New Insights in the Pathophysiology of Ovarian Cancer and Implications For Screening and Prevention

The American Cancer Society estimated that 21,290 new cases of ovarian cancer will be diagnosed, and 14,180 deaths from ovarian cancer will occur during 2015.[1] A woman has a 1:70 lifetime risk of being diagnosed with ovarian cancer, the second most common gynecologic malignancy, with the highest mortality rate.[2] Early-stage cancer is associated with vague, nonspecific symptoms, and therefore most cases are diagnosed at an advanced stage when treatments are less successful. A woman’s risk for ovarian cancer typically takes known risk factors into account. Certain reproductive and other factors (early menarche, late menopause, nulliparity, contraceptive pill use, family history, carriers of genetic mutations, etc.) are known to modify individual risk.[3] Several screening tests (ultrasound, tumor markers) have been evaluated, but none has proved to be sufficiently effective.[2]

Various theories about the etiology of ovarian cancer have been proposed, and each histologic type probably has a specific etiology.[4] Most ovarian cancers are epithelial in origin, and within this group the serous type is the most frequent. One of the most widely accepted theories is that epithelial surface injury occurs with each ovulation. This theory holds that serous ovarian cancer begins in the Fallopian tube from where it spreads onto the ovarian surface.[5] The site of ovulation is affected by intensive repair mechanisms involving inflammatory processes. The cyclic secretion of high concentrations of steroid hormones (estrogen, progesterone, and androgens) may also have a carcinogenic effect, as do carcinogens ascending through the genital tract. Furthermore, when the tumor spreads to the ovary, it seeds the peritoneum as well. Thus, by the time ovarian cancer is diagnosed, it is already at an advanced stage. If this theory proves correct, we may have an opportunity to reduce the frequency of epithelial ovarian cancer and may actually have something to offer in terms of prevention, at least to women at higher risk.

A New Paradigm for Pathogenesis of Ovarian Cancer

Nezhat and colleagues classify ovarian cancers on the basis of etiology into two groups. Type I cancers originate from various ovarian pathologies (borderline ovarian tumors, endometriomas). These cancers typically have a more favorable prognosis because they are diagnosed at an earlier stage and metastasize more slowly. The more frequent type II tumors originate from the fimbriated end of the Fallopian tube and have a less favorable prognosis because they are often diagnosed at an advanced stage.

Cancers associated with endometriosis are accompanied by typical symptoms of endometriosis (pain, dysmenorrhea, dyspareunia), whereas type II cancers are associated with nonspecific, vague gastrointestinal symptoms.

Few effective preventive measures can be offered. Contraceptive pills are known to lower the risk for ovarian cancer, most likely by reducing ovulation and gonadotropin levels as well as reducing blood flow at menstruation. This positive effect can be seen for both epithelial and nonepithelial cancers.

Tubal ligation (most likely by eliminating retrograde menstruation) is known to reduce the risk primarily for clear cell and endometrioid cancers. More recently, the benefits of salpingectomy have been discussed. Bilateral salpingo-oophorectomy upon completing childbearing is already recommended to women carrying risk-increasing mutations (BRCA1 and BRCA2). Bilateral salpingectomy, when pregnancy is no longer desired, should be considered at the time of surgery for benign diseases even for women who are not at high risk for ovarian cancer. On the other hand, the immediate surgical risks as well as the potential impact of bilateral salpingectomy on ovarian function must be considered.

Viewpoint

In recent years, the potential role of the Fallopian tube in the etiology of ovarian cancer has been proposed.[5] It is believed that the most common, serous epithelial cancer may actually develop in the Fallopian tube and spread from there onto the ovary. Not surprisingly, it may spread to any other adjacent organ or to the peritoneum as well. The problem with this type of cancer is that it is mostly asymptomatic early on. The nonspecific abdominal pain, feeling bloated, fullness, lack of appetite, slowly changing bowel habits, etc., often do not point in this direction. Other screening measures (use of ultrasound for diagnosis, checking tumor markers) have not been successful as neither of them is specific enough to warrant surgery.

If, however, the type of cancer with the least favorable prognosis indeed originates from the Fallopian tube, we may have a way to prevent such cancers. Ovarian cancer typically is diagnosed in the fifth or sixth decade of life when women no longer plan on or are able to have children. Therefore, the tube no longer plays an important role for them. If these women (especially those at higher risk) undergo elective salpingectomy, then a good proportion of the cancers could be prevented.[6] It also has to be considered that the surgical procedure itself is not without immediate procedure-related risks. Furthermore, the removal of the tube may adversely affect blood flow to the ovaries and therefore may compromise their activity. The full impact of surgery likely depends on the patient’s age, however. If it is done after age 40 years, the long-term health risks associated with some compromise in ovarian function are likely to be minimal. If the procedure is done at a younger age, it may be associated with significant long-term health risks. In the case of younger women, the resulting infertility or the inability to reverse the procedure also need to be considered. The patient has to be counseled that a salpingectomy is not reversible, should she change her mind later on. Such a definite surgical approach could still be recommended to those at high risk for cancer (strong family history, carrier of genetic mutations).

In this review, the role of endometriosis was emphasized. Women with endometriosis are known to be at higher risk for ovarian cancer.[4] Endometriosis affects 10%-15% of women, and management requires an individualized approach. The desire for future fertility, risk factors for ovarian cancer, and age, for example, must be considered when making a recommendation for medical or surgical treatment, especially if the surgical treatment is radical, such as oophorectomy/hysterectomy. Only around 1% of women with endometriosis will develop ovarian cancer; therefore, surgery for all as a “general rule” cannot be recommended.[7] However, long-term medical treatment (eg, contraceptive pills) to suppress endometriosis can be suggested to women diagnosed with the disease. Regular ultrasound evaluation for changes in size and appearance of endometriomas and surgery for those with worsening symptoms or growing adnexal masses could be considered.

Many questions must still be answered before general recommendations can be made. For now, however, it seems that we may have tools in the future to combat a disease with a high mortality rate.

To read this article and viewpoint on Medscape, click here.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s