Endometriosi e Cancro

Pubblicato : 2010 World Endometriosis Society, Society e-Journal Volume 12 No 1, 2010 8

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Negli ultimi anni  ci sono state diverse pubblicazioni  nelle quali si ipotizza sempre di più una associazione tra cancro ed endometriosi. Noi riteniamo che ciò non è vero. Dal nostro punto di vista i dati pubblicati sono insufficienti e  spesso incompleti , per cui, essendo tali  articoli  potenzialmente dannosi, in quanto potrebbero creare falsi allarmismi nelle donne affette da endometriosi, meritano quanto meno una  appropriata discussione.

Innanzitutto,la fisiopatologia dell’endometriosi ,ancora oggi,non è ben chiara .L’ipotesi etiopatogentica proposta da Koninckx ed altri nel 1997, “endometriotic disease theory”, considera le lesioni sottili superficiali come una normale e fisiologica condizione che  in maniera intermittente si verifica  in tutte le donne in età fertile,  mentre le lesioni tipiche, le cistiche e le profonde  sono da considerare come un tumore benigno e quindi causate da una alterazione del genoma determinata da diversi fattori inclusi quelli ambientali, ciò spiega anche l’ereditarietà, gli effetti della diossina e delle radiazioni, ed anche le mutazioni dell’endometrio delle donne affette da endometriosi .Sebbene l’Ipotesi di Sampson (impianto di cellule endometriali che affluiscono con la mestruazione retrograda attraverso le tube)  vista la presenza di  cellule vivo  nel liquido peritoneale   e la loro potenzialità di impianto,è molto attraente , non spiega  la progressione e mai , tra l’altro, è stata provata la progressione da un tipo all’altro di endometriosi .  consideriamo l’endometriosi come tumore benigno,  secondo la teoria di Koninckx  è normale che vi siano delle similitudini con tutti gli altri tumori benigni.

Brinton et al (1997)  hanno pubblicato  una odds ratio di 1.9 e 4 for developing ovarian cancer in women with endometriosis or ovarian endometriosis respectively, a conclusion based upon a Swedish hospital discharge diagnosis of endometriosis. The study of Melin et al (2006) finds an odds ratio of 1.2 equally based on a hospital discharge diagnosis of endometriosis. It can be anticipated that this group of women, in comparison with women without a diagnosis of endometriosis, had had more interventions, more pelvic pain, more medical treatments of endometriosis and probably more infertility treatments. Having been diagnosed with ovarian endometriosis means probable surgery of the ovary, very often focal coagulation leaving behind at least carbon deposits. It also means more adhesion formation etc. It is intellectually unfair to pick one aspect only –endometriosis– for the comparison of two groups of women who differ in many other aspects. This indeed is a fundamental problem of correlation and association statistics. Logistic regression and statistical model building were developed to find out which are independent and which are important factors. This obviously has not been done for the association of endometriosis and cancer. A second bias might have been introduced when analysing national discharge statistics. In most women ovarian endometriosis is diagnosed by ultrasound; and in a recent IOTA review (Van Holsbeke, in press) of over 2500 cysts, a risk of an (borderline) ovarian cancer was found in 1%. This could seem to support the argument, but analysing the data in detail, this is true only for women after menopause, a period of life that seems hardly associated with endometriosis. It would not be surprising if many women who did not have ovarian endometriosis by pathology ended up with a primary hospital discharge diagnosis of endometriosis. Tubal ligation Tubal ligation is associated with a decreased risk of ovarian cancer, a lower incidence of PID, and absence of retrograde menstruation. Tubal ligation, however, also influences in some women ovarian function and blood supply at least as evidenced by irregular cycles. Today we do not know how to explain exactly the decreased incidence of ovarian cancer in these women. The absence of retrograde menstruation does not seem logical as an explanation; indeed women with severe cystic ovarian endometriosis will have a higher incidence of infertility and thus a lower probability of undergoing tubal sterilisation. Accuracy of diagnosis It is surprising that the diagnosis of endometriosis is so easily accepted in the articles using hospital discharge records, knowing that the diagnosis of endometriosis is bound to have biases. Whereas for typical and deep lesions the probability of histological confirmation is very high, the rate of histological confirmation of subtle lesions is low, mainly dependent upon the expertise of the surgeon and the pathologist. Also for cystic ovarian endometriosis the histological confirmation of endometriosis, defined as stroma and glands, is not that well established and often pathology returns as ‘compatible with endometriosis’; most of these women, however, will be discharged as having endometriosis. Especially after menopause the diagnosis of endometriosis risks to be erroneous. Indeed, the occurrence of ‘cystic ovarian endometriosis’ or ‘large cystic ovarian endometriosis’ in women who did not have an existing cystic ovarian endometriosis before menopause is something rare and suspicious by definition. From the available data it is difficult to judge how strict the diagnosis of endometriosis was. Anyway, it would not be surprising, that many of these women were erroneously diagnosed as having had endometriosis. For recent prospective studies where women were followed by serial ultrasound Kobayashi et al (2009, 2008) the bias is obvious given that the ultrasound diagnosis of endometriosis has a specificity of 88% only. Moreover in the group of the 12% false positives the ovarian cancer incidence was 18% after menopause versus 0.6% before menopause (Van Holsbeke, in press). It is moreover questionable not to perform surgery in menopausal women with an ultrasound diagnosis of endometriosis. Menopause Unopposed oestrogen administration following menopause is associated with an increased risk of endometrial hyperplasia and adenocarcinoma. Following menopause, existing endometriosis will become inactive but will not disappear. Considering the prevalence of endometriosis in women before menopause it is very surprising that oestrogen-only therapy following menopause (in women without an endometrium) is not associated with an epidemic of adenocarcinomas originating from the endometriosis. This even looks as if endometriotic cells, although hormonally responsive, are pretty resistant to malignant transformation. Metastatic behaviour Especially deep endometriosis has invasive and „metastatic‟ behavior because of the positive lymph nodes. In our series of over 2000 deep nodules, only one however has turned out to be malignant, and this in a postmenopausal woman (unpublished data). In conclusion, the data describing an association between endometriosis, in particular cystic ovarian endometriosis, and ovarian cancer can be interpreted in many different ways. Today we do not consider the data sufficient to consider women with endometriosis or cystic endometriosis at risk for developing ovarian cancer, a conclusion already reached by others (Somigliana et al, 2006). It reminds us of the fact that so many ovaries have been removed prophylactically after age 50 to find out recently that women with ovaries live longer than women without ovaries (Parker et al, 2009)

„It ain’t so much the things we don’t know that gets us into trouble. It’s the things we do know that just ain’t so‟ Josh Billings

Philippe R Koninckx and Anastasia Ussia

KULeuven, Belgie en Gruppo Italo Belgo, Roma Italia

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