Is it time to change theconsensus guidelines ?

Dr Efraim SieglerCarmel Medical Center

ChairmanThe Israeli Society of Colposcopyand Cervical & Vulvar Pathology

in the First Trimester -2-3CINObservation or LETZ ?

NO Conflict of interests

3.3/100.000

Arch Gyn Obs (2013) 287;245-250

130/100.000

Population –based study of 8.8 million births in Canada

CIN

CANCER CX

CARMELMedical Center

3% of Cervical Cancer occurred in pregnant

Women

McIntyre –Seltman –Obs Gyn ClinNorth Am:2008:35:645-658

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Women with high-grade CIN require treatment;

observational follow-up is not an option !

Cytopathology 2009,20,5-16

CIN 2-3 Management

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Why are we treating CIN 2-3 ?

1. Diagnose Cervical Cancer

2. Prevent Cervical Cancer

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Cervical Cancer is found in some 2% of women with HSIL ( on PAP Test ) , risk rises with age,

and is low in 21-24 years women Jones BA & al: Arch Pathol Lab Med 2000;124;672-81

CX Cancer is found in 5.4% of women with HSILon PAP Test +HPV HR + .

Katcki HA & al :JLGTD 2013;Vol 17;Issue 5, S50-S55

Why are we treating CIN 2-3 ?

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2.3% ( 1683 LLETZ operations because CIN 2- 3 )

Siegler E, Bornstein J; LLETZ in Israel ;

Invasive carcinoma diagnosed in excisional specimens of women treated because CIN 2-3 lesions

Up to 7% if unsatisfactory colposcopyDuddan BD et al : AJOG 1999;180(2)276-82

Gynecologic And Obstetric Investigation 2011; Vol. 72 (2), pp. 85-9

Why are we treating CIN 2-3 ?

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Mc Credie M & al The Lancet Oncology, Volume 9, Issue 5, Pages 425 - 434, May 2008

Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study

In 143 women managed only by punch or wedge biopsy, cumulative incidence of invasive cancer of the cervix or vaginal vault was

31·3% (95% CI 22·7—42·3) at 30 years,and 50·3% (37·3—64·9) in the subset of 92 such

women who had persistent disease within 24 months.However, cancer risk at 30 years was only 0·7% (0·3—1·9) in

593 women whose initial treatment was deemed adequate or probably adequate, .and whose treatment for recurrent disease was conventional

Preventing Cervical Cancer

During the years 1965- 1975 Dr. Green didn't treat patients with CIN 3

80%

Schiffman M ,Rodriguez AC. Heterogeneineity in CIN 3 diagnosis Lancet Oncology 2008:9:404-408

CIN 3

20% of CIN 3 progress to

Invasive Carcinoma within 5 years

5 30

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GUIDELINES OF CIN TREATMENTS in PREGNANCY

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Journal of Lower Genital Tract Disease Vol 11 No 4,2007,223-239

Cytopathology 2009,20,5-16

Guidelines of CIN TREATMENTS in PREGNANCY

Obs & Gyn Vol 112,No 6 Dec 2008 p1419-1444

Massad LS & al JLGTD Supplement April 2013 S1-S27

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Management of ACOG Abnormal Pap & CIN in pregnancy( 2008 )

Hunter M. & al ; CIN in Pregnancy AMJOG July 2008 ;Vol 3-9

TREAT ONLY IF INVASION IS SUSPECTED

Why delay Treatment ?

1.CIN 2-3 doesn't progress to Invasion !

2.The treatment is very dangerous ! Abortions,severe bleeding, premature delivery ) (

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10-70 % Regress /Disappear

25-47% Persist 3%-30% Progress !

Palle C et al : April 2000 Acta Obst Gynec Scand79;306-10;2000Vlahos G et al : Gyn Obstet Invest 2002;54;78-81Yost NP et al ;Obs Gyn 93;359-362;1999Douviers et al :Gynecol Obs fertility 31;851-855;2003.

Fader AN,&al; AJOG 2010;203;113e1-6

CIN Lesions during Pregnancy :

The risk of CIN 2-3 to progress to Invasive Carcinoma ?

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PROGRESNo(%)

PERSIS%

REGRES %Dig AgeNo

-Name

04753HSIL 22.6104Fader : AJOG 2010068-70CIN 2-324153Yost : Ob& Gyn 19990HSIL 2381 Wetta LA : JLGT 2009

04852HSIL25<7Cubo Abert :JLGTD 2012

Regression- Persistence Progression to Carcinoma

CIN 2-3 In pregnancy

345 0

Carcinoma Cervix U S

Cervical Cancer Incidence in women :Younger than 20 years was 0.05/100,000 women Women at 35-39 years was 15/100,000

30-40

Surveillance Epidemiology and End Results ( SEER ) Nov 2010;Nat Cancer Inst 2011

CARMELMedical Center

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NOName No

PatMeanAge

Dig Regress (%)

Persist (%)

Progress (%)

1 Copolla A :Gyn Onc :67:162-165 ( 1997) 26 26 CIS 88 2(8%)

2 Giraud: J Gynecol Obstet Biol Reprod (Paris). 1997; 16 CIN 3 3(18%)3 Pale C : Acta Obs Gyn Scandina 2000 Apr ;79;(4) 306-10 97 28 CIN 2-3 8 89.6 2(2%)4 Mitsushasi A ; Int J Obst & Gyn 71(2000) 237-239 9 2 ( 22.2%) 5 Vlahos G :Gy Ob Inves 2002 :54:78-81 78 28 CIN 2-3 61 38.4 06 Kaplan K :Cancer Cytopathology 2004:102;228-32 28 26 HSIL 100 3(10.7%)

7 Robova H :Eur J Gynaecol Oncol. 2005;26(6):611-4. 62 6(9.7%)8 Ackerman S ::Acta Obstet Gynecol Scand.

2006;85(9):1134-1137 77 CIS 34% 63.1% 2(2.6%)

9 Frega A:Anticancer Research 27:2743-2746(2007) 16 31 CIN 3 62.5 37.5 1(4.7%)10 Serati M:Acta Obstet Gynecol Scand.

2008;87(12):1296-300.36 30 CIN 2-3 47 52 0

11 Cubo-Abert M :JLGTD 16(1) 34-38 Jan 2012 ( Over 25 years ) 33 >25 HSIL 26 67 2 (6.1%)12 Coppolilo: Acta Obst Gyn Scan 2013:92;293-7 30 CIN 2-3 16.7% 70% 4( 13.3%) 13 Schaefr K : Int J Gynaecol Obstet. 2012 Aug;118(2):141-4. 27 31 CIN 3 89 3(11%) 14 Karrberg C : Acta Obstet Gynecol Scand. 2013 Jun;92(6):692-9. 42 30 CIN 3 3(7.1%)

15 Siegler E : J Low Gen Tract Disease Vol 18 No 2 2014:162-68 31 32.5 CIN 2-3 4 (12.9%)

37 (6.0%)

CIN 2- 3 in Pregnancy - Progression to Carcinoma OVER 25 years old

60837

)6.1%(Rome 3.2015 SIEGLER

NOName No

PatMeanAge

Dig Regress (%)

Persist (%)

Progress (%)

1 Copolla A :Gyn Onc :67:162-165 ( 1997) 26 26 CIS 88 2(8%)

2 Giraud: J Gynecol Obstet Biol Reprod (Paris). 1997;26(5):496-502

16 CIN 3 3(18%)

3 Pale C : Acta Obs Gyn Scandina 2000 Apr ;79;(4) 306-10 97 28 CIN 2-3 8 89.6 2(2%)4 Mitsushasi A ; Int J Obst & Gyn 71(2000) 237-239 9 2 ( 22.2%) 5 Vlahos G :Gy Ob Inves 2002 :54:78-81 78 28 CIN 2-3 61 38.4 06 Kaplan K :Cancer Cytopathology 2004:102;228-32 28 26 HSIL 100 3(10.7%)

7 Robova H :Eur J Gynaecol Oncol. 2005;26(6):611-4. 62 6(9.7%)8 Ackerman S ::Acta Obstet Gynecol Scand.

2006;85(9):1134-1137 77 ???? CIS 34% 63.1% 2(2.6%)

9 Frega A:Anticancer Research 27:2743-2746(2007) 16 31 CIN 3 62.5 37.5 1(4.7%)10 Serati M:Acta Obstet Gynecol Scand.

2008;87(12):1296-300.36 30 CIN 2-3 47 52 0

11 Cubo-Abert M :JLGTD 16(1) 34-38 Jan 2012 ( Over 25 years ) 33 >25 HSIL 26 67 2 (6.1%)12 Coppolilo: Acta Obst Gyn Scan 2013:92;293-7 30 ? CIN 2-3 16.7% 70% 4( 13.3%) 13 Schaefr K : Int J Gynaecol Obstet. 2012 Aug;118(2):141-4. 27 31 CIN 3 89 3(11%) 14 Karrberg C : Acta Obstet Gynecol Scand. 2013 Jun;92(6):692-9. 42 30 CIN 3 3(7.1%)

15 Siegler E : J Low Gen Tract Disease Vol 18 No 2 2014:162-68 31 CIN 2-3 4 (12.9%)

37 (6.0%)

CIN 2- 3 in Pregnancy - Progression to Carcinoma OVER 25 years old

608

1

Women over 25 years with CIN 2-3 lesions

had a risk of 6.1 % to progress

to Invasive Carcinoma

37)6.1%(

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Albert Szent-GyörgyiNobel Prize 1937Vit C discovery

Discovery consists of looking at

the same thing as everyone else

and thinking something

different

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Why are the wrong recommendations ?

• Mixing different grade of CIN in one article .

• Mixing different ages in one article .

• Mixing complications of LLETZ treatments during all the trimesters of pregnancy in one article .

• Old articles ( Knife Cone ) .

• 90-95 % of CIN 2-3 doesn't progress to Invasive Cancer in one year!(5-10% will progress to invasion )

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The gestational age range of those

patients who had significant morbidity

was 27–34 weeks

:

Robinson January 1997 Vol 64, 153–155

Copolla A :GynOnc 1997 :67:162-

1652 (8%) Cancer

Yost : Ob& GyMean age:

24 years

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Morice P ,Uzan C ,Gouy S –The Lancet Volume 379, Issue 9815,Pages 558-9,11.2 2012

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CIN 2-3 diagnosed during pregnancy Partial data from ISRAEL registry 2006-2014

women were diagnosed with CIN 2-3 76years 32.5Average age

•Final pathological results are known in 74 women

• Cervical Cancer 5 women 6. 8% • CIN 2-3/ AIS 56 women 75.7%• CIN 1 4 women 5.4%• Normal 9 women 12.2%

Total 74 women 100%

Siegler E (1, 4), Vaknin Z (2, 5) Amit A (3, 4), Lavie O (1, 4), Mackuli L (1), Auslender R (1, 4), Weissman A (2, 4)and The Israeli Colposcopy Group-Department of Obstetrics and Gynecology, Carmel Medical Center (1), Assaf Harofe Medical Center (2),Rambam Medical Center (3), Rappoport Faculty of Medicine, Technion Insitute of Technology (4), Haifa, Israel, Sackler Faculty of Medicine, Tel Aviv University (5), Tel Aviv, Israel

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INVASIVE CARCINOMA 2 women ( 5.8% )

)64.7%(22 women :CIN 2-3

CIN 1 / Normal 10 women ( 29.4% )

Total 34 women

1 Women still pregnant1 Women lost to follow up.

• Doctors recommendation• Women preference.

CIN 2-3 during PREGNANCY OBSERVATION Group

36 women were followed during pregnancy Average age - years 32.4

In 34 women the final pathological result is known :

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INVASIVE CARCINOMA : 3 women (7.5 %)

CIN 2-3 /AIS : 34 women (85%)

CIN 1- Normal Histology : 3 women ( 7.5% )

• Total 40 women (100%)

40 women underwent LLETZ till 14 weeks Average age - years 32.5

CIN 2-3 during PREGNANCY LLETZ Treatment Group-( I Trimester)

* 1 women =18 weeks

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CIN 2-3 during PREGNANCY LLETZ Treatment Group-( I Trimester)

40 women underwent LLETZ till 14 weeks

• ANESTHESIA : • 32 operations –General anesthesia: • 8 operations local anesthesia .

Complications :

• No women suffered massive / severe bleeding .

• 2 women were treated because minor bleeding

• 1 women –Cervical suture at 22 w / Delivery 37 weeks

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7 women underwent LLETZ and D +C

• 4 women - Missed Abortion before LLETZ .• 3 women - Termination of Pregnancy .

33 women continued their pregnancy

• 23 women - ( 69.7 %) Term delivery • 2 women - ( 6.1 %) Late preterm delivery (34,34 W)• 7 women - ( 21.2%) Ongoing III Trimester • 1 women - ( 3%) Ongoing II Trimester

CIN 2-3 during PREGNANCY LLETZ Treatment Group-( I Trimester)

40 women underwent LLETZ till 14 weeks

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*

Diagnose Invasive Cancer in 7.5% of the women .

No case of severe bleeding/ abortion .

Most of delivery –Term or Late pre term .

No case of recurrence after delivery .

Our Experience with 40 LLETZ during the first trimester

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TotalLLETZTreatment

Observation

5(6.8%)3(7.5%)2 (5.8%)CANCER

56 (75.7%)34(85%)22 ( 64.7%) CIN 2-3/AIS

13(17.5%) 3(7.5%)10 (29.4%) CIN 1/ NORMAL

743634TOTAL Final Pathology) (

2ONGOING/ LOST

764036TOTAL

CIN 2-3 diagnosed during pregnancy Partial data from ISRAEL 2006-2014

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No

Author (year) I st TrimesLLETZ

CinIII

Invasive Ca./MIC

Term deliveries

1 Dunn 1981 1 1 1(100%)2 Hannigan

1982 ( Knife Cone )13b ? 7c ( 100%)

3 Robinson 1996 2 1 2 (100%)4 Penna -1998( Laser) 8 8 8(100%)5 Fambrini (2007)

(Laser)26 2

6 Mitsuhashi 2000 9 5 2 9 (100%)7 Frega 2007 5a 4 1 5(100%)

8 Schaefer 2012 18 16 2 16 (88%)2 Late Preter

9 Siegler 2014 40 34 3 24(82?%)2= 34,34,w

TOTAL 118 69 10(8.5% )

LLETZ /LASER CONE till 16 weeks

( This study -Not Published )

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HippocratesBC 377-460

Science is the father of knowledge,

but opinion breeds ignorance.

For too many years the treatment of pregnant women is based on opinions,

Its it time for guidelines and decisions based on science

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François-Auguste-René Rodin

LLETZ during the first trimester appears to be a safe procedure with few complications.

The benefit of diagnosing Cervical Cancer in 6-10% of the women should be considered against the risk of complications .

In each women a personalized treatment should be selected according to the pathological results, the colposcopic image ,the HPV type ? the risk factors of the women and the patient preference.

Also DURING PREGNANCY

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*Williams –Obstetrics 16Th

Edition

Muller CY :Obs Gyn Clin N Am 32(2005) 533-546

Dunn TS ; Gyn Oncol 90(2003) 577-580

DURING PREGNANCY ALSO

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BAHAI GARDENSHAIFA

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TEL HASOMER CIN 3 -11.2014 SIEGLER