WES e-Journal : Spring 2004

The next IFFS meeting will be held in Montreal, May 23-28, 2004. As Secretary-General of WES and member of the organizing committee of the IFFS meeting, I would like to take this opportunity to welcome you all to Montreal. The meeting promises to be extraordinary and I encourage everyone to attend.

Endometriosis and cancer is a topic of constant interest. In this issue of the newsletter the topic is addressed by Dr Agneta Bergqvist in her article Endometriosis and The Risk of Malignancy.

Rodolphe Maheux
Secretary-General

In March 2002, Procrea, a Montreal Biosciences company, marketed the MetrioTest, a minimally invasive diagnostic tool for endometriosis. The MetrioTest was presented as an uncomplicated procedure requiring only an endometrial biopsy and a blood sample. Quote: “A single 15-minute session carried out in the doctor’s office without anesthesia is all that is required.”

The presence of endometriosis was based on the ratio of a series of different markers, mostly inflammatory, and Procrea claimed that in 95% of cases this test could establish whether a patient had endometriosis. Widespread enthusiasm followed. In April 2002, the MetrioTest won the GENESIS award for Innovation at BioHealth 2002, the gala organized by the Quebec BioIndustries Network.

This new test for endometriosis was then advertised in medical journals and at different clinical meetings. It was also reviewed in women’s magazines. Many physicians started to offer it as an alternative to laparoscopy to patients presenting with infertility or pelvic pain.

The procedure raised the hopes of many patients. Additionally the company announced a new collaboration to identify gene mutations that predispose women to endometriosis. It was hoped that this would lead to a second or even third-generation MetrioTest in the near future

Then the shock: in July 2003 , following the decision of their main investor to stop financing, the administrators of Procrea BioSciences all resigned. The company ceased its activities, leaving doctors and patients who believed in them on their own.

Many lessons can be learned from this adventure. In the new few years we will see many new tests developed to detect endometriosis. As was the case with the MetrioTest some will be presented without giving access to the underlying data, on the basis that the inventors have to protect their patent.

The MetrioTest was based on detection of the inflammatory response provoked by endometriosis but was it better than the old CA125 or CA19-9 or the clinical exam or pelvic ultrasound? The data was just not there. We cannot find a single reference to the MetrioTest in PubMed. In future physicians should resist using new tests in their practice without access to comparative trials proving their positive and negative predictive values.

When should a laparoscopy be performed to diagnose endometriosis? Almost never for the sole purpose of diagnosing endometriosis. We don’t know a lot about the natural history of the disease or about the best option to stop its progression. Laparoscopy should therefore be done when the physicians thinks that, if endometriosis is present, laparoscopic vaporization is the best option for the patient. We should not do a laparoscopy to diagnose endometriosis but to treat it.

In patients with pelvic pain Ocs, especially given continuously, AINS and psychological support should be preferred initially to laparoscopy. In patients with infertility, it is rarely indicated before 18 months of infertility but should usually be performed before recommending assisted reproductive technologies (ARTs). Laparoscopic surgery doubles the pregnancy rate in the 9 months following the procedure and is not associated with the high multiple pregnancy rate of ARTs.

Endometriosis is an enigmatic disease; we still do not agree on its exact etiology; we do not know how to predict or stop its natural history; many recurrences are observed following our different treatments. It can be compared to arthritis: it may be quite painful but it is almost never cancerous or pre-cancerous. To diagnose it by laparoscopy may do more harm than good, especially in teenagers presenting with pelvic pain. “Primum, non nocere” should remain our first objective. What we need is not a new test to diagnose endometriosis but new tools to help us understand the natural history of this disease, predict the rapidity of its progression, and decide what treatment is best for individual patients at their particular stage of the disease.

Agneta Bergqvist, AnnaSofia Melin, Per Sparen. Dept. Of Obstetrics & Gynecology, Danderyds Hospital and Huddinge University Hospital, Dept. Of Medical Epidemiology & Biostatics, Karolinksa Institutet, Stockholm, Sweden.

As far back as 1925 Sampson (17) presented indications of the development of ovarian cancer from endometriotic tissue. Since then several publications have indicated an association between endometriosis and cancer, the ovaries being the most common site for this coexistence (1,2). However, an increased risk for different types of malignancy in women with endometriosis has also been shown. In a Swedish register study Brinton et al (3) found an overall relative risk for cancer in endometriosis patients compared to the general population (standardized incidence ratio, SIR 1.2). The highest risk was for ovarian cancer (SIR 1.9), non-Hodgkin’s lymphoma (SIR 1.8), breast cancer (SIR 1.3) and malignant melanoma (SIR 1.2). For patients with a history of long-standing endometriosis there was an increased risk of endocrine tumors and in long- standing ovarian endometriosis, the relative risk of ovarian cancer was further increased (SIR 4.2).

This study has now been extended to include about 64,000 women with endometriosis, with a longer follow-up (4). The study, which will be presented at the IFFS congress in Montreal, May 2004, confirmed a significantly increased risk of ovarian cancer (SIR 1.43), non-Hodgkin’s lymphoma (SIR 1.24), brain tumours (SIR1.22), and endocrine malignancies (SIR 1.36) compared to the general population. Adenomyosis was not related to an increased risk of ovarian cancer.

A newly published independent Swedish study, using the same national registers and including about 28,000 women with endometriosis, also showed that women with endometriosis have a significantly higher risk of ovarian cancer (Odds ratio, OR 1.34). However there was no increased risk of ovarian cancer in women with other benign ovarian cysts or functional cysts (5).
All three register studies showed an increased risk of ovarian cancer in long-standing endometriosis (3,4,5). Women who were diagnosed with ovarian endometriosis early in life had the highest increased risk for ovarian cancer. It was also found that such women get ovarian cancer earlier in life than the general population (4,6).

Women from families with endometriosis run a higher risk of developing cancer: breast cancer (26.9% compared to 0.1% in the general population); melanoma (9.8% compared to 0.01% in the general population): ovarian cancer (8.5% compared to 0.04% in the general population). In women with ovarian cancer the frequency of previous endometriosis is higher than in the general population, above all in cases with clear cell cancer (40-70%), endometrioid cancer (21-43%), but seldom in cases with serous adenocarcinoma (3-9%) or mucous adenocarcinoma (0-3%) (1,7-11). Ovarian endometriosis has consistently been reported to be related to epithelial ovarian cancer and in two case-control studies conducted by Ness et al (12,13), endometriosis proved to be a risk factor for ovarian cancer. Thus, several studies indicate that endometriosis might be a precursor to clear cell cancer and endometrioid cancer in the ovaries.

Erzen et al (14) suggested that there is a distinct entity of Endometriosis Associated Ovarian Carcinoma (EAOC) differing from other ovarian carcinomas in several aspects. They found that patients with EAOC had a lower stage of cancer, a distribution of histological subtypes that differs from the general population (ie. endometrioid and clear cell cancer being the most common), predominantly lower grade endometriosis lesions and significantly better over-all survival as compared with the group of other ovarian carcinomas. Several studies have shown that endometriosis-related malignancies have a favorable prognosis (11,15,16). Women with extra-ovarian cancer arising in endometriosis are more likely to be postmenopausal (11).

Sampson (17) formulated criteria for the definition of malignancies arising from ovarian endometriosis. They included: 1) the coexistence of carcinoma and endometriosis in the same ovary; 2) the presence of tissue resembling endometrial stroma surrounding characteristic epithelial glands; and 3) the exclusion of a secondary malignant tumor metastatic to the ovary.
In 1953 Scott (18) further specified the criteria by adding: 4) the demonstration of benign endometriosis contiguous with the malignant tissue.
A close morphologic relationship between atypical endometriotic tissue in the ovaries and epithelial ovarian cancer has been shown (19-21), as well as a transition from typical endometriosis to atypical endometriosis and transition from atypical endometriosis to carcinoma (8,17). Metaplasia was found in 63% of ovarian endometriosis that did not occur together with ovarian cancer but in all cases that occurred together with epithelial ovarian cancer (19). Although, as far as is known, malignant transformation of endometriotic tissue is rare, complete destruction of an original endometriotic tissue by the cancer growth, masking a connection, can never be proven.

The frequency of malignant transformation of ovarian endometriosis has been estimated to be 0.7-5.0% (7,20) but cancer development in extra-ovarian endometriosis has also been described. Other endometriotic sites shown to have transformed into malignancy are the bowel, bladder, peritoneal wall, laparotomy scars in the abdominal wall, vagina, fallopian tubes, parametrium, and the inguinal region (11,22-24).

Pathogenic factors for ovarian cancer have been difficult to find but inflammation has been proposed as one factor, causing cell damage, oxidative stress and an increased level of different cytokines and prostaglandins that might be mutagenic. Ness and Cottreau (25) showed in a case-control study that factors suppressing ovulation and thereby decreasing the need of surface repair of the ovary (like pregnancy, breasting-feeding for more than 12 months and the use of oral contraceptives), decreased the risk of ovarian cancer.

Factors increasing the inflammatory response in the ovaries, like endometriosis and the use of talc, increased the risk of ovarian cancer. Hysterectomy and tubal ligation decreased the risk of ovarian cancer (4,25,26). This suggests that processes which decrease the risk of inflammatory response to foreign material in the abdomen and/or ovaries also protect against ovarian cancer. There is data suggesting that retrograde menstruation (in the case of endometriosis) or other “irritants” landing on the ovaries cause an inflammatory response that in some cases results in malignancy. Another suggested risk factor for ovarian cancer is hyperestrogenism, either endogenous or exogenous, that might also be a significant risk factor for the development of cancer from endometriosis (27).

Lower levels of Ki67 in atypic endometriotic tissue than in ovarian cancer but higher than in typical endometriosis, indicate that atypical endometriosis is precancerous (9). Chromosome inactivation and TP53 mutation has been shown in ovarian cancer that seems to have developed from endometriosis (2). Allelic typing of endometriotic tissue and neighbouring ovarian cancer have shown the same line (2). Loss of heterozygoty (LOH) in endometriotic tissue has been shown in some chromosomes (6q (60%), 10q (40%)) (28), usually close to tumour suppressor genes for DNA restoration (29). The corresponding frequency in endometrioid ovarian cancer was 43% and in serous ovarian cancer 28%. There are indications for involvement in the malignant transformation of endometriotic tissue into endometrioid cancer of different tumor suppressor genes, indicating further that somatic genetic changes represent early phases of the malignant transformation of benign endometriotic cells (30).

Conclusions
Growing data support a connection between endometriosis and malignancy. Further studies to explore this relationship, not only in connection to ovarian cancer, are urgently needed.

1. Jimbo H, Yoshikawa H, Onda T et al. (1997). Prevalence of ovarian endometriosis in epithelial ovarian cancer. Int J Gynaeol Obstet 59:245-50.
2. Jiang X, Morland SJ, Hitchcock A et al. (1998). Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Res 58:1707-12.
3. Brinton L A, Gridley G , Persson I et al. (1997) Cancer risk after a hospital discharge diagnosis of endometriosis .Am J Obstet Gynecol 176:572.
4. Melin A, Sparén P, Persson I et al. Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Submitted for publication.
5. Borgfeldt C, Andolf E (2004). Cancer risk after hospital discharge diagnosis of benign ovarian cysts and endometriosis. Acta Obstet Gynecol Scand 83:395.
6. Takahashi K, Kurioka H, Irikoma M et al. (2001). Benign or malignant ovarian neoplasms and ovarian endometriomas. J Am Assoc Gynecol Laparosc 8:278.
7. Erzen M , Kovacic J (1998). Relationship between endometriosis and ovarian cancer. Eur J Gynaecol Oncol 19:553.
8. Ogawa S, Kaku T, Amada S et al. (2000). Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study. Gynecol Oncol 77:298.
9. Yoshikawa H, Jimbo H, Okada S et al. (2000). Prevalence of endometriosis in ovarian cancer. Gynecol Obstet Invest 50 (Suppl. 1):11.
10. Stern R C , Dash R, Bentley R C et al. (2001). Malignancy in Endometriosis: Frequency and Comparison of Ovarian and Extraovarian Types. Int J Gynecol Pathol 20:133.
11. Modesitt S C , Tortolero-Luna G, Robinson J B et al. (2002). Ovarian and Extraovarian Endometriosis-Associated Cancer. Obstet Gynecol 100:788.
12. Ness R B, Grisso J A , Cottreau C et al. (2000). Factors Related to Inflammation of the Ovarian Epithelium and Risk of Ovarian Cancer.Epidemiology 11:111.
13. Ness R B, Cramer D W, Goodman M T et al. (2002). Infertility, Fertility Drugs, and ovarian cancer: A Pooled Analysis of Case-Control Studies. Am J Epidemiol 155:217.
14. Erzen M, Rakar S, Klancar B et al. (2001). Endometriosis-Associated Ovarian Carcinoma (EAOC): An Entity Distinct from Other Ovarian Carcinomas as Suggested by a Nested Case-Control Study. Gynecol Oncol 2001;83:100-108.
15. Komiyama S, Aoki D, Tominaga E et al. (1999) Prognosis of Japanese patients with ovarian clear cell carcinoma associated with pelvic endometriosis: clinicopathologic evaluation. Gynecol Oncol 72:342.
16. Leiserowitz GS, Gumbs JL, Oi R et al. (2003) Endometriosis-related malignancies. Int J Gynecol Cancer 13:466.
17. Sampson J (1925). Endometrial carcinoma of the ovary. Arising in endometrial tissue in that organ. Arc Surg 10:1.
18. Scott RB, Te Linde RW, Wharton LR Jr (1953) Further studies on experimental endometriosis. Am J Obstet Gynecol 66:1082.
19. Fukunaga M, Ushigome S (1998). Epithelial metaplastic changes in ovarian endometriosis. Mod Pathol 11:784.
20. Nishida M, Watanabe K, Sato N et al. (2000). Malignant transformation of ovarian endometriosis. Gynecol Obstet Invest. 50 (Suppl. 1):18.
21. Oral E, Ilvan S, Tustas E et al. (2003). Prevalence of endometriosis in malignant epithelial ovary tumours. Eur J Obstet Gynecol Reprod Bio 109:97.
22. Slomovitz B M , Soslow R A , Chang R C et al. (2002). Serous adenocarcinoma of the inguinal region arising from endometriosis followed by a successful pregnancy. Gynecol Oncol 87:152.
23. Chen KT (2002). Endometrioid adenocarcinoma arising from colonic endometriosis mimicing primary colonic carcinoma. Int J Gynecol Pathol 21:275.
24. Petersen VC, Underwood JC, Wells M et al. (2002). Primary endometrioid adenocarcinoma of the large intestine arising in colorectal endometriosis. Histopathology 40:171.
25. Ness RB, Cottreau C (1999). Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst 91:1459.
26. Riman T, Persson I, Nilsson S (1998). Hormonal Aspects of Epithelial Ovarian Cancer. Clin Endocrinol 49:695.
27. Zanetta GM, Webb MJ, Li H et al. (2000). Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis. Gynecol Oncol 79:18.
28. Obata K, Hoshiai H (2000). Common genetic changes between endometriosis and ovarian cancer. Gynecol Obstet Invest 50 (Suppl.):39.
29. Goumenou AG, Arvanitis DA, Matalliotakis IM et al. (2000). Loss in heterozygosity in adenomyosis on hMSH2, hMLH1, p16Ink4 and GAT loci. Int J Mol Med 6:667.
30. Bischoff FZ, Simpson JL (2000). Heritability and molecular genetic studies of endometriosis. Hum Reprod Update 6:37.

18th World Congress on Endometriosis, Sept 15-17, 2005, Maastricht, Netherlands.

International Federation of Fertility Society (IFFS ) Meeting, Palais des Congres, Montreal, Canada. May 23-28, 2004.

Good news! It’s still not too late to register for the World Congress on Fertility & Sterility, held in Montreal May 23-28, 2004. The Congress takes place tri-annually and is regarded as the “main event” in the field. This year’s congress promises to be particularly exciting with key-note addresses on major topics of interest. The world’s second-largest French-speaking city, Montreal is renown for its numerous universities, medical and scientific research centres, as well as for its cultural and artistic life, its excellent restaurants and its hotel network. English is widely spoken and Spanish has recently become the city’s third language. Montreal is now the largest biotechnology centre in Canada and the tenth largest in North America. Information can be found at: www.iffs2004.htm or email info@iffs2004.com

CICE Laparoscopic Training Course on Endometriosis, 5-7 May 2004, International Centre for Endoscopic Surgery, Clermont-Ferrand, France.

The XVIII European Congress of Obstetrics & Gynaecology, 12-15 May 2004, Athens, Greece.

5th Congress on Controversies in Obstetrics & Gynaecology, 3-6 June 2004, Las Vegas, USA.

European Society of Human Reproduction & Embryology, 27-30 June, 2004, Berlin, Germany.

8th Regional Meeting of the ISGE: Endometriosis, 6-8 September 2004, Cape Town, South Africa.

The UK National Endometriosis Society (established in 1981) is holding another National Awareness Day on July 7, 2004. Once again women will gather in the lobby of Westminister Hall, in the Houses of Parliament, to lobby their MPs. Last year more than 200 women were in attendance and they were well received. This year is hoped that there will be more than a thousand. The actual lobbying is combined with a letter writing campaign so that those who cannot travel to London can still take part. The campaign aims to raise awareness of endometriosis and to obtain more funding for research.

Agneta Bergqvist, MD, PhD, Karolinska Institutet, Stockholm, Sweden, has been appointed as the new chairman for the Special Interest Group (SIG) Endometriosis and Endometrium within the frame of the European Society of Human Reproduction and Embryology (ESHRE). She has been the deputy chairman of SIG Endometriosis and Endometrium since it started in 1999. Professor Bergqvist’s work has focused on endometriosis clinically and scientifically for 25 years. She has published almost 100 original papers, mainly related to the pathogenesis and hormonal regulation of endometriosis and the infertility associated with the disease. She created and has been the chairman of a national reference group for endometriosis for a decade (Endometrios ARG).

The new deputy chairman of SIG is Professor Thomas D’Hooghe, University Hospital, Leuven, Belgium. Professor D’Hooghe’s work has focused on the pathogenesis of endometriosis in humans and baboons.

A group within SIG is working to create a consensus document on the management of endometriosis that should be available at the ESHRE Congress in Berlin in June this year. From this structured guidelines will be formulated, which it is hoped will be available in the Fall.

On April 4, 2004 Dr Stephen Kennedy of the Nuffield Dept Obstetrics & Gynaecology, University of Oxford, England, ran the Paris marathon in a time of 3 hours, 53.19 min to raise money for research into certain types of ovarian cancer, which may be associated with endometriosis. The aim of his research is to establish a clearer understanding of the genetic causes of these cancers. So far Dr Kennedy has raised 11,240 pounds. His target is twenty-five thousand pounds.

1: Ford, J etal: Pain, quality of life and complications following the radical resection of rectovaginal endometriosis.

2: Weissman, AM et al: The natural history of primary dysemorrhoea: a longitudinal study.
BHOG, 2004 Apr. 111, 345-52.

3: Lebovic, DI: Peritoneal macrophages induce RANTES (regulated on activation, normal T cell expressed and secreted) chemokine gene transcription in endometrial stromal cells.
J Clin Endocrinol Metab, 2004, 1397-401.

4: Nap, AW: Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab, 2004, 1089-95.

5: Yoshida, S et al: Hepatocyte growth factor/Met system promotes endometrial and endometriotic stromal cell invasion via autocrine and paracrine pathways. J Clin Endocrinol Metab, 2004, Feb 823-32.

6: Utsunomiya, D: Endometrial carcinoma in adenomyosis: assessment of myometrial invasion on T2-weighted spin-echo and gadolinium-enhanced T1-weighted images.
AJR American J Roentgenol, 2004, Feb, 399-404.

7: Razzi, S: Treatment of severe recurrent endometriosis with an aromatase inhibitor in young ovariectomised woman. BJOG, 2004 Feb. 182-4.

8: Wong, KH, Siman, JA: In vitro effect of gonadotropin-releasing hormone agonist on natural killer cell cytoysis in women with and without endometriosis. Am J Obstet. Gynecol, 2003 Jan 44-49.

Spring issue of the WES e-newsletter was prepared by Gillian Hobbs in conjunction with Familles PCO