borderline tumor of the ovary -...

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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

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Mik

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on

Inva

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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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© AdB 2010

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 ?


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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 !


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%)


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


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


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5

10

15

20

25

30

35

40

45

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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

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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

borderline tumor of the ovary -...

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