endometriosis & cancer• (12) somigliana e, vigano' p, parazzini f, stoppelli s,...

Moscow 17-20/1/2017

Endometriosis & Cancer

Phil ippe R. Koninckx *,***

Anastasia Ussia **,***

*Prof em KU leuven Belgium, Univ Oxford UK, Univ Sacro Cuore, Italy, Honorary Consultant UK, Hon Prof Moscow Univ

** Consultant Univ Sacro Cuore, Gemelli, Roma

***Gruppo Italo Belga, Leuven –Rome, Belgium Italy.

I l Bel lo i l Bruto I l Cattivo

Facts

Cancer and endometriosis

Should we take Action ?

Arguments PRO

Associations : clear cell and endometrioid

mutations

Interpretation : Arguments to doubt

Analysis of associations

Bias of endometriosis

Cause and effect

Conclusions

Ovarian carcinoma :1% lifetime risk

• Frozen pelvis

• Reactivation ?

• Dualistic pathophysiology

• Low grade : from borderline & endometriosis mutations in ARID1A, BCL2, BRAF, CTNNB1, ERBB2, KRAS, PIK3CA, PPP2R1A, PTEN, and ZNF217

• High grade : from fimbriae chromosomally highly unstable,

mutations : TP53 mutations in > 95% (rarely in type I).

aberrant expression of BRCA and its downstream genes mutation or epimutation

Serous Clear cell Endometrioid Mucinous Transitional Mixed

Prevalence %

69 12 10 3 1 6

Low grade

X X X x

High grade

X X x

‘endometriosis’ AND ‘cancer’ AND ‘review’

• (1) Anifantaki F, Boutas I, Kalampokas T, Kalampokas E, Sofoudis C, Salakos N. Association of endometriosis and breast cancer: mini review of the literature. Arch Gynecol Obstet 2016; 293(1):5-10.

slight correlation BRAC I BRAC II : inconclusive

• (2) Heidemann LN, Hartwell D, Heidemann CH, Jochumsen KM. The relation between endometriosis and ovarian cancer - a review. Acta Obstet Gynecol Scand 2014; 93(1):20-31.

an increased risk of clear-cell and endometrioid epithelial ovarian cancer when histologically verified endo

• (3) Zafrakas M, Grimbizis G, Timologou A, Tarlatzis BC. Endometriosis and ovarian cancer risk: a systematic review of epidemiological studies. Front Surg 2014; 1:14.

The main limitation of studies was the lack of operative confirmation of endometriosis

• (4) Worley MJ, Welch WR, Berkowitz RS, Ng SW. Endometriosis-associated ovarian cancer: a review of pathogenesis. Int J Mol Sci 2013; 14(3):5367-5379.

data molecular events associated with EAOC development from endometriosis,

• (5) Munksgaard PS, Blaakaer J. The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations. Gynecol Oncol 2012; 124(1):164-169.

• (6) Munksgaard PS, Blaakaer J. The association between endometriosis and gynecological cancers and breast cancer: a review of epidemiological data. Gynecol Oncol 2011; 123(1):157-163.

• (7) Pergialiotis V, Lagkadas A, Polychronis O, Natsis S, Karakalpakis D, Giannakopoulos K. Endometriosis-associated ovarian cancer. Presentation of a case report and review of the literature. Eur J Gynaecol Oncol 2011; 32(6):682-685.

• (8) Sayasneh A, Tsivos D, Crawford R. Endometriosis and ovarian cancer: a systematic review. ISRN Obstet Gynecol 2011; 2011:140310.

endometriosis AND cancer AND review

• (9) Wei JJ, William J, Bulun S. Endometriosis and ovarian cancer: a review of clinical, pathologic, and molecular aspects. Int J Gynecol Pathol 2011; 30(6):553-568.

• (10) Vlahos NF, Kalampokas T, Fotiou S. Endometriosis and ovarian cancer: a review. Gynecol Endocrinol 2010; 26(3):213-219.

• (11) Baldi A, Campioni M, Signorile PG. Endometriosis: pathogenesis, diagnosis, therapy and association with cancer (review). Oncol Rep 2008; 19(4):843-846.

• (12) Somigliana E, Vigano' P, Parazzini F, Stoppelli S, Giambattista E, Vercellini P. Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence. Gynecol Oncol 2006; 101(2):331-341.

• (13) Steed H, Chapman W, Laframboise S. Endometriosis-associated ovarian cancer: a clinicopathologic review. J Obstet Gynaecol Can 2004; 26(8):709-715.

• Vigano P, Somigliana E, Parazzini F, Vercellini P. Bias versus causality: interpreting recent evidence of association between endometriosis and ovarian cancer. Fertil Steril 2007;88:588–93.

• Kobayashi H, Kajiwara H, Kanayama S, Yamada Y, Furukawa N, Noguchi T, et al. Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (review). Oncol Rep 2009;22:233–40.

Sayasneh, A., Tsivos, D., and Crawford, R. Endometriosis and ovarian cancer: a systematic review. ISRN.Obstet.Gynecol. 2011, 140310. 2011

Sayasneh, A., Tsivos, D., and Crawford, R. Endometriosis and ovarian cancer: a systematic review. ISRN.Obstet.Gynecol. 2011, 140310. 2011

Results.

• 7/8 studies, have shown an increased risk of ovarian cancer.

• However, the effect size is modest (OR, RR, and SIR) ranging between 1.32 and 1.9 (95% CI).

remember >2.5 to be considered significant

• A causative relationship cannot be confirmed.

• There is increasing evidence on the role of genetic mutations in ovarian clear-cell and endometrioid carcinoma developing from endometriosis.

• Conclusion. More evidence is needed before suggesting any change in the current management of endometriosis.

Endometriosis and Ovarian carcinoma

Molecular considerations

• Genes /phenotypes in both

• Mutations at TP53

• K ras

• Co-occurrence and transition

• Surgery and IVF are obviously complementary

Guo, S. W Fertility and Sterility . 31-8-2015.



Arguments PRO


mutations

Arguments for doubt



Cause and effect ?

Conclusions

Vigano, P., Somigliana, E., Parazzini, F., and Vercellini, P. Bias versus causality: interpreting recent evidence of association between endometriosis and ovarian cancer. Fertility and Sterility 88(3), 588-593. 2007.

Vigano, P., Somigliana, E., Parazzini, F., and Vercellini, P. Bias versus causality: interpreting recent evidence of association between endometriosis and ovarian cancer. Fertility and Sterility 88(3), 588-593. 2007.

• A relationship between endometriosis and specific histotypes (clear cell and endometriod)

• but the low magnitude of the risk observed is consistent with the view that ectopic endometrium undergoes malignant transformation with a frequency similar to its eutopic counterpart

Prevalence • RR : Relative risk women with OVCA with Endo P(O|E)

with OVCA without Endo P(O|E)

• Depends on P(E) and P(E) in cancer

is independent of P(O)

• Thus RR for all subtypes of endo

Endometriosis and Ovarian Carcinoma Association

Guo, S. W Fertility and Sterility . 31-8-2015.

Prevalence

• Excess of endometriosis : with 10% P(E) RR : 3,59 clear cell

• Deficit in serous

• Extensive heterogeneity

• Smaller studies more postive association


Guo, S. WFertility and Sterility . 31-8-2015.

Case control

• Women with and without OvCA

• Association with risk factors …….

and thus with all factors associated with these factors

• Cause and effect

• Small increase in RR

• and Heterogeneity +++ (funnel)

8,2 hospital discharge records

12,4 pathology proven endo

(infertiity)


Case control

• Duration between diagnosis of endo and of OvCA

• Little info about type of endo, adenomyosis

• Little info on endo treatment


Case control

• Little info on treatment

• Drop of RR to 0.3 (.12 to .74) after complete removal( Sweden from National register) : thus a 70% protection




Arguments PRO


mutations

Arguments for doubt



Cause and effect ?

Conclusions

• Subtle 80%

• Typical 30%

• Cystic 10%

• Deep 2%

• Adenomyosis >50%

• Histologic confirmation

• Experience of the surgeon

• Hospital based records ??

• Over-representation • infertility and Pain

• And thus of all associated factors

Prevalence of endometriosis The water of a river cannot raise above its source


Arguments PRO

Associations and mutations

Arguments for doubt

Analysis and Bias of endometriosis

Cause and effect ?

Conclusions

Ovarian cancer : Risk factors

•

• infection ?

• Sounds like endometriosis

•


Histopathology ??

• [1] clear evidence of endometriosis close to the tumor (‘‘proximity’’);

• [2] the carcinoma must be seen to arise in endometriosis and not to be invading it from other sources (‘‘arising from endometriosis’’);

• [3] presence of tissue resembling endometrial stroma surrounding characteristic glands (‘‘endometrial stroma plus glands’’).

• the demonstration of a histology-proven transition from benign endometriosis to cancer (‘‘transition’’)


Conclusion I • From oncologic perspective

• Exces of endo in ovarian cancer

• Higher RR in women with endometriosis

• Similar biochemical/genetic alterations

• Both are clonal in origin

• But

Analysis suggest sampling problems : size & heterogeneity

• From endometriosis perspective

• Histology cannot give temporal data

• Endo prevalences are weak data The water of a river cannot raise above its source

Should we take action ?

• Screening, lab, imaging

• But the incidence of all new cases is reported to be 12.1 per 100,000

women per year ( Surveillance Epidemiology and End Results: http://seer.cancer.gov/statfacts/html/ovary.html,

Even a 99% sensit and 99% specif test -> of 100 positive 97 false

• Risk reducing surgery • Salpingectomy : mainly for type II non associated

• Oophorectomy : no

• Surgery and IVF are obviously complementary

http://seer.cancer.gov/statfacts/html/ovary.html



Guo, S. W. Endometriosis and ovarian cancer: potential benefits and harms of

screening and risk-reducing surgery. Fertility and Sterility . 31-8-2015.

Ovarian cancer : epidemiology II

• types I low-grade

• arises through well-recognized sequences from borderline serous tumors or putatively from endometriosis, and is frequently early stage and low-grade, with a relatively indolent disease course

• mutations in ARID1A, BCL2, BRAF, CTNNB1, ERBB2, KRAS, PIK3CA, PPP2R1A, PTEN, and ZNF217 (20).

• type II high-grade

• more common, present in advanced stage (stage II–IV) in more than 75% of cases, and is highly aggressive (20). They seem to originate from the fimbrial

epithelium (20). • chromosomally highly unstable, contain TP53 mutations in more than 95% of

cases, and rarely harbor mutations found in type I tumors (20, 21). of type II tumors have aberrant expression of BRCA and its downstream genes due to either mutation or epimutation (22).

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endometriosis & cancer• (12) somigliana e, vigano' p, parazzini f, stoppelli s,...

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