endometriosis & cancer• (12) somigliana e, vigano' p, parazzini f, stoppelli s,...
TRANSCRIPT
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
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.
Cancer and endometriosis
Should we take Action ?
Arguments PRO
Associations : clear cell and endometrioid
mutations
Arguments for doubt
Analysis of associations
Bias of endometriosis
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
Endometriosis and Ovarian Carcinoma 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)
Endometriosis and Ovarian Carcinoma Association
Case control
• Duration between diagnosis of endo and of OvCA
• Little info about type of endo, adenomyosis
• Little info on endo treatment
Endometriosis and Ovarian Carcinoma Association
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
Endometriosis and Ovarian Carcinoma Association
Cancer and endometriosis
Should we take Action ?
Arguments PRO
Associations : clear cell and endometrioid
mutations
Arguments for doubt
Analysis of associations
Bias of endometriosis
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
Cancer and endometriosis
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
•
Guo, S. WFertility and Sterility . 31-8-2015.
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’’)
Endometriosis and Ovarian Carcinoma Association
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
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).
•
•
Guo, S. WFertility and Sterility . 31-8-2015.