Ovarian Cancer

of all the cancers to which women are prey, this is the deadliest. By the time it's discovered in the majority of cases, odds of a cure have already dropped to little more than 1 in 10. Fortunately, this kind of cancer is also quite rare. Your overall chances of developing it are 1 in 100—in contrast to a breast cancer rate of 1 in 9. Even if you're in the group at greatest risk—women in their 50s and 60s—the odds against you are still only 1 in 70. In a typical year, some 20,000 American women find out they have ovarian cancer, and more than 12,000 die from it. Like all cancers, this one is most dangerous when discovered late. Hope of a cure in the most advanced stage is only 5 percent. On the other hand, there's much more reason for optimism if your doctor finds the disease early, when chances of a cure are 2 to 1 in your favor. The catch, however, is in finding it. Who's at Greatest Risk As with many cancers, doctors just don't know what exactly causes the growth of cancerous ovarian cells. Current theory is that a number of factors—some controllable, many not—may influence the development of ovarian cancer. One proposal suggests a link between the number of times a woman ovulates during her life and her risk of developing ovarian cancer: The more she has ovulated, the greater the risk. Some researchers have noted that for 99.9 percent of the human history, women ovulated much less frequently than they do today, since so much time was spent in pregnancy and breast feeding. One expert has estimated that our remote ancestors might have had only about 50 menstrual cycles in an entire lifetime compared to more than 400 that the average American woman has today. Whether this theory is true or not remains to be proven, but it may help explain why the following factors tend to increase the risk of ovarian cancer:   

Ovulation for more than 40 years Never being pregnant or having your first pregnancy after age 30 Late menopause

The theory might also help explain why oral contraceptives, pregnancy, and breastfeeding appear to protect against ovarian cancer, since you don't ovulate when you are on the Pill, pregnant, or breastfeeding. In fact, one study showed that using oral contraceptives, even for just a few months, can markedly reduce the risk of ovarian cancer, with the protection lasting for years. Other factors—unrelated to ovulation—that are thought to increase the risk of ovarian cancer include:   

A family history of ovarian or uterine cancer (especially mother or sister) Having had breast cancer or benign breast disease Having had colon or rectal cancer or polyps

A history of mumps infection before the start of menstruation and a diet high in animal fat may also play a role. Researchers have speculated that the use of talcum powder in the

vaginal and anal area might increase the risk of ovarian cancer, perhaps because the powder can enter the reproductive tract and settle on the ovary, possibly causing irritation. How the Disease is Diagnosed If your doctor feels a mass that might indicate an enlarged ovary, he or she will usually send you for an ultrasound (sonogram) of the pelvic area. This is a painless diagnostic test that allows your doctor to see your internal reproductive organs by bouncing sound waves off of them. It is usually performed in the doctor's office. Generally, if a mass is small, and only one ovary is involved, the chances are very good that it is benign (noncancerous). It may still require treatment (see chapter 9, “What You Need to Know About Ovarian Cysts”), but at least you will know it's not cancer. A blood test called the CA125 assay can also provide useful diagnostic information, especially in postmenopausal women. This test also measures a substance that can be associated with ovarian tumors. A higher level of this substance than is normal, coupled with an ultrasound that shows a significant mass, can lead your doctor to suggest that further exploration is needed. However, like many tests, the CA125 assay can produce a false positive result, predicting that a cancer is present, when, in fact, the mass is benign. If the ultrasound and blood tests suggest that a mass might be cancerous, your doctor will recommend a laparotomy (surgery done through the abdomen), in order to make a clear diagnosis. Stages of Ovarian Cancer If your doctor makes a diagnosis of ovarian cancer, he or she will categorize it as one of 4 stages of the disease. Stage I is the earliest stage in which only the ovaries are involved. About twothirds of Stage I patients can look forward to a cure. In Stage II, the cancer will have spread from an ovary to other parts of the pelvis. As with most cancers, as the disease begins to spread, survival rates decrease. About half of those diagnosed with Stage II ovarian cancer will survive after treatment. The majority of cases are diagnosed at Stage III, at which point the disease involves the lymph nodes and/or other parts of the abdomen. About 13 percent of patients diagnosed with Stage III cancer are cured. The most advanced form is Stage IV which has a very low survival rate—only about 5 percent of those diagnosed with Stage IV ovarian cancer will survive for five years. The overall fiveyear survival of all patients with ovarian cancer, regardless of stage, is about 30 percent.

CANCER'S INSIDIOUS ATTACK ON THE OVARIES Because ovarian cancer often develops without any troubling symptoms, your only warning could be discovery of an enlarged ovary during your annual physical exam. If your doctor does encounter a mass while checking your pelvic area, he or she will probably follow up with an ultrasound look at the internal organs, followed by a blood test for a tumor-related substance. Surgery may be needed if both tests suggest the possibility of cancer.

Surface Epithelial Tumors Cancer is not a single disease, but encompasses well over a hundred distinct diseases of different organs. Normally cells divide only when additional cells are required for normal body function. However, at certain times the controls that regulate when a cell divides are lost. This results in accumulation of more and more cells without order. Eventually these cells grow into a mass and this is termed a 'tumor'. It is important to understand that not all tumors are cancer: PATHOGENESIS — The majority of primary ovarian tumors derive from epithelial cells on the surface of the ovary, although they can also arise from other cell types (germ cell tumors, sex cord-stromal tumors, and mixed cell type tumors). Epithelial cancer of the ovary derives from malignant transformation of the epithelium of the ovarian surface, which is contiguous with the peritoneal mesothelium (show table 1) [1]. The molecular events leading to the development of EOC are unknown. Mutations and/or overexpression of the oncogenes HER2 c-myc and K-ras, Akt, and of the tumor suppressor gene p53 have frequently been observed in sporadic ovarian cancer [2-4]. Inactivation of the tumor suppressor genes PTEN and p16 may occur. Epigenetic phenomenon also play a role in tumorigenesis [5]. However, the molecular pathways underlying ovarian cancer progression are poorly understood. Although germline mutations in BRCA1, BRCA2, and other genes have been implicated in a small fraction of cases (see "Genetic factors" below), epidemiologic and experimental evidence suggests that ovarian carcinogenesis is predominantly driven by factors associated with reproduction and ovulation [6,7]. In addition, mucinous and nonmucinous ovarian tumors may have different causal mechanisms related to ovulatory life [8]. Two general hypotheses have been proposed to explain the pathogenesis of EOC:

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Incessant ovulation with repeated trauma and repair to the ovarian epithelium, which afford an opportunity for genetic mutation and cellular neoplasia [9,10]. This theory is supported by the protective effect of multiparity and oral contraceptive pills on the incidence of EOC (see below).

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Excess gonadotropin secretion, promoting high estrogen concentrations, which lead to epithelial proliferation, and, possibly, malignant transformation [11]. Other hormones also may contribute.

In the United States, ovarian cancer is the fourth most frequent cause of cancer death among women, following lung, breast, and colorectal cancers. Each year, approximately 26,000 women are diagnosed with ovarian cancer and 14,000 die of it. Germline mutations in BRCA1, BRCA2, or other genes have been implicated in a small fraction of cases. However, it has been suggested that, for the great majority of patients, the risk of epithelial ovarian cancer could be related to "incessant ovulation" (i.e., to the chronically repeated formation of stromal epithelial clefts and inclusion cysts following ovulation) or to some type of hormonal stimulation of ovarian epithelial cells, either on the surface of the ovary or within ovarian inclusion cysts, possibly mediated through excessive gonadotropin secretion. From the evidence to date, the relative importance of these two hypotheses--incessant ovulation and gonadotropin stimulation--cannot be distinguished. While either or both may play a role in the development of ovarian cancer, it appears that an additional major factor must also be involved. The purpose of this review is to evaluate evidence for and against the incessant ovulation and gonadotropin hypotheses, as well as to consider the possibility that risk of ovarian cancer may be increased by factors associated with excess androgenic stimulation of ovarian epithelial cells and may be decreased by factors related to greater progesterone stimulation. Many features of the evidence bearing on the pathophysiology of ovarian cancer appear to support a connection with androgens and progesterone.