Camran Nezhat, MD

Endometriosis - defined as the presence of endometrial-like glands and stroma in any extrauterine site - is a common disease occurring in 7-10% of all women, and is often associated with chronic pelvic pain and infertility. Apart from these significant individual problems women with endometriosis and their families may face, this disease has a significant impact our society due to its chronic nature 

The symptoms of endometrioses are variable and its course is often unpredictable. While some women may be asymptomatic, the most common manifestations are pelvic pain, particularly with periods, dispaureunia, pain associated with bowel movements, and dysuria or hematuria in cases of bladder involvement.  Despite significant improvements in understanding of this disease, the pathogenesis of endometriosis remains unclear. There are several theories that were suggested; most prominent includes theory of retrograde menstruation associated potentially with genetic susceptibility for the disease. Also theories of hematogeneous and/or lymphogenic spread, genetic link, or defects in immunocompetency have been suggested

The link between endometriosis and ovarian cancer is well recognized and has perplexed physicians for a long time 

. Epidemiological studies have suggested a specific link with endometrioid and clear-cell ovarian cancers, but no firm evidence established endometriosis as an ovarian cancer precursor lesion. Several lines of clinical evidence have supported the observation that non-serous ovarian carcinomas such as endometrioid and clear-cell carcinomas arising from atypical endometriotic foci have a higher likelihood of early diagnosis, as the associated endometriosis can cause pelvic pain or infertility requiring specialized gynecologic care including diagnostic laparoscopy. Deligdisch et al. reported a series of 76 cases of stage I ovarian carcinomas and documented that non-serous carcinomas (54/76) were diagnosed because of the associated symptoms including pelvic pain associated with endometriosis or vaginal bleeding associated with hyperestrogenism and endometrial pathology

. Interestingly they also found that serous carcinomas were frequently found in asymptomatic women with breast cancer diagnoses 

. These and similar observations support the emerging dual model of ovarian carcinogenesis. According to this model, Type I cancers are low grade, slowly developing ovarian carcinomas (including endometrioid, mucinous and low grade serous) associated with KRAS, BRAF, PTEN and B-catenin mutations and often associated with endometriosis. Type 2 is high-grade serous carcinomas associated with TP53 mutations that develop rapidly, are more aggressive and their origin is now thought to be tubal epithelium 

In the recent remarkable study reported in Lancet Oncology, the team of researchers from the Ovarian Cancer Association Consortium (OCAC) performed pooled analysis of 13 case-control studies and confirmed that women with self-reported history of endometriosis have significantly increased of clear cell carcinoma (odds ratio 3.05) and endometrioid ovarian cancer (odds ratio 2.04) 

. In addition the authors show, for the first time, that endometriosis is associated low-grade serous ovarian carcinomas, doubling its risk in women with endometriosis

.  However, there was no association between endometriosis and high-grade serous carcinomas or other subtypes of ovarian cancer in the study.

Taken together these findings will have considerable clinical implications and may affect the ways we think about strategies for ovarian cancer screening and prevention. In particular, the emerging knowledge of the link between ovarian cancer and endometriosis gives us an unprecedented opportunity to develop comprehensive screening plans to aid in the early detection and prevention of specific types of ovarian cancer in women with endometriosis. Such planning should include:

1) Identification of all women with endometriosis – either surgically documented or self-reported by symptoms;

2) Careful  follow up of ovarian presumed endometriomas by imaging studies, perhaps by MRI, for any characteristics changes such as mural formation;

3) Complete surgical resection of all endometriotic foci in women undergoing surgical treatment and tissue evaluation of ovarian endometriomas to rule out malignancy;

4) Hormonal treatment aimed at reducing the risk of cancer in high-risk women.

While it is well known that most women with endometriosis do not develop ovarian cancer, the women and their physicians should always discuss these new findings, carefully document and discuss any new symptoms and formulate plan for regular evaluations and treatment.


1. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis-cost estimates and methotologic perspective. 

 2007;13:395-404.
2. Burney RO, Giudice LC: The Pathogenesis of Endometriosis. In Nezhat C, Nezhat F, Nezhat C, (eds): Nezhat’s Operative Gynecologic Laparoscopy and Hysteroscopy. 

New York, New York: Cambridge University Press

, 2008:251-7.
3. Munksgaard PS, Blaakaer J. The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations. 

 2012;124:164-69.
4. Nezhat F, Datta MS, Hanson V, et al. The relationship of endometriosis and ovarian malignancy: a review. 

 2008;90:1559-70.
5. Deligdisch L, PÃ©nault-Llorca F, Schlosshauer P, et al. Stage I ovarian carcinoma: different clinical pathologic patterns. 

 2007;88:906-10. 6. Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. 

 2008;26:5284-93.
7. Pearce CL, Templeman C, Rossing MA, et al. on behalf of the Ovarian Cancer Association Consortium. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. 

Articles

Emerging information on the link between ovarian cancer and endometriosis gives us an unprecedented opportunity to develop comprehensive screening plans for early detection and prevention of specific types of ovarian cancer.

Endometriosis and Risk of Ovarian Cancer: An update


 A fibroid is a benign tumor of the uterus. Various terms are used to refer to the tumor, such as fibromyoma, myofibroma, leiomyofibroma, fibroleiomyoma, myoma, fibroma, and fibroid. Of these, fibroid is the most common term, although myoma is more accurate.


 The incidence of fibroids is uncertain, but they are the most common tumors of the uterus and female pelvis. It has been estimated that one out of every four to five women older than 35 years of age has a uterine fibroid. It is also well documented that patients of African descent have a higher incidence of fibroids than Caucasian women, although the reason for this is not known. Leiomyomas are responsible for about one-third of all hospital admissions for gynecological services.


 The exact cause of uterine fibroids is not known, but it has been suggested that they arise from persistent small embryonic germ cells. Most studies have shown that the hormones estrogen and progesterone are involved in myoma growth. Most of the tumors occur during the reproductive years and usually become smaller after menopause. Oral contraceptives may cause myomas to enlarge. Older women who have never had children may have an increased risk of developing myomas. Women who have given birth have a decreasing risk of developing these tumors. A woman who has had five term pregnancies has only one-fifth the risk of developing a fibroid when compared to a woman with no children. Interestingly, the risk is reduced in women who smoke but increased in obese women.


 Most fibroids, even large ones, do not cause any symptoms. Indeed, most are discovered incidentally during a routine gynecological exam. Distortion of the normal abdominal wall contour due to a large tumor may also be discovered during self-exam. Patients with symptomatic fibroids typically have excessive or prolonged menses. This may sometimes cause anemia due to the large amount of bleeding. After bleeding, pressure is the second most common symptom of myomas. Pressure on the bladder can produce urinary frequency and urgency and, occasionally, inability to urinate. Pressure on the rectum may cause constipation. In cases of extremely large fibroids, pressure on the pelvic vessels may cause edema or varicose veins in the legs. Kidney symptoms are also possible if the fibroid extends upwards.

, a feeling of heaviness in the pelvis, or pain upon intercourse are also common symptoms. The pain may be dull or sharp, but is usually intermittent. Occasionally, fibroids cause dysmenorrhea (pain during menses). Myomas may also be related with infertility, especially if the myoma distorts the cervix enough that it becomes occluded. Pregnancy causes growth in size of any preexisting myomas, potentially causing an otherwise asymptomatic myoma to become symptomatic.


 In many cases, treatment is not necessary, particularly if there are no associated symptoms, if the tumors are small, or if the patient is postmenopausal. However, any patient with a diagnosed myoma should be carefully examined every three to six months to check for any unusual growth. If the patient is symptomatic, the myoma should be treated. Medical treatment, such as GnRH analogues, are available. They are effective, causing most myomas to shrink after a few months. Unfortunately, the myomas regain their original size several months after treatment is discontinued. Thus, surgery is still the best treatment option Common surgeries consist of either
 myomectomy (removal of the myoma alone) or hysterectomy (removal of the uterus and any associated myomas).

Traditionally, the surgeries were done by laparotomy (making a large abdominal incision) and excising the appropriate tissue. However, recent advances in surgical technology now allow most patients to be treated with new minimally invasive techniques, consisting of laparoscopic myomectomy or laparoscopic hysterectomy. Laparoscopic surgery

 is performed via three or four small incisions in the abdomen. The myomas are then removed through these incisions by first cutting them into small pieces inside the abdomen, then removing each small piece. This has many advantages, because it leads to shorter hospital stay (about 24 hours, compared to three days after laparotomy) and less postoperative pain (due to a smaller incision, which leads to less scar tissue). It is also a good choice for any women desiring children in the future, because it causes less pelvic adhesions.

For further information regarding laparoscopic removal of myomas, e-mail 

Endometriosis is a disorder in which abnormal growths of tissue, histologically resembling the endometrium, are present in locations other than the uterine cavity. Although endometriosis was described in detail more than 100 years ago, it continues to be one of the unsolved, enigmatic diseases affecting women. It is often called "the career woman's disease," because it occurs almost exclusively in women of reproductive age. Endometriosis is usually confined to the pelvis in the region of the ovaries, uterosacral ligaments, cul-de-sac, and uterovesical peritoneum.

The development and extension of endometrial tissue in the uterine muscles is termed adenomyosis. It can also affect the bowel, especially the rectum, colon and appendix. Endometriosis is one of the most common reasons for pelvic pain and infertility.


 There are three main theories as to the cause of this elusive disease, but the exact etiology remains a mystery. The most common and scientifically valid theory is a combination of immunological alteration and retrograde menstruation- direct transportation of viable endometrial cells through the fallopian tube into the pelvis which then implants in ectopic sites. Other suggestions are coelomic metaplasia, which proposes that peritoneal epithelial cells change to endometrial cells. The last theory is lymphatic spread/mechanical transport, where the cells are picked up by the lymphatic or circulatory system and ferried about the body.


 Endometriosis is a common and important health problem. Its exact prevalence is unknown because surgery is required for its diagnosis, but it is estimated to be present in 10% of all reproductive age women. It is seen in 1-2% of women undergoing sterilization, in 10% of hysterectomy surgeries, and in 16-31% of laparoscopies. Endometriosis has a higher incidence among Caucasians than among people of African descent. Some genetic influences in the development of endometriosis have been described. Studies have found that 7-9% of endometriosis patients' first-degree female relatives are diagnosed with the disease, significantly greater than the control rate of 1-2%.
 
 

Unfortunately, there is no current noninvasive test for diagnosing endometriosis. However, the typical symptoms include infertility, ovarian cysts, or chronic pelvic pain

 such as generalized vague and sometimes sharp pain; painful periods (dysmenorrhea); painful intercourse (dyspareunia); back pain; and painful ovulation. Pain with bowel movement and bladder pain can also exist. The symptoms are often related to the menstrual cycle, generally resulting from functioning endometrial tissue or scarring in the affected site. Pelvic examination may confirm suspicion. However, in mild to moderate stages of endometriosis, physical and pelvic examinations may be completely normal. Pain or bleeding from any site coinciding with menses should raise suspicions of endometriosis and lead to careful evaluation of specific anatomic areas involved such as lungs, umbilicus, previous incisions, bowel, bladder, ureters and diaphragm.


 Different hormonal therapies, such as birth control pills, progesterone, danazol, GnRH analogs, and recently RU486 have been used with some success to decrease the size of endometriotic lesions. This treatment can be used alone or in conjunction with surgery. Preoperative hormonal therapy has been shown to create a pelvic environment with much less blood flow and reduce inflammatory reaction, making surgical identification and removal of endometriotic lesions easier.

In the past, surgical treatment of endometriosis included laparotomy and hysterectomy. This was mainly due to the fact that surgeons were unfamiliar with endometriosis and how to treat it. A fairly recent improvement in technology, called operative videolaseroscopy, has revolutionized the way patients are treated for endometriosis. The advantages over laparotomy include a smaller incisional site (1/4-1/2 inch vs. 4-6 inches), shorter hospital stay (one day vs. 3-5 days) and a shorter recovery period (1 or 2 weeks vs. 4-6 weeks).

Through operative videolaseroscopy, endometrial implants can be coagulated, excised or ablated using a carbon dioxide laser or electrosurgery. Laparoscopic scissors and a laser can be used to cut lesions close to vital structures. Laparoscopic restoration of pelvic anatomy, especially at the area of the posterior cul-de-sac, is not simple and should only be undertaken by a surgeon who is familiar with performing surgery on genital, gastrointestinal, and urinary tract.

For further information on laparoscopic surgery for treatment of endometriosis, e-mail 

A fibroid is a benign tumor of the uterus. Various terms are used to refer to the tumor, such as fibromyoma, myofibroma, leiomyofibroma, fibroleiomyoma, myoma, fibroma, and fibroid. Of these, fibroid is the most common term, although myoma is more accurate.

Fibroids

 A Novel Device for Peritoneal Access in Laparoscopic Surgery

"Safe abdominal entry and prevention of retroperitoneal vascular  injuries during laparoscopic surgery are the ultimate goals of any  laparoscopic surgeon.  Dr. Linda Nicoll and colleagues very capably have  been able to describe a new technique and technology that prevent  almost all retroperitoneal vascular injuries during laparoscopic entry."

 -    Linda M. Nicoll MD, Madelein Lemyre MD, Dorian Bosev MD, Jian Qun Huang MD, Lisa Bhagan MD and Camran Nezhat MD

 email us with their comments and questions

 by using the comment links at the end of each article.


           Editor-in-Chief
 "New Frontiers in Reproductive Medicine"
           OBGYN.net

afe abdominal entry and prevention of retroperitoneal vascular injuries during laparoscopic surgery are the ultimate goals of any laparoscopic surgeon.  Dr. Linda Nicoll and colleagues very capably have been able to describe a new technique and technology that prevent almost all retroperitoneal vascular injuries during laparoscopic entry.

Frontiers in Reproductive Medicine

Because endometriosis is a common disease entity among infertile patients with a prevalence of up to 50%

,  one could argue that without laparoscopy clinical work-ups can not  completely rule out all of the causes of infertility. The decision to  perform laparoscopy on patients with infertility is very complex owing  to a number of factors, such as maternal age, semen parameters, tubal  patency, pelvic symptoms, insurance coverage, surgical risks, and  availability of surgical expertise. Presently, many clinicians would  advocate proceeding to IVF in patients with “unexplained” infertility  without laparoscopic evaluation. However, the etiology of infertility  cannot be totally unexplained unless the presence of endometriosis as a  cause has been ruled out. In women with undiagnosed endometriosis,  fertility treatments not only may be less effective but also may  contribute to progression of disease

.
   
   One of the advantages of laparoscopic evaluation of infertile patients  is that the surgical findings could change the handling of their  clinical cases. A study done by Tanahatoe et al. showed that  laparoscopic evaluation of patients undergoing infertility treatment  resulted in surgical treatment of endometriosis rather than further  assisted reproductive techniques in 25% of their patients

.  In addition, in infertile couples, laparoscopy reveals abnormal  findings in 21%–68% of cases with a normal hysterosalpingogram (HSG)

.  The additional value of laparoscopy over a normal HSG depends not only  on the prevalence of disclosed pathology but also on the contribution of  the diagnostic laparoscopy with regard to the decision of which  treatment should be applied. Although time is of the essence in many  clinical cases, the installation of laparoscopic treatment into the  management of infertility early on could alleviate the need to  continually expose patients to fertility medicines by altering the  treatment strategy. This approach may also improve the results of  assisted reproductive treatment.
   
   Several epidemiologic and molecular investigations have supported a link between endometriosis and ovarian cancer

  and endometriosis has been found in significantly higher frequency in  women undergoing surgery for endometroid and clear-cell subtypes of  ovarian cancers

. According to the literature, the incidence of malignant transformation is approximately 1% in patients with endometriosis

.  Without laparoscopic evaluation, the diagnosis of these serious  pathologies may be delayed. Obviously when discussing the pros and cons  of endoscopic surgery with infertility patients, the possible detection  of neoplasms at the time of surgery should be addressed. In addition,  the long-term effect of hormonal fertility treatments on female cancers  is currently unknown. Although direct causal link between ovarian  stimulation and cancer has not been established, until the relationship  between ovulation induction and ovarian cancer risk is defined more  accurately, a high index of vigilance is indicated. This is especially  true in women with endometriosis.
   
   Given the complexity of this matter, and the lack of prospective  randomized trials to provide further clarification, a consensus on this  subject in our field is far from being reached; the outcome of our  retrospective study has raised some issues that deserve further  discussion. We reported the outcome of patients with unexplained  infertility, who have failed at least 1 cycle of IVF and who  subsequently underwent either laparoscopy, additional IVF cycles,  controlled ovarian hyperstimulation with intrauterine insemination, or  no treatment.
   
   Our study

 was meant to offer an  alternative to repeated IVF attempts or oocyte donation in women who had  failed IVF. We acknowledge that patients need an indivualized approach  to infertility treatment and that every woman may not need to undergo a  laparoscopic evaluation in order to achieve pregnancy. However, in  patients who have not been able to achieve success by other methods,  laparoscopy is a reasonable option. Our findings suggest that thorough  laparoscopic treatment of endometriosis can be quite effective at  improving pregnancy rates. In our study, 22 out of 29 patients (76%)  achieved pregnancy after laparoscopic treatment of endometriosis. We  concur that our study suffers from the handicaps of retrospective  trials, and owing to the confounding factors elaborated by Drs. Penzias,  Diamond, Adamson, and Hershlag, this study is limited in its ability to  generalize the effect of laparoscopic treatment of endometriosis in all  infertile patients. Further prospective randomized trials need to be  performed to clarify this issue. However, this report should encourage  practitioners to offer a thorough laparoscopic evaluation and treatment  of endometriosis to patients who have failed IVF. After all, even some  of the most advanced cases of endometriosis might result in pregnancy  following surgical intervention

.
   
   Deepening the understanding of the mechanisms involved in infertility  associated with endometriosis will allow further improvement of the  outcome of infertility treatments and better care for endometriosis  patients. Although it is still early to state the last words on this  topic, we believe that laparoscopic diagnosis and treatment of  endometriosis is a rational approach to increasing the probability of  conception either spontaneously or with assisted reproductive treatment,  especially in patients with multiple IVF failures. 
   
   

 We appreciate the comments of  Drs. Penzias, Diamond, Adamson, and Hershlag concerning our paper. The  correspondents further elucidated the long-standing controversial issue  of the management of endometriosis-related infertility. We gratefully  acknowledge the efforts of Drs. Farr Nezhat, Ceana Nezhat, and Rosa  Moghadam in preparation of this manuscript.

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10. Saio N, Tsunoda M, Nishida M, Morishiu Y, Takimoto Y, Kuho T, et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 000;60;7052â 6.    

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14. Lavy Y, Lev-Sagie A, Holtzer H, Revel A, Hurwitz A. Should laparoscopy be a mandatory component of the infertility evaluation in infertile women with normal hysterosalpingogram or suspected unilateral distal tubal pathology? Eur J Obstet Gynecol Reprod Biol 2004;10:11464â8.    

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21. Mohr C, Nezhat FR, Nezhat CH, Siedman DS, Nezhat C. Fertility considerations in patients with bowel endometriosis. J Laparoendosc Surg 2005;9:16 â24.1588 Nezhat et al. Is consensus possible with an enigma? Vol. 84, No. 6, December 2005

Because endometriosis is a common disease entity among infertile patients with a prevalence of up to 50%, one could argue that without laparoscopy clinical work-ups can not completely rule out all of the causes of infertility. The decision to perform laparoscopy on patients with infertility is very complex owing to a number of factors, such as maternal age, semen parameters, tubal patency, pelvic symptoms, insurance coverage, surgical risks, and availability of surgical expertise.

Camran Nezhat, MD

Articles

Endometriosis and Risk of Ovarian Cancer: An update

Fibroids

Frontiers in Reproductive Medicine

The dilemma of endometriosis: is consensus possible with an enigma?