Ovarian Cancer

Ovarian cancer is a non specific term for a variety of cancers that originate in the ovary. There are about 20 microscopically distinct types. They can be classified into three large groups, epithelial cancers, germ cell tumors, and specialized stromal cell cancers. There are three groups because the ovary contains collections of cells with three distinct origins and functions.

During embryonic development when the fetus is at about eight weeks from conception the organ systems are being formed. There is on each side of the fetal abdominal cavity, an area that is destined to become the ovary. Into this area special cells migrate from the yolk sac which are destined to become the ova or eggs. These cells are also called germ cells or sex cells. Also in these two areas are cells that are specialized for the manufacture of steroid hormones. Covering all of this is the mesothelium which in the adult is recognized as the peritoneum, the lining of the abdominal cavity. Thus, the future ovary is covered with mesothelium and contains germ cells and steroid producing cells. At birth and through adult life the ovary will function as a producer of ova and the steroid hormones, estrogen and progesterone.

During each menstrual cycle a germ cell will mature into an egg contained in a follicle, or cyst. While maturing the egg, the ovary produces estrogen. The follicle cyst is covered with the epithelium that once was the mesothelium. At ovulation, the follicle breaks and out comes the egg. The remnant of the follicle cyst produces progesterone, and is called the corpus luteum. The epithelial covering gives rise to the epithelial ovarian cancers. The germ cells to the germ cell tumors and the steroid producing cells to the specialized stromal cell cancers. About 80% of ovarian cancers are epithelial. About 20% are of germ cell origin and what little is left are of specialized stromal cell origin.

In addition, there are others that are very rare. The ovary is also a site for metastasis from other cancers, especially the intestinal cancers and breast cancer.

The germ cell tumors are of note because they commonly occur in young women, 50% are in women younger than 21 years of age. They are also of note because these can be very aggressive and virulent cancers, which however, with chemotherapy can be prevented from recurring. They are also noteworthy because the teratomas have the potential to form complete adult type tissues. The common name of a mature teratoma is "dermoid." It can contain hair, teeth, bone and brain tissue. Often they are full of skin. They are not malignant but very rarely can have a secondary malignancy such as a melanoma or a squamous cell cancer of skin. Some contain thyroid tissue and can cause hyperthyroidism. Teratoma means monster which is an apt name for these ovarian tumors full of teeth and hair. If the tissue is immature or fetal in appearance then they are malignant.

The specialized stromal cell tumors are rare but of interest because they can produce hormones. Granulosa and theca cell tumors are often mixed and can produce estrogen. If it occurs in a young girl it can produce premature sexual development which will also stop the bones from growing and thus short stature. Sertoli-Leydig cell tumors produce male hormones and will cause defemininization then masculinization with male pattern baldness, deep voice, excessive hair growth and enlargement of the clitoris. The specialized stromal cell cancers are usually not aggressive cancers and usually involve only one ovary.

The majority of ovarian cancers are the epithelial adenocarcinomas and are what most people mean when they say ovarian cancer. Most of the remaining discussion will be refer to epithelial ovarian cancers. Like adenocarcinomas elsewhere they are graded and include a spectrum of disease from benign cysts to low grade borderline cancers to grade I, II, and III cancers. These cancers are often cystic and spread easily throughout the abdomen on all the peritoneal surfaces. This is not suprising since their origin is the same as that of the peritoneum. The peritoneum itself can give rise to an identical cancer long after the ovaries have been removed.

SCREENING FOR OVARIAN CANCER

1. The incidence of ovarian cancer is low. Of the approximately 40,000,000 women in this country who are of an age to be at risk there are only about 20,000 cancers diagnosed each year. That is only about 1 in 2,000. Since two thirds of the cancers are at an advanced stage at diagnosis that leaves only about 1 in 10,000 who would be both asymptomatic and have no physical findings. So, the incidence is very low on an annual basis.

2. There is no recognized progression from an early premalignant change to an early cancer to an advanced cancer. Screening will only be helpful if you can find a change before it turns into a cancer or find a very early cancer before it progresses to an advanced cancer. Unlike premalignant changes on the cervix that can be found with the Pap test, there is no such progression to cancer in the ovary that is known at this time.

3. The positive and negative predictive values of both the Ca-125 test and ultrasound techniques are too low. There are too many other reasons for a positive test other than cancer. If the Ca-125 is elevated in a screened population where there is expected to be only 1 cancer in every 2,000-10,000 women, then it will be elevated for some other reason about 99 to 1 times. The positive predictive value is less than 1%. This means that for every 100 positive tests only one will be due to cancer. Likewise, a negative test is wrong half of the time in women with ovarian cancer and is therefore essentially meaningless. The Ca-125 is a good test to follow treatment in a person already diagnosed with ovarian cancer but is of no value to use to go looking for cancers.

4. There is no easy way to evaluate an abnormal test. All you can do is say that your cancer test is positive but that it is probably wrong by a factor of 99 to 1, and maybe you should just forget about it. Or, you could repeat it in several months and pick the best two out of three results. Or, if you wish to pursue it, you will eventually have to remove the ovaries to prove that there is no cancer. Unlike the abnormal Pap test that can easily be evaluated as many times as you wish there is no easy way to evaluate an abnormal Ca-125 or ultrasound test.

5. There is no recognized professional organization that has evaluated this problem that recommends screening. It may be possible someday but not now.

FAMILIAL OVARIAN CANCER

Those with a familial syndrome are advised to have their ovaries removed by age 35. There are no recommendations for women who have one or more relatives with ovarian cancer but no documented familial syndrome. They should also consider surgery since there is no good way to follow them and they may be at the beginning of a gene mutation. The gene responsible for familial ovarian cancer is thought to be the same as the one for some breast cancers. At present there is no routine test available for testing for this gene. There are several familial ovarian cancer registries and, if you are concerned about a familial syndrome, you should consult one of these:

M. Steven Piver, MD
Director, Gilda Radner Familial Ovarian Cancer Registry
Roswell Park Cancer Institute
Buffalo, New York 14263

Beth Y. Karlan, MD
Director Ovarian Screening Program
Department of Obstetrics and Gynecology
Cedars-Sinai Medical Center
University of California Los Angeles School of Medicine
8700 Beverly Blvd Los Angeles, Ca 90048

Henry T. Lynch, MD
Department of Preventive Medicine
Creighton University School of Medicine
2500 California Plaza
Omaha, Nebr. 68178

RISK FACTORS FOR OVARIAN CANCER

SYMPTOMS

Ovarian cancer spreads on the surfaces of the intestines and can cause obstruction. Sometimes it will spread into the lining of the lung cavity and cause shortness of breath. Often there will be a several month history of digestive problems that are not specific. X-rays of the abdomen, upper GI studies and barium enemas will fail to find the cancer. Only when the fluid is detected by an ultrasound test or a CT scan will the diagnosis be considered. The diagnosis is made at exploratory surgery.

SURGERY FOR OVARIAN CANCER

STAGES OF OVARIAN CANCER
Stage I
I	Limited to the ovaries.
IA	One ovary involved.
IB	Both ovaries involved.
IC	One or both ovaries involved but with cancer on the surface of the ovary, rupture of the ovarian cyst, malignant ascites or positive abdominal washings.
Stage II
II	Spread to adjacent pelvic structures.
IIA	Spread to uterus or tubes.
IIB	Spread to pelvic peritoneum.
IIC	Confined to the pelvis but with malignant ascites or positive peritoneal washings.
Stage III
III	Spread to the upper abdomen.
IIIA	Microscopic involvement of the abdominal structures.
IIIB	No nodules greater than 2 cm (about an inch).
IIIC	Nodules greater than 2 cm, or positive pelvic and abdominal lymph nodes.
Stage IV
IV	Distant spread, beyond the abdomen, in the liver, lung, etc.

The stage is determined at surgery. If there are cancer nodules all over the abdomen then it is obviously a stage III cancer. If only one ovary is apparently involved then there has to be an extensive search for microscopic cancer on the other abdominal structures and in the lymph nodes. An early stage is assigned only after a more advanced stage has been excluded.

In addition to stage, the grade is also important. There is a grade designated grade 0. This refers to an epithelial adenocarcinoma of low malignant potential, also called a borderline cancer. These cancers tend to be indolent and although they may be stage III, not recur for many years without treatment. Grade I adenocarcinomas are easily identified as being from a glandular origin. Grade III cancers are difficult to identify as glandular, they are also called poorly differentiated. Grade II cancers are intermediate in appearance. Grade I cancers are expected to behave the best, grade III the worst.

Any woman with an enlarged ovary is considered to have an ovarian cancer and is operated, except those women who are found to have a simple cyst less than 10 cm in size and who are ovulatory or early pregnant. These women can be followed conservatively and reexamined in four weeks. If the cyst is gone or getting smaller, then it can be followed until it is gone. They had a functional cyst. Every ovulating woman gets a cyst every cycle. This follicle cyst is usually about 2cm when it breaks and releases the egg. Sometimes the follicle cyst does not break and persists and gets larger. It will eventually break on its own, but if detected during this time a cancer will also have to be considered. It should be allowed to go away on its own. Or, the follicle cyst ruptures and becomes a corpus luteum cyst. This will also go away by itself.

Persistent ovarian cysts will have to be operated to exclude or diagnose a cancer. An ultrasound test can often distinguish between a simple cyst and a complex cyst. A simple cyst is just a fluid filled structure. A complex cyst has internal structures or solid areas within it. A simple cyst can be followed, a complex cyst or solid tumor should be operated.

TREATMENT OF OVARIAN CANCER

This conservative surgery is indicated in the following situation.

1. The patient has a strong desire for further childbearing and is otherwise fertile.
2. The cancer is stage IA. Grade 0, I, or sometimes II epithelial cancer.
3. The cancer is a stage I germ cell cancer or a specialized stromal cancer.

Otherwise, all ovarian cancer patients receive a maximal surgical effort so that the residual is small. This will give them a better chance for a complete response to chemotherapy. If a segment of intestine has to be removed, then that is done. Sometimes this will result in a colostomy. If all the large pieces of cancer can be removed then a maximum effort is indicated. All the cancer can seldom be removed, but if no piece larger than 1-2 cm remains after surgery then that is considered to be an optimal cytoreduction surgery. After surgery almost all patients will require additional treatment.

The whole abdomen needs to be treated. Sometimes this can be accomplished by radiation. This is not a popular treatment in this country because of the possible major side effects and because chemotherapy seems to work as well. Another way to radiate the abdomen is to instill a radioactive substance into the abdomen. The radioactive isotope of phosphorus, called P-32, is used. This is a one time instillation and the entire abdominal contents receive a dose of several thousand RADs to a depth of several millimeters. It is used only when good distribution is assured and only microscopic amounts of cancer are present.

Chemotherapy consists of receiving the drugs soon after surgery and it is repeated every 3 or 4 weeks if all is going well. There are usually six courses of treatment. How do you know if it is working? If there is any measurable cancer, then you can tell if it is getting bigger or smaller. If there was ascites initially which has not recurred then that is good evidence of success. If the Ca-125 was elevated and reverts to normal then that is evidence of a good response. If the Ca-125 rises or the ascites returns or a new cancer is detected then that indicates failure of the chemotherapy.

Stage IA and IB, grade I cancers usually require no further treatment. All stage IC and all grade III cancers receive treatment, either with chemotherapy or P-32. All stage II and stage III cancers receive chemotherapy

The most popular regimen at this time is a platinum and Taxol. The side effects are well tolerated by most women, although most will have hair loss. The near term response is excellent. The long term response is not good but about 15% of those with suboptimal residual are apparently cured.

Response to chemotherapy: