borderline tumor of the ovary -...
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© AdB 2010
Borderline Tumor of the OvaryBorderline Tumor of the Ovary= BOT = LMP Tumors= BOT = LMP Tumors
Taylor, 1929: „semi-malignant tumors of the ovary“
UICC, 1964: separate entity
FIGO, 1971: serous cystadenoma with proliferating activity
but with no infiltrative destructive growth (low
potential malignancy)
WHO, 1973/1999: „borderline malignancy“
(low malignant potential)
Should not be used anymore: Borderline Carcinoma, Carcinoma of
low malignat potential
du Bois A, Ewald-Riegler N, du Bois O, Harter P , Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833including > 100 series with > 10,000 pts.
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Epidemiology BOT vs. Ovarian Cancer
SHERMAN; ME et al. Hum Pathol 2004:
Pts. with BOT are younger (and fitter !?)Pts. with BOT are younger (and fitter !?)
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Epidemiology BOT vs. Ovarian Cancer
BOT are diagnosed more frequently in FIGO stage IBOT are diagnosed more frequently in FIGO stage I
du Bois A, Ewald-Riegler N, du Bois O, Harter P , Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
FIGO I in BOT:6,362 pts. in serie unselected for FIGO stage
FIGO I FIGO II-IV
FIGO I in invasive OC:6,362 pts. in serie FIGO World Report 26
Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary, Int J Gynecool Obstet 2006;95 (suppl 1): S 161- S 192
FIGO I FIGO II-IV
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Survival BOT and invasive Ovarian CarcinomaFIGO World Report Vol. 26
Pts. with BOT have a much better prognosis !Pts. with BOT have a much better prognosis !
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Mucinous Histology in BOT vs. Ovarian Cancer
du Bois A, Ewald-Riegler N, du Bois O, Harter P , Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
S-BOT and M-BOT:5,808 pts. in series unselected for histology
S-BOT M-BOT others
Helen J Mackay, Mark F Brady, Amit M Oza, Alexander Reuss, Eric Pujade- Lauraine, Anne M Swart, Nadeem Siddiqui , Nicoletta Colombo, Michael A Bookman , Jacobus Pfisterer, Andreas du Bois, Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial ovarian cancer. Abstract IGCS, Bangkok 2008
Mucinous and serous histo-typein invasive OC: metaanalysis of 8 GCIG studies including 9,791 pts.
serous mucinous others
© AdB 2010K Levanon et al. JCO 2008
„Two-Pathways-Hypothese“
High-grade Pathway
Low-grade Pathway
• Tube (via TIC)
• surface epitheliumof the ovary
• Mullerian epitheliumperitoneum
• Inclusion cysts
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Landen CN et al. JCO 2008
„Two-Pathways-Hypothese“
Inactivation of tumor-suppressors
Like protein phosphatase 2a (PP2A),
p53, or pRb in vitro induce
invasiveness of BOT
MM Woo et al., Gynecol Oncol 2008
Still under debate:Still under debate:•• malignant transformationmalignant transformationoror
•• coincidence (susceptibility)coincidence (susceptibility)of de novo carcinomaof de novo carcinoma
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Prognostic Factors
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Implants in BOT• non invasive
• epithelial• desmoplastic
• invasive
Courtesy by Frieder Kommoss & Stefan Hauptmann:
Prognostic factors: FIGO stage / Implants
Literatur review*:
• 75 series including 7.268 pts.; 80% FIGO I
• Recurrences
• all histo-types: FIGO I: 5,8% FIGO > I: 25,4%
• S-BOT only: “ 6,3% “ 30,2%
non invasive invasive
Still a BOT !
* du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
© AdB 2010Seidman und Kurman 2000; du Bois et al. 2009
Prognostic factor: invasiveness of implants
Metaanalysis (23 series)
Median observation period: 89 months
FIGO stage II/III: 467 pts.
non-invasive implants: 363 (78%)
recurrence:
died:
Survival rate :
n.a.
17 (4.7%)
95%
invasive implants: 104 (22%)
recurrence:
died:
Survival rate:
n.a.
35 (34%)
66%
30 series
905 pts.
839
19,6%
n.a.
237
40,7%
n.a.
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Prognostic factors in S-BOT
Literature review*:
• Microinvasion:
• 17 series, 265 pts.
• in 12,3% of S-BOT
• recurrence rate 23,2%• prognosis independent of FIGO (?)
• micropapillary growth:
• 17 series, 305 pts.
• in 9.5% of S-BOT
• recurrence rate 36,1%
• prognosis independent of FIGO (?)
© F. Kommoss
© F. Kommoss
* du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
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Clinics
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Clinical, pre-OP diagnosis in BOT= the majority of pts. are primarily operated inadequately
(at least 25% each understaged and or overtreated –> frozen section?)
Spain: Cusido M et al. Gynecol Oncol 2007
Pre-OP diagnosisNumber of hospitals: 323
3,4%(n=11)
8,4%(n=27)
19,5%(n=63)
(n=91)
54,2%(n=175)
0%
50%
unclear suspectcancer
probablybenign
suspectBOT
n.a.
Multiple answers were allowed
100% 48,4% 22,3% 27,3% 2%
!! !!
28,2%
Germany: Coumbos A, Könsgen D, Sehouli J, Kühn W 2006
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Re-Staging after incomplete staging initially?
Author Pts.Pts. with up-staging = pts. with residuals detected during Re-staging
inital FIGO stage
definitive FIGO stage
all serous BOT
n % n %
Fauvet 2005 30 6 20 5/n.a. - 5 x FIGO IA1 x FIGO IC
2 x IB, 1 x IA, 2 x IIIA1 x IIIC
Maneo 30 11 33 n.a./22 -
Odegaard 21 1 6 n.a. - 21 x FIGO I IA -> IB
T.-Colomer 7 1 14 1/n.a. - 7 x FIGO IA IA -> IB
Hopkins 15 7 46 n.a. - 7 x FIGO I A 2x IB/C, 1 x IIA, 1 x IIB, 3 x III
Darai 42 9 21 6/17 35 28 x FIGO IA12 x FIGO IC1 x FIGO IIA1 x FIGO IIC
2 x IB, 2 x IIIA/C1 x IIIC1 x FIGO IIB1 x FIGO IIIC
Fauvet 2004 54 8 15* 7/29 24 41 FIGO I
13 FIGO II/III
3 x IB,1x IIA, 1x IIB, 1x IIIA, 1x IIIC1x FIGO IC-> IIIC-
Snider 27 5 19 4/13 31 27 x FIGO I 1 x IA-> IB, 3 x II, 1 x III
Querleu 30 8 27 4/12 33 30 x FIGO IA 4 x IC, 2 x IIIA , 1x IIIC
Camatte 28 14 50 14/n.a. - 28 x FIGO I 9 x FIGO IA/B -> IC, 5 x IIIA
all 284 70 24,7% 21/71 29,6%
du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
Impact of reImpact of re--staging on recurrence rate (possible) staging on recurrence rate (possible) –– on survival (probably low) ?on survival (probably low) ?
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Therapy guidelines in BOT - HSK-Standard(adapted from German AGO-Guidelines)
• vertical laparotomy (or: informed consent for endoscopy)
• inspection and palpation of whole abdominal cavity
• Cytology and blind peritoneal biopsies
• resection of all adhesions or suspect lesions
• omentectomy
• bilateral salpingoophorectomy and hysterectomy (or: informed consent for fertility sparing surgery)
• appendectomy in M-BOT or unknown histo-type
• (intra-OP frozen section ?) and post-OP centralpathology review in all cases
• no lymphadenectomy (without any prognostic impact)
• no post-OP chemotherapy
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When do you give adjuvant chemotherapy to BOT pts. ?
(survey in 323 hospitals treating BOT)
J Sehouli et al, BMC 2009
53,6%
(n=173)51,4%
(n=166)
31,9%
(n=103)
10,5%(n=34)
77,1%
(n=249)
52,9%(n=171)
73,7%
(n=238)
R2
Res
ect
ion
Mik
roin
vasi
on
Inva
sive
Impl
anta
te
Sta
ge
I
Sta
geII
Sta
geII
I
Sta
ge
IV
53,6%
(n=173)51,4%
(n=166)
31,9%
(n=103)
10,5%(n=34)
77,1%
(n=249)
52,9%(n=171)
73,7%
(n=238)
R2
Res
ect
ion
Mik
roin
vasi
on
Inva
sive
Impl
anta
te
Sta
ge
I
Sta
geII
Sta
geII
I
Sta
ge
IV
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Why do we not give adjuvante chemotherapy ?
C Trope et al., Gynecol Oncol 1993
Metaanalysis of 4 prospective studies in Norway including BOT FIGO I/II
• survival without adjuvant therapy: 99%
• with adjuvant therapy (radio-/chemotherapy): 94%
TA Longacre et al, Am J Surg Pathol 2005
276 pts. with BOT and at least 5 years follow-up
• 113 pts. with FIGO II-III
• 52 pts. with adjuvant therapy (34 Chemo, 8 Rad, 10 Chemo+Rad)
-> 71% survived after126,5 months median follow-up (60-516 mos.)
• 61 pts. without adjuvant therapy
-> 87% survived after 93 months median follow-up (60-270 mos.)
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Literature (no randomized trials!):
• 34 series with 693 pts. with adjuvant chemotherapy and
1.253 pts. without adjuvant chemotherapy
with chemotherapy without chemotherapy
FIGO II-IV FIGO I FIGO II-IV FIGO I
pts. WithRelapse
Pts. With relapse
Pts. With relapse
Pts. With relapse
546 185
(33,9%)133 19
(14,3%)
533 60
(11,3%)550 42
(7,6%)
Why do we not give adjuvante chemotherapy ?
du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
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Prognostic factor: surgery of BOT• Cystectomy vs. salpingoophorectomy
Yokoyama Y et al. BJC 2006
Risk for recurrence:
Cystectomy Unilateral Salpingoophorectomy
Bilateral Salpingoophorectomy
Pts (FIGO I) 33 100 180
Recurrence 10 (30%) 11 (11%) 3 (2%)Poncelet Y et al. Ann Surg Oncol 2006
Literature:• 27 series: 435 pts. with cystectomy and 1.718 pts. with USO/BSO• recurrence rate: 31,4% after cystectomy
7,7% after USO/BSO
• Prognosis: PFS +++, quo ad vitam (+/?) --> informed consent !> informed consent !
du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
x 2x 2
x 5x 5--1515
x 4x 4
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• Laparoscopy (LSK) „versus“ Laparotomy
Author Pts.FIGO II/III
Laparotomy Laparoscopy
Pts. Rupture Relapse Pts. Rupture Relapse
Liapis 93 22,6% 86 k.A. 5 7 k.A. 3
Lackmann 16 100% 15 k.A. 3 1 k.A. 1
Desfeux 118 - 54 k.A. 5 48 k.A. 1
Poncelet 313 - 218 40 12 95 34 12
Maneo 62 1,6% 32 7 7 30 16 11
Romagnolo 113 11,5% 61 18 6 52 4 7
De Iaco 168 14,9% 112 27 19 57 24 8
Ren 234 31,2% 182 20 19 45 16 7
Fauv et 358 8,4% 209 14 19 149 51 18
Odegaard 107 - 69 11 0 38 11 0
Nezhat 11 18,2% - - - 11 k.A. 2
Palomba 32 9,4% - - - 32 5 19
Darai 25 4,0% - - - 25 12 4
Seracchioli 19 - - - - 19 2 1
Tinelli 43 - - - - 43 6 3
alle: 1.038 137 95 652 185 97
Rupture in pts. with information: 137 of 771 (17,8%) 185 of 585 (31,6%)
Relapse in pts. with information: 95 of 1.038 (9,2%) 97 of 652 (14,9%)
du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
x 2x 2x 1.5x 1.5
Less adverse events vs higher risk Less adverse events vs higher risk --> informed consent !> informed consent !
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• Fertility sparing versus radical surgeryLiterature: 67 series
FIGO Stages
Fertility sparing OP Radical OP
Pts.Relapse
Pts. Relapseall Ovary only
all FIGO 2.868 439 303 3.735 182
(%)* 15,7 %439 of 2.794
74,5 %284 of 381
4,9 %
FIGO I 1.810 223 168 2.076 52
(%)* 12,6 %190 of 1.504
84,8 %168 of 198
2,4 %49 of 2.076
FIGO II-III 256 97 53 437 54
(%)* 44,8 %94 of 210
54,0 %47 of 87
13,9 %48 of 345
* % of those cohorts with complete information available
du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
x 1.5x 1.5
higher recurrence risk outside ovary in FIGO IIhigher recurrence risk outside ovary in FIGO II--IIIIII--> informed consent !> informed consent !
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Outcome BOT• Recurrence• need for Re-OP• death ?
Outcome • children • Endocrinum• cosmesis (LSK)• Morbidity (LSK)
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Outcome relapsed BOT -> invasives (low grade) carcinoma?
Literature: 89 series
Pts.
Recurrence deceased
Pts.invasive
recurrenceof disease
(DoD)DID
all: 8.234 pts. 919 201 269 333
Recurrence rate: 11,0% 27,5%of all recurrences
26,2%of all recurrences
All with >5 yrs.follow-up: 4.903 pts.
616 167 191 252
recurrence rate: 11,7% 33,3%of all recurrences
30,4%of all recurrences
Relation DoD : DID = 1 : 1,7
du Bois A, Ewald-Riegler N, du Bois O, Harter P, Borderline tumors of the ovary – a systematic review. Geburtsh Frauenheilk 2009; 69 : 807-833
© AdB 2010
0
5
10
15
20
25
30
35
40
45
50
1 - 5 5 - 10 10 - 15 15+ Jahre
Silva 06 Nakashima 90 Bell 88 Pratt 02 Suh-Burgmann 06Sykes 97 Winter 02 Bostw ick 86 Laurent 08 Casey 93Crispens 02 Desfeux 05 Ji 96 Julian 72 Kennedy 96Longacre 05 Morice 03 Trope 93 Buttin 02 Hogg 06McKenney 06
Pts. Deceased due to relapsed BOT
0
5
10
15
20
25
30
35
40
45
50
1 - 5 5 - 10 10 - 15 15+ Jahre
only series with > 7 years median follow-up
34% 30% 14% 19%
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Recommendation HSK: Treatment of BOTChild bearing desire
no
Radical surgery
fertilitysparing OP
Implants
Consider re-OP aftercompletion of family
planningno yes
no yes
non-invasive
invasive
Cytologie,Omentectomy,
Peritoneal biopsies,Appendectomy
(in M-BOT)
Hysterectomyand
Adnexexstirpationbilaterally (BSO)
Adnexexstirpation unilaterally (USO)
orcystectomy unilaterally
(CE – after. USO)or
USO+CE ifbilateral BOT
yes -
Follow-up for at least 15 years including anamnesis, gyne exam.,VUS
microinvasionmicropapillary typeintracyst. carcinoma