The endometriosis-ovarian cancer connection: the case against preventive surgery/CA-125 as a biomarker for malignant transformation of endometriosis

11 02 2009

To the Editor:

In their informative review on the relationship between endometriosis and ovarian malignancy (1), Nezhat and co-workers conclude that, given “the strong relationship between endometriosis and ovarian cancer […], appropriate and timely resection and elimination of disease should be practiced.”

The results of epidemiologic studies are somewhat discordant, with relative risks between 1.3 and 2 being the most frequent finding (2). This means that, in the worst scenario, the lifetime probability of developing ovarian cancer increases from 1/100 to 2/100. This information may be delivered as a frightening 100% risk increase, or as a 98% chance, instead of 99%, of not developing ovarian malignancy. Also infertile subjects have a standardized incidence ratio for ovarian cancer of 2 (2.7 in case of primary infertility), and women with an affected first-degree relative (except BRCA 1 and 2 subgroups) are similarly at doubled risk (3). As a comparison, the lifetime probability of developing breast cancer is 1/20.

The authors foster “earlier and more meticulous surgical intervention for complete disease removal.” Radicality during conservative procedures constitutes good surgical practice, but, given the relapsing nature of endometriosis, it seems unlikely that it might reduce ovarian cancer risk substantially. “Earlier” surgery raises the problem of extending the diagnostic process to asymptomatic subjects and of operating women without otherwise established indications (4, Table 1).

Nezhat et al. foresee the use of proteomic techniques with the objective of identifying endometriosis more accurately. In fact, whereas endometriomas may be recognized easily with ultrasonography, superficial implants escape detection. Indeed, ovarian malignancy may arise in both lesions. However, the issue of screening for endometriosis opens a Pandora’s box, as there are no definitive data demonstrating that early surgical treatment of limited implants is associated with a reduced risk of disease progression and, ultimately, of cancer development. Moreover, women could be left with a generic diagnosis without the knowledge for discriminating between different degrees of clinical severity. This could generate excessive concerns and could potentially result in conflicts of interest and misuse of health care resources. Lowering the level of surgical indications should be considered with caution, due to a probably unfavorable cost/benefit/harm ratio.

Finally, therapies with immunosuppressant and antiangiogenetic drugs and aromatase inhibitors have been hypothesized (1), but also the use of oral contraceptives, that dramatically reduces the risk of ovarian cancer particularly in patients with endometriosis (5), should be mentioned. 

TABLE 1. Characteristics of an optimal screening test.
• The condition sought should have significant risk of morbidity and mortality.
• Diagnosing the disease before symptoms occur results in better outcomes than waiting for symptoms.
• A useful follow-up test is available to determine which individuals with a positive screening test require treatment.
• Consensus exists regarding proper management of abnormal test results.
• The risk of complications from the test and subsequent evaluation and treatment is lower than the risk of morbidity and mortality from the disease.
• The test is accurate and reliable.
• The cost of testing and treating asymptomatic disease are acceptable.

Modified from Massad (4).

Paolo Vercellini, M.D.a, b, c
Fabio Parazzini, M.D.a, b, d
Edgardo Somigliana, M.D., Ph.D.a, b, c
Paola Viganò, M.D.c
Giorgio Bolis, M.D.a, b, e
Luigi Fedele, M.D.a, b
aIstituto Ostetrico e Ginecologico “Luigi Mangiagalli”, University of Milan,
bFondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena
cCenter for Research in Obstetrics and Gynecology (C.R.O.G.)
dClinical Epidemiology Unit, Istituto di Ricerche Farmacologiche “Mario Negri”
eGynecologic Oncology Unit, Department of Obstetrics and Gynecology
University of Milan
Milan, Italy

1. Nezhat F, Datta S, Hanson V, Pejovic T, Nezhat C, Nezhat C. The relationship of endometriosis and ovarian malignancy: a review. Fertil Steril 2008; 90:1559-70.

2. Somigliana E, Viganò 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;101:331-41.

3. Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althius MD, Mabie JE, Westhoff CL. Ovarian cancer risk associated with varying causes of infertility. Fertil Steril 2004;82:405-14.

4. Massad LS. Assessing new technologies for cervical cancer screening: Beyond sensitivity. J Low Gen Tract Dis 2008;12:311-5.

5. Modugno F, Ness RB, Allen GO, Schildkraut JM, Davis FG, Goodman MT. Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis. Am J Obstet Gynecol 2004;191:733-40.

Published online in Fertility and Sterility  doi: 10.1016/j.fertnstert.2009.02.034


 To the Editor:

I enjoyed reading the Modern Trends review by Nezhat et al (1). Under the section of Clinical Implications, Diagnosis of endometriosis, they mention “the importance of biomarkers in diagnosing patients with endometriosis, and thus a population with an increased cancer risk.”

Since most women with endometriosis will not progress to ovarian cancer, what is most important is not only to identify a biomarker for endometriosis but one that is associated with a greater likelihood for malignant transformation to help decide when extreme measures, e.g., total abdominal hysterectomy and bilateral oophorectomy, should be considered as a treatment.

There presently exists a biomarker that is commonly shared with ovarian carcinoma and endometriosis and that is an elevated CA-125 level (2-4).  Some cases have been reported where women had ovarian cysts (some of them complex with a very high serum CA-125 levels) and yet laparoscopic evaluation found no evidence of malignancy but merely the presence of endometriosis (2-4).

However one of these 3 women who first presented at age 46 was strongly advised to have an exploratory laparotomy and oophorectomy for suspected ovarian cancer by both our reproductive endocrine group and the gynecologic oncology group based on the presence of a 23mm ovarian cyst with low level internal echoes and a serum CA-125 level that rose from 231 IU/mL to 1385 IU/mL over 5 months.  She only wanted to do a laparoscopy and so she found another reproductive endocrine group willing to do a laparoscopy.  The ovarian biopsy revealed ovarian stroma with hemosiderin-laden macrophages, consistent with endometriosis, but not diagnostic of endometriosis, since endometrial glands and stroma were not identified.  Nevertheless, classic pigmented benign lesions that looked like endometriosis were ablated with Yag laser (2,5).

Five years later she showed a large pelvic mass of 144mm x 107mm x 120mm .  Laparotomy showed a clear cell ovarian carcinoma (5).  She died within 1 year of surgery.

The two other women were age 33 and 39 years old at the time of presentation.  They were seen 15 and 20 years ago and have been lost to follow-up so it is not known if they eventually developed ovarian cancer or not.

My point is simply this:  that until better markers are developed a high level and/or rapid rise of serum CA-125 levels should make one highly suspicious of the eventual development of ovarian cancer in a woman with endometriosis.  Thus the presence of this biomarker may be important in guiding therapeutic decisions.  I did not notice the mention of CA-125 levels in your review, so I wanted to add this anecdotal experience.

Jerome H. Check, M.D., Ph.D.
The University of Medicine and Dentistry of New Jersey
Robert Wood Johnson Medical School at Camden
Cooper Hospital/University Medical Center
Department of Obstetrics and Gynecology
Division of Reproductive Endocrinology & Infertility
Camden, New Jersey

1.  Nezhat F, Datta S, Hanson V, Pejovic T, Nezhat C, Nezhat C.  The relationship of endometriosis and ovarian malignancy: a review.  Fertil Steril 2008;90:1559-70.

2.  Canney PA, Moore M, Wilinson PM, James RD.  Ovarian cancer antigen CA-125: a prospective clinical assessment of its role as a tumor marker.  Br J Cancer 1984;50:765.

3.  Check JH, Coates TE, Nowroozi K.  Extreme elevation of serum CA-125 in two women with severe endometriosis: case report.  Gynecol Endocrinol 1991;5:217-20.

4.  Check JH, Hornstein MD:  Endometriosis causing very high early first trimester serum CA 125 levels.  Int J Gynecol Obstet 1995;48:217-8.

5.  Check JH, Check ML, Kiefer D, Aikins J Jr.  Ovarian cancer in a woman previously diagnosed with endometriosis and an extremely high serum CA-125 level.  Clin Exp Obst Gyn 2001;28:83-5.

Published online in Fertility and Sterility  doi: 10.1016/j.fertnstert.2009.02.036

The Authors Respond:
We appreciate the interest by Dr. Check and Dr. Vercellini et al in our manuscript (1).

Dr.  Check has highlighted the importance of the CA-125 tumor marker in the follow up of patients with endometriosis.  CA-125 is a surface protein antigen that can be elevated in numerous benign and malignant conditions including certain epithelial types of ovarian carcinoma, such as clear cell carcinoma.  Unfortunately, this marker is neither sensitive nor specific enough to be used reliably for screening of ovarian cancer.  We do agree that in a patient with an ovarian endometrioma, there is a need for a careful follow up with pelvic imaging such as an MRI or ultrasound and serum CA-125 levels.  If there are significant changes, the lesion must be removed and evaluated for potential malignant transformation.

Vercellini et al discussed the approach that we advocated in our paper, namely early and thorough surgical intervention in patients with endometriosis.  We agree that the complex relationship between endometriosis and ovarian cancer requires a comprehensive and thoughtful approach for screening for atypical lesions and treatment.  “Earlier and more meticulous surgery” does not entail operating on asymptomatic individuals.  However, women with endometriosis and ovarian endometriomas diagnosed based on clinical and imaging studies must be followed carefully for possible malignant transformation.  Approximately 9% of the ovarian malignancies, particularly clear cell and endometrioid subtypes, arise in the context of concomitant endometriosis (2).  The majority of stage I ovarian cancers have been shown to be endometrioid or clear cell carcinomas associated with endometriosis (3). 

Several studies have detected aneuploidy and loss of heterozygosity and signs of clonal evaluation in endometriotic foci.  It is possible that surgical excision successfully removes the clonal focus, thus preventing potential malignant transformation.  We believe that swift and definitive action is the treatment of choice rather than expectant or hormonal suppressive therapy. 
Screening for ovarian malignancies in the setting of concomitant endometriosis is a difficult task.  We advocate complete excision during surgical management of ovarian endometriomas which may harbor occult malignancies, rather than performing cyst aspiration without providing definitive tissue diagnosis. 

In summary, the epidemiological, molecular, and pathophysiological studies show that the risk of ovarian cancer is increased in patients with endometriosis, especially in patients with infertility and long-standing endometriosis.  Continued research will further elucidate the connection between endometriosis and ovarian malignancies.

Farr Nezhat, M.D.a
M. Shoma Datta, M.D.b
Veneta Hanson, Ph.D.c
Tanja Pejovic, M.D.d
Ceana Nezhat, M.D.e
Camran Nezhat, M.D.f,g
aSt. Luke’s – Roosevelt Hospital Center
University Hospital of Columbia University
College of Physicians and Surgeons
New York, New York
bDepartment of Obstetrics, Gynecology and Reproductive Science and
cDepartment of Pathology
Mount Sinai Medical Center
New York, New York
dDivision of Gynecologic Oncology
Department of Obstetrics and Gynecology
Center for Women’s Health
OHSU Center for Women’s Health
Portland, Oregon
eAtlanta Center for Special Pelvic Surgery
Atlanta, Georgia
fDepartment of Obstetrics and Gynecology, and
gDepartment of Surgery
Stanford University Medical Center
Palo Alto, California

1. Nezhat F, Datta S, Hanson V, Pejovic T, Nezhat C, Nezhat C. The relationship of endometriosis and ovarian malignancy: a review. Fertil Steril 2008; 90:1559-70.

2. Stern RC, Dash R, Bentley RC, et al. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types.. Int J Gynecol Pathol 2001; 20:133-139.

3. Deligdisch L, Penault-Llorca F, Schlosshauer P, Altchek A, Peiretti M, Nezhat F. Stage I ovarian carcinoma: different clinical pathologic patterns. Fertil Steril 2007;88:906–10.

Published online in Fertility and Sterility  doi: 10.1016/j.fertnstert.2009.02.035




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