prognostic factors of ovarian cancer
TRANSCRIPT
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Prognostic Factors ofOvarian Cancers
Prof.Veena AgrawalM.D., MICOG, WHO Fellow USA,Diploma in USG
Dept of Obstetrics. & Gynaecology
G.R.Medical College
Gwalior, M.P. INDIA
Dr R. Gautam
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Ovarian cancer accounts for 32% of allgynecologic malignancies.
causes 55% of all gynecologic cancer
deaths. Over 75% of Ovarian Cancers cases
are diagnosed at an advanced stage.
5-year overall survival is 20-30%.Aljoa MANDI ET AL 2001
J.M. CLASSE et al 2004
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Initial surgery is primodial.
In Stage IA and IB patients with grade Itumors do not require adjuvanttreatment.
Patients with stage greater than aboveare at high risk for recurrence, due tomicrometastatic disease, and should
thus undergo chemotherapy.
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There is a wide spectrum of clinicalbehaviours from an excellent prognosisand high likelihood of cure to those with
rapid progression and poor prognosisirrespective of clinical stage of thedisease, most probably reflecting differentbiological properties of the tumour.
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Prognostic Factors
Ethnicity & Race
Age
Stage of Disease
Histology
Tumor grade Tumor markers
Site-specificsurgical
treatment. Size of residual
disease
Tumor response
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Ethnicity & Race
African-American women have a 30% greaterrisk and are more likely to die earlier whencompared to Caucasian women David Greenberg2004, JillS. Barnholtz-Sloan,2002
Non-Hispanic white women had age-adjustedincidence rates that were slightly higher(13.3/100,000) than rates for American
Indians (11.4) and Hispanics (10.7) over the24-year period. Schiff M et al 1996
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Age
Advanced age remains an adverseprognostic factor even after adjustment fortreatment and comorbidity factors. O'Malley Cd et al2003,Chan JK et al Obstet Gynecol. 2003
Young patients have survival rates as high as75% across all stages, compared with 40% inthe overall population Rodriguez M,et al 1994,Lee CK,et al 1999
A ten year increase in age induces a 1.6times greater risk of death. Balvert-Locht et al. 1991, Markmanet al. 1993, Baker et al. 1994, Curtin et al. 1997, Eisenkop et al. 1998).
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One age-related reason for anincreased risk of cancer may be anaccumulation of somatic cell mutations.
Loss of heterozygosity on chromosome17 (deletion of a proportion of achromosome containing a putativetumor suppressor gene) increases withagePieretti & Turker 1997
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Stage of disease FIGO staging is "surgicopathologic
stage".
Most powerful predictor of prognosis
In many studies the patients are dividedinto two groups: early (Stage I and II)and advanced stage (stage III and IV),
because the survival in early stagedisease is significantly better than thatin advanced disease.
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Stage IA and IB patients with grade Itumors have a 5-year survival of over90%
Despite the high response rates of initialtreatments (i.e.,70-80%), the medianprogression-free survival of advanced
ovarian cancer is 16-22 months, and the5-year overall survival is20-30%.
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Factors correlate with poorprognosis in same stage
In early stage are histopathological type(serous vs. non-serous), degree or grade ofdifferentiation, the presence of denseadhesions, large volume ascites andspontaneous rupture of a cyst (Malkasian et al. 1984, Demboet al. 1990, Vergote et al. 2001)
In advanced stage the amount of residualtumour, performance status, type of
chemotherapy, substage, age of the patient,grade and in some studies histologicaltype Malkasian et al. 1984, Einhorn et al. 1985, Hunter et al. 1992, Venesmaa 1994a,Makar et al. 1995, Munkarah et al. 1997, Eisenkop et al. 1998, Bristow et al. 1999, Naik etal. 2000, Akahira et al. 2001, Vergote et al. 2001.
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Grade
No grading system available mainly becausethe same criteria are not applicable to allhistological types
Grading is clinically important only for stage1
No need of three grade systems usuallyproposed
Should be classified into either low or highgrade, because chemotherapy is withheld for
low grade stage I tumors in view of theiroutstanding prognosis when untreated Ovariancancer net
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Histologic Subtype
The prognostic significance of the histologicaltype is limitedFriedlander 1998.
It determines the chemoresponsiveness oftumor.
Glutathione S-transferase-pi (GST-pi), MDR(multidrug resistance)-1, and p53 expression
pattern is closely related to histologic subtypeof ovarian cancer, although they are notsignificant predictors of survival. Ikeda K et al 03
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Histopathological type Mucinous and endometrioid tumours are
more often diagnosed at early stages, whichcontributes to their more favourableprognosisMalkasian et al. 1984, Friedlander 1998.
Advanced stage mucinous tumours areknown to a have poor prognosis, probablydue to their chemoresistanceMakar et al. 1995.
Clear cell carcinomas are suggested to havea more aggressive biological naturecompared to the other typesMakar et al. 1995.
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Tumors with a micropapillaryarchitecture be designated"micropapillary serous carcinomas," andthose lacking these features, "atypical
proliferative serous tumors.
Presence of a micropapillaryarchitecture in the primary ovarian
tumor is a strong predictor of invasiveimplants. Seidman JD, Kurman RJ.2000
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Volume of Residual Disease
Standard therapy for advanced case consistof Optimal debulking - reducing tumor size to< 2 cm followed by platinum basedchemotherapy
Maximum cytoreduction is one of the mostpowerful determinants of cohort survival BristowRE et al 2002
Proponents point out that prognosis &survival correlate with residual disease.
Critics argue that survival advantage resultsfrom the biological inherent predisposition.
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Peritoneal cytology
Presence of ascites at the time oflaparotomy for ovarian cancer has been
associated with poor prognosis Patients with normal peritoneal
cytological specimens had better
survival rates than patients withabnormal findings
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Tumor rupture at surgery
Data are conflicting on tumor ruptureand capsular penetration at the time of
surgery. Findings warrants reassigning of stage I
or II tumor to IC or IIC , the prognostic
value of these features is unclear.
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Systematic lymphadenectomy (LNX)might be of benefit in conjunction withprimary optimal cytoreductive surgery inadvanced epithelial ovarian cancer (OC)
patients who do not respond toplatinum-based chemotherapy
No survival benefit could be seen in
platinum-sensitive patients. Seiji Isonishi 2004
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Platinum sensitivity
Patient relapsing 6 weeks after the endof cisplatin therapy are defined as beingPlatinum sensitive,whereas whosedisease progress in less than 6 weeksare considered Platinum resistance Loehreret al 88,Motzer et al 91,Gershenson 93
Interval from surgery to commencementof chemotherapy is not an independentprognostic factor for progression-freesurvival. Flyn nPM et al 03
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Primary Site of Tumor
The primary site of tumor was the onlyindependent prognostic factor for survival
& event-free survival of Malignant germcell tumors in childhood - gonadal hadgood survival than extragonadal Study "TCG 91". 03
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Tumor Markers No single biological tumor factor will
give accurate prognostic information forall ovarian cancer patients. On the other
hand, a combination of two or moreindependent factors may yield animproved overall prognostic index
In 1979 the significance of serum tumormarkers either before surgery orchemotherapy was studied.
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Tissue Tumor Markers
Oncogenes
ERBB2
MYC Ets-1
Tumor suppressor
genes BRCA 1
P53
Cell cycleregulators
p21 p27
DNA ploidy(aneuploidy)
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Markers of cellproliferation Ki67
AP2 Topoisomerase II
Growth factors PDGFR- fact de
crestere derivat dintromboocite
VEGF-fact de cersterea endoteliului vascular
CSF-fact de stimulareal coloniilor
Adhesion molecules CD44 -catenin
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ProteolyticEnzyme
UPA
UPAI1 KLK-5
MMP2
Collagen IV
Steroid HormoneReceptors
E and/or p
receptors Others
Hyaluronan
Bax Bcl-2
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Serum tumor markers
CA125
TATI
CEA CASA
Inhibin A
IAP VEGF
CSF-1
Soluble FAS
Interleukin 6 MAGE4
Tetranectin
HCG Progesterone /
estrogen
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CA125
CA125, a small heavily glycosylatedglycosylphosphatidylinositol - linked cellsurface protein,with molecular mass from220-1000kDa, is the most widely used
prognostic factor tumor marker in Epihtelialovarian cancer management.
Localized in most serous, endometrioid, andclear cell; mucinous tumors express this
antigen less frequently CA125 is, nevertheless, not sensitive and
specific enough to be used for diagnosis orscreening.
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Sensitivity is 69.8%,Specificiy 72.3%,
Positive Predictive value 49.2% &Negative Predictive value 86.2%Marinovic et al1997
Sensitivity may be improved by
measuring multiple complementarytumor markers such as OVX1, M-CSF(macrophage colony stimulating factor).
Normalisation in
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Tumor Markers in Ovarian
Germ Cell TumorsTUMOR HCG AFP LDH CA-125
Mixed germ cell tumorEmbryonal carcinoma
Endodermal sinus tumor
Dysgerminoma
Immature teratoma
Choriocarcinoma
++
-
-
+
++
+
-
-
+
+
++
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+
+
?
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Continued:
Dosage of HCG, LDH and FP isinformative in follow-up of germ cell
tumors Its prognostic value not clearly
established
Increased value signals a tumor relapsebut clinical progression can occur inabsence of increased signals.
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Presence of Progesterone
ReceptorsIn serous cancers presence ofprogesterone receptors is a favorablefactor of prognosis and, as a rule,associates with a high degree of tumourdifferentiation indicate the efficiency of
hormonotherapy and chemotherapy.Kolosov AE, Novichkov EV. 03
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Androgenic State in Women
Heightened androgenicity is linked to thepathogenesis and tumor biology ofepithelial ovarian cancer.
Li AJ, 03
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Patients' Psychological
Constitution Variables "genetic or hereditary risk",
"hormone replacement therapy" and "use oftobacco or alcohol" had no significant
influence on survival. "psychic disorders" and"parity" were found to be of strong prognosticinfluence,
Link between patients' psychologicalconstitution and course of disease suggestspsychotherapeutic support to be helpful forovarian carcinoma patients.
von Georgi R et al 02
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New Researches
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Loss of Heterozygosity on
theX Chromosome
Loss of heterozygosity (LOH) at micro-satellite markers DXS454 (Xq21-q23)appeared to be correlated with reducedsurvival
Hogdall EV et al 04 .
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Angiogenesis
Progression of disease depends ondynamism of angiogenesis.
But acc Sonmezer M et al 04 angiogenesisdoes not appear as a prognostic factor inepithelial ovarian cancer
Gene expression of Angiopoietin-1 (Ang-1) &
Angiopoietin-2 (Ang-2), might present apertinent diagnostic tool to select a high-riskgroup of patients Hata K,et al 2004
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Angiogenesis (CD 34 )
Endothelial marker CD 34 is a usefulmarker in determining tumourneovascularisation which might be ofprognostic relevance in patients with
ovarian cancer Heimburg S et al 99, Blok R et al 04
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Angiostatin Expression
The presence of angiostatin expressionand absence of VEGF expression arefavorable prognostic factors with regard tosurvival in ovarian carcinoma patients.
Yabushita H et al 03
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Vascular Endothelial
Growth Factor Vascular endothelial growth factor (VEFG) in
epithelial ovarian cancer did not affect patients'
survival but is an important mediator of ascitesformation Sonmezer M et al 04
Increased expression of VEGF-C, VEGF-D andVEGFR-3 was significantly associated with LN
and peritoneal mets outside the pelvis VEGF-D was found to be an independent
predictor of poor outcome Yokoyama Y et al 03
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ETS-1 a Transcription Factor
ETS-1 might act as an angiogenicmediator in, and be a prognostic factorfor, ovarian cancers.
Khatun S et al 03
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p53 Mutations
Abnormalities of p53 expression is an inducerof apoptosis. Expression of p53 wassignificantly associated with the tumor gradeand disease-free survival (DFS)
p53 status, and epidermal growth factorreceptor (EGFR) status were all independentand significant prognostic factors with regardto disease-free survival Berker B et al 02, Skirnisdottir I et al 2004
p53 mutations and over expression of K-rasaffect prognosis of ovarian endometrioidcancer but not clear cell cancer.Okuda T, et al 2003
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p21 Expression
p21 is a direct p53 response gene. p21expression is closely related to
sequenced p53 mutations and positivep21 staining can be an independent poorprognostic factor in p53-null ovarian
cancer. Rose SL et al 03
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Ki67 Antigen
Immunostaining (MIB 1Monoclonal Antibody)Proliferation index detected by Ki67 antigen
immunostaining may represent an indicator ofaggressiveness in serous ovarian tumors andan additionally useful prognostic factor incystoadenoma, probably independent of and
apparently more significant than the tumorarchitectural grade and the disease FIGO stage
G. Gioele Garzetti et al 02
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AgNORs Count in
Cancer Cell Mean number of AgNORs per nucleus
correlates better than grading with the
effect of chemotherapy in serousovarian cancer.
The quantitative assessment ofAgNORs is better prognostic factor
when compared to grading for theeffectiveness of adjuvant chemotherapyin serous ovarian cancer.
Gottwald L et al 03
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Cyclooxygenase-2 (COX-2) COX-2 over-expression is associated with
increased proliferation, reduced apoptosis,and angiogenesis.
Expression of COX-2 also was correlated withtumor angiogenesis but not with epidermalgrowth factor receptor (EGFR), Her-2/neu, orp53 expression.
COX-2 expression was correlatedsignificantly with survival in patients with high-grade, high-stage serous ovarian carcinoma
Ali-Fehmi R et al 03
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Prostasin - A Potential serum marker forovarian cancer.It is a secretory proteinpresent in prostate that is overexpressed in
epihtelial ovarian cancer Mok SC et al 2001
Osteopontin A Potential serum marker. AnRNA spotoverproduced in ovarian cancer
Kim J-H etal 2002
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Y Box-Binding Protein-1 andP-Glycoprotein
Co-expression of Y box-binding protein-1
and P-glycoprotein emerged as apromising relevant biomarker forunfavorable prognosis for survival in
epithelial ovarian cancer.Huang X, et al 2004
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Polo-like Kinase Isoform
The Polo-like kinase (PLK) family comprisesthree serine/threonine kinases, functionallyinvolved in signal transduction pathways
essential for the accomplishment of mitosis inboth normal and malignant cells.
PLK1 is a novel independent prognosticmarker in ovarian carcinomas. Inhibition of
PLKs might represent an interesting newtargeted approach for chemotherapy ofepithelial ovarian cancer.
Weichert W, et al 2004
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Lysosomal Aspartyl
Protease Cathepsin DStromal cathepsin D expression was anindependent prognostic factor for disease-
free survival (DFS) in patients withinvasive cancer, while cathepsin Dexpression missed to be of prognostic
value for overall survival (OS) in invasiveovarian cancerLosch A et al 04
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Multidrug Resistance-1Protein
Expression of multidrug resistance-1protein inversely correlates with paclitaxelresponse and survival in ovarian cancerpatients
Penson RT et al 04
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Type I & III CollagenMetabolites & Peritoneal Cells Malignant tissue growth induces marked
biochemical and structural changes in theextracellular matrix of the tumour and its
surrounding tissues. High preoperative serum type I collagendegradation (ICTP) & type III collagen (PIIINP)and a low type I collagen (PICP, PINP) ratio
correlate with poor prognosis Serum collagen metabolites, especially ICTP,
are important indicators of prognosis in epithelialovarian ca. Marja Simojoki2003
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Thrombocytosis
Thrombocytosis is a frequent preoperativefinding in ovarian and peritoneal carcinomasand may be a marker of aggressive tumorbiology.
Li AJ et al 04
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Fibronectin
Fibronectin is involved in tumourneovascularisation and metastasis, preventsapoptosis and is considered to be
immunosuppressive It is an important prognostic factor in ovarian
ca and may be central to tumour progression
Offer new treatment possibilities since several
agents may antagonize the mechanism offibronectin expression. Franke FE et al 03
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DAX-1 (Nuclear Receptor)
DAX-1 is a member of the nuclear receptorsuperfamily and is thought to be involved inthe regulation of steroidogenesis
DAX-1 immunoreactivity is considered to be anew independent marker of poor prognosis oradverse clinical outcome in patients with
epithelial ovarian carcinoma, possibly throughaltering in situ steroids production.Abd-Elaziz et al 03
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ERBB2 Gene Amplification
Increased copy number of ERBB2 was alsoassociated with high tumor grade, greaterpatient age, large residual tumor size, highproliferation index, aberrant p53 and negativeprogesterone receptor status.
A significant association was found betweenERBB2 amplification and ERBB2 protein overexpression.
Over-expression of ERBB2 protein wasassociated with poor overall survival, but theprognostic value was weaker than that ofERBB2 gene copy number status.
Lassus H et al 04
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KLK15 ( Kallikrein Gene )
KLK15 is a newly cloned human kallikreingene
KLK15 is up-regulated mainly by androgensand to a lesser extent by progestins in cancercell lines.
KLK15 expression is an independent marker
of unfavorable prognosis for ovarian cancer.Yousef GM et al 03
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Human Embryonic-Lethal
Abnormal Vision-LikeProtein HuR
Dysregulation of cellular distribution of themRNA stability factor HuR result in anincreased expression of COX-2, anincreased proliferative rate, and may lead
to a reduced survival time.Denkert C et al 04
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Protein Kinase Ciota
Alteration of PKC isoform expression may beinvolved in progression of ovarian ca.
Univariate survival analysis showed that
amongst other yet k/n prognostic parameters(FIGO stage, histopathological grading,proliferation index) PKCiota expression in pri.ovarian ca correlated significantly (p=0.024)with a reduced median survival time, but wasnot an independent prognostic factor.
Weichert W et al 2003
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YKL-40
YKL-40 (human cartilage glycoprotein-39), amember of family 18 glycosyl hydrolases, is agrowth factor and is secreted by cancer cells.
High plasma level in patients with ovarian
cancer stage III is related to shorter survival.Hogdall EV et al 2003
Proved to be an independent prognosticfactor in a multivariate Cox analysis including
serum CA-125 and clinical/histologicalparameters and is related to short survival inpatients with recurrent ovarian cancer.
Dehn H et al 03
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Bikunin Gene Expression
Low bikunin mRNA expression by ovarianca cells may identify patients with ovariancarcinoma who are at high risk for earlydisease recurrence and a poor prognosis.
Tanaka Y et al 03
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Skp2 Protein Expression
Skp2 expression might play an important rolein the development and progression of
ovarian adenocarcinomas, and Skp2 overexpression is an independent prognosticmarker of ovarian adenocarcinoma patients.
Skp2 protein expression is examined byimmuno-histochemistry
Shigemasa K et al 03
EMMPRIN
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EMMPRIN(Extracellularmatrix
Metalloproteinase inducer) EMMPRIN is a member of the
immunoglobulin superfamily of adhesionmolecules and has a role in the activation ofseveral matrix metalloproteinases (MMP).
EMMPRIN is a novel marker of poor outcome
in serous ovarian ca and is co-expressed withother MMP-1, MMP-9 and the alphav andbeta1 integrin subunits.
Davidson B et al
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PEA3 mRNA PEA3 mRNA expression is associated with
poor survival in advanced-stage ovarian ca.
Association b/n PEA3 mRNA expression andthe expression of the beta (1) integrinsubunit, basic fibroblast growth factor, andEMMPRIN, points to the central role of thistranscription factor in tumor progression inovarian ca.
Davidson B et al 03
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Cyclin E Expression Cyclin E is a key regulator of the G(1)-S
transition its expression was not associatedwith age, race, stage, grade, cell type but
associated with advanced, sub-optimallydebulked ovarian cancer patients
High cyclin E expression was an independentpoor prognostic factor for patients with
advanced ovarian ca, and it was associatedwith amplification of the cyclin E gene.Farley J et al 03
Mit A ti t d P t i
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Mitogen-Activated ProteinKinase Phosphatase-1
(MKP-1) MKP-1 (CL100) is involved in inactivation of
MAP-kinase pathways, regulation of stress-
responses and suppression of apoptosis. Immunohistochemical expression of MKP-1
protein was reduced in tissue from LMPtumors and invasive ovarian ca compared to
normal ovaries and cystadenomas and maybe associated with shorter progression-freesurvival times
Denkert C et al 02
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Maspin
Maspin is a noninhibitory member of the
serpin family and over expression wassignificantly associated with a high tumorgrade and may serve as an adverse
prognostic factorSood AK et al 02
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Conclusion
Significance of various prognostic factors areunclear and difficult to evaluatebecause of inconsistencies and confusion inthe literature.
But all ovarian tumors are independentlyeffected by stage at diagnosis, histologicalsubtype, tumor grade and vol. of residual
disease after surgery Of the three, the most important are stageand vol. of residual disease
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