sourceyearInternational
standardTM
Cord blood1972IS 72/225AFP Cord blood1972IS 72/225AFP
Liver metastases
1973IRP 73/601CEAmetastasesPurified β hCG
& nicked HCG1975IS75/537HCG
1975IRP75/551bHCG
90:102000IS/670PSA 90 10C :F
2000IS/670PSA
Free purified2000IS96/668F-PSA
--noneCA125CA15-3CA19-9CA72-4
Intermediate summaryIntermediate summary
Case A: tumor markers for tumor Case A tumor markers for tumor localization?
CASE AClinical findings:
Female,74 years oldClinical findings
Increased liver size and tenderness
Acute symptoms:Stomach ache,
Laboratory findings:
Fullness
Weight loss-7kg in 2 months
Cholestatic tests impairment and increased LDH
Imaging findings:
Additional health status:
Imaging findings
Infiltrated liver with metastatic pattern
asthma
diabetes
hypertension
hypothyroidism
A huge tumor in colonoscopy
CEACEAIgG supergene family
ImmunoglobulinsT cell receptor
CEACA 125CA15-3 p
Growth factor receptorN-CAM
CA602
Biliary glycoprotein Non specific cross reacting agent
Coreprotein
Core chain Peripheral chainCore chain Peripheral chain
CA 72-4CA 546
CA 19-9CA 50
Lewis antigen and CA 19-9
Colorectal Cancer
10%
5% 3%
15% CE15% CEA
CA 19 938% 29%
CA 19-9
CA 242 CA 242 …
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic Colorectal Cancer (Section 3C)
2003
Guideline recommendations for tumor markers use 2007
Colorectal Cancer:
CEA
Screening and diagnosing noScreening and diagnosing – no
staging / prognosis, detecting recurrence monitoring therapy yesrecurrence, monitoring therapy – yes
Use immediate postoperative-no
Intermediate summaryIntermediate summary
k f l l Case A: tumor markers for tumor localization -no-nofollow-up- yesfollow up yes
Case B: tumor markers as screen method to l t li ? rule out malignancy?
CASE Bmale 87 years oldmale,87 years old
Acute symptoms:W kWeakness
Burning on urination
Weight loss 15kg in last Weight loss-15kg in last year
Additional health Additional health status:dyslipidemia y p m
hypothyroidism
do you know?...
"Elementary, my dear Watson” has not d i f Si C D l b ks b t appeared in any of Sir Conan Doyle books, but
in the first Sherlock Holmes film…..
Intermediate summaryIntermediate summaryC A k f l li i Case A: tumor markers for tumor localization -
no
Case B: tumor markers as screen method to ruleCase B: tumor markers as screen method to ruleout malignancy- only PSA: yes
Case C: tumor markers as a diagnosis mean in a Case C tumor markers as a diagnosis mean in a monitored patient with additional suspicion of paraneoplastic involvement (hypercoagulation)?p p yp g
CASE CMale 73 years oldMale, 73 years old
Acute symptoms:Shortness of breath after a long flight with diagnosis of PE and DVT
Additional health status:Hypertension
Hyperparathyroidism
BPH with PSA 10ng/ml
Colon polypectomy
Prostate cancer
Prostate CancerThe most wide spread tumor in menThe most wide spread tumor in men
Histological found in 42% of men over 50y (NO tests >75y- task force)
Low mortality rate, but in advanced disease-no cure
Th m t f l TM f d lm t l i l i th t tThe most useful TM, found almost exclusively in the prostate,but in all prostate diseases
NCCN 2004-cut off 2.5 ng/ml
Stamey 2004: the PSA era in USA isover- the test is all but useless
NCCN 2004 cut off 2.5 ng/ml
Catalona 2005: PSA saves lives(17% diagnosed with PC- 84% will survive( gdue to PSA early detection and treatment)# deaths(USA) 1997-42000
2007-27000
Thompson 2005: no cut-off level effectively identifiesmen with the disease
Prostate Cancer• Free PSA (uncomplexed form)
– 5-40% of PSA
%f PSA ↑ more benign
• PSA Complexes (cPSA) S omp exes (c S )
– PSA--1-antichymotrypsin (ACT)
– (60-95% of PSA)(60 95% of PSA)
– PSA--1-protease inhibitor (API)
(1 2 5% of PSA)– (1-2.5% of PSA)
– …etc.
No previous prostate manipulations
Significant change-above the test total error
PSA parametersPSA parametersT-PSA age dependent
/ yearsng/ml<49<2.5<59<3 5 <59<3.5<69<4.5<79<6.5
low specificity in olderF-PSA above 13%
796.5
Variability of kitsPSA velocity <0.75 ng/ml/year3 f ll-3 years follow-up
PSA density <0.15 ng/ml per gr tissueinaccuracy of TRUSinaccuracy of TRUS
PSA biological rolesgPro-PSA
PSA Physiological substrate(s)
Activation (hk2)
y g ( )Inhibitors (Zn, Serpins) Other competing proteases
Effect
beneficialCell differentiation
harmfulResistance to tamoxifen
Reduced cell growth rate
d f
Releases mitogens
Stimulates cell growthInduction of apoptosis
Antiangiogenic stimulus
g
Activates cytokines
Promotes invasionstimulusReduced migration
Promotes invasion
Promotes metastasisSemen liquefaction
Guideline recommendations for tumor markers use 2009
Prostate Cancer: PSA
Screening (with DRE), diagnosis, prognosis,
monitoring – yesg y
% free PSA – (PSA 4-10 ng/ml and DRE negative)
diagnosis – yes
h l l d Trousseau’s syndrome: multiple definitions and multiple mechanisms
-hypercoagulability syndrome associated with cancer-By its original definition, the di i f T ’ diagnosis of Trousseau’s
, retrospectsyndrome is made in when the occult malignancy is foundfound
Intermediate summaryIntermediate summaryC s A: t m m k s f t m l li ti n Case A: tumor markers for tumor localization -
noCase B: tumor markers as screen method to rule
l nl PSA: sout malignancy- only PSA: yes
Case C: tumor markers as a diagnosis mean in a monitored patient with additional suspicion of p pparaneoplastic involvement (hypercoagulation)?- yesyp y
Other frequent questions:CA -125 in males and PSA in females:
Use of TM for follow-up of rare malignancies: mesotheliomathat developscanceris a rare form ofmalignant mesotheliomamore preciselyMesothelioma(
CA 125 in males and PSA in females:Possible, but not recommended
that developscanceris a rare form of , malignant mesotheliomamore precisely , Mesothelioma(.mesotheliumfrom the protective lining that covers many of the body's internal organs, the
.asbestosIt is usually caused by exposure to
Use of TM in samples other than serum (sputum, peritoneal wash,
Possible, but not recommended
pleural effusion, cyst fluid etc.):
No relative valuesUsually no possibility of follow-up
When to perform TM?p-Before any treatment: surgery, chemotherapy,
radiotherapy, hormonal therapypy, py
-After therapy:-2-10 days according to t1/2 of the TMh 3 h d i h fi -each 3 months during the first two years
after treatment and each half year for the next 3 years
-before each treatment change
-With each suspicion of recurrence
When restaging-When restaging
-2-4 weeks after a clinical unexpected significant increase in 4 weeks after a cl n cal unexpected s gn f cant ncrease n the marker level during monitoring
WhatWhat will bewill bein thein the
future?future?
MALDI, matrix-assisted laser desorption/ionization; TOF,
time of flightt me of fl ght
During cancer development, cancer cells and/or the surrounding microenvironment and/or the surrounding microenvironment generate proteins and peptides of different type and in different concentrations than normal cells concentrations than normal cells. Can be analyzed by imaging-based mass spectrometry and the patterns compared with controls to identify cancer-specific with controls to identify cancer specific changes that may prove to be clinically useful.