OVARIAN CANCER
ORIGIN OF OVARIAN CANCER
CLASSIFICATION OF OVARIAN CANCERS
SCREENING FOR OVARIAN CANCER
FAMILIAL OVARIAN CANCER
RISK FACTORS FOR OVARIAN CANCER
SYMPTOMS
SURGERY FOR OVARIAN CANCER
STAGING
MANAGEMENT OF OVARIAN CYSTS
TREATMENT OF BORDERLINE OVARIAN CANCER
TREATMENT OF EPITHELIAL OVARIAN CANCER
TREATMENT OF OTHER TYPES OF OVARIAN CANCERS
SECOND LOOK SURGERY
WHAT TO DO WHEN NOTHING IS WORKING
FALLOPIAN TUBE CANCER
INTRAPERITONEAL ADENOCARCINOMA
Ovarian cancer is a nonspecific 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.
ORIGIN OF OVARIAN CANCERS
During embryonic development when the fetus is at about eight weeks post 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. The abdominal cavity is a
large space lined with peritoneum in which are contained all of the intestines, the liver and in women,
the uterus, tubes and ovaries. 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. Cancers metastatic to the ovary are
referred to as Krukenberg tumors.
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 cause 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. 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
surprising 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.
The remainder of this article is primarily concerned with epithelial ovarian cancers.
SCREENING FOR OVARIAN CANCER
There have been many attempts to screen for ovarian cancers. None have been shown to be worthwhile.
Screening means looking for a cancer in a person who has no symptoms and who has no physical findings
suggestive of a cancer. That means those who are well and normal. The two methods used to try to screen
for ovarian cancers are the Ca-125 blood test and ultrasound examinations. The reason that screening is
not advised is because:
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. This 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
woman in 10,000 who would be both asymptomatic and have no physical findings. So, the incidence of
finding an unsuspected ovarian cancer 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 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 the results of 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.
Those with a documented familial ovarian cancer syndrome where the lifetime risk of developing ovarian
cancer is about 50% are advised to have annual physical examinations and consider an annual pelvic
sonogram. Those who have set up ovarian cancer screening programs for women with a family history of
ovarian cancer have not reported any substantial benefit. Even if you decided to undergo regular Ca-125
and pelvic sonogram testing, how often should it be done? Every year seems not very adequate for ovarian
cancer. How long should it be done? For the next 30 years?
FAMILIAL OVARIAN CANCER
It has been reported that from 1% to 5-10% of ovarian cancers are thought to be due to an inheritable
syndrome. For those that are, the other female members of the family have a lifetime risk of about 50% of
developing ovarian cancer. If there are several members in several generations with ovarian cancer then
this may represent a familial syndrome. In general the lifetime risk of developing ovarian cancer is
about 1.7%. If there is one first degree relative with ovarian cancer then the risk is about 3-5%. If
there are two or more relatives with ovarian cancer then the risk is about 7%. Familial ovarian cancers
tend to occur at an early age, before 50 years, and tend to be advanced serous epithelial cancers.
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. There is a commercially available test for this gene, but its
usefulness is undetermined. 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, M.D.
Beth Y. Karlan, M.D.
Henry T. Lynch, M.D.
RISK FACTORS FOR OVARIAN CANCER
Epithelial ovarian cancers tend to be a cancer of affluent societies where expected life spans are long.
An increased risk factor, other than age, is nulliparity or delayed childbearing. A decreased risk is
seen with multiparity and with prolonged use of birth control pills. The mechanism for this protective
effect is thought to be that the number of ovulations is reduced. Each ovulation requires the breakage of
the ovarian follicle and the repair to the ovarian surface. Reparative processes means increased cell
divisions, or mitoses. Each mitotic event is a time of risk for a mutation to occur. There have been some
unsubstantiated claims that the use of talcum powders contaminated with asbestos can cause ovarian
cancers. Dietary factors are difficult to determine but if present are very weak in their association.
One study has even associated yogurt with an increased risk. More recently there has been a purported
increased risk with the use of fertility drugs. The cause of ovarian cancer is unknown.
SYMPTOMS
There are no symptoms of early ovarian cancer. Occasionally an ovarian cyst will be detected on a routine
gynecologic examination. A cyst can break and bleed and that will also cause enough symptoms to cause the
woman to seek help. Otherwise, the cancer is usually far advanced before it is diagnosed. The symptoms
will be due to a build up of fluid in the abdomen called ascites. Some women will present with several
gallons of ascitic fluid.
Ovarian cancer spreads on the surfaces of the intestines and can cause obstruction. Sometimes it will
spread into the lining of the lung cavity causing fluid to accumulate which can 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 because these tests
evaluate the inside of the intestines and the insides are always normal. The problem is on the outside of
the intestines. Only when the fluid is detected by an ultrasound test or a CT scan or a mass is felt will
the diagnosis be considered. The diagnosis is made at exploratory surgery.
CLASSIFICATION OF OVARIAN CANCERS
Epithelial serous
mucinous
endometrioid
clear cell
papillary serous
Brenner cell
undifferentiated adenocarcinomas and sarcomas
Germ cell teratomas
mature teratomas
immature teratomas
struma ovarii
carcinoid
dysgerminoma
embryonal cell carcinoma
endodermal sinus tumor
primary choriocarcinoma
gonadoblastoma
Specialized stromal cell cancers
granulosa cell tumor
theca cell tumor
Sertoli-Leydig cell tumor
hilar cell tumor
Director, Gilda Radner Familial Ovarian Cancer Registry.
Roswell Park Cancer Institute.
Buffalo, New York 14263.
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.
Department of Preventive Medicine.
Creighton University School of Medicine.
2500 California Plaza.
Omaha, Nebr. 68178.
SURGICAL STAGES OF OVARIAN CANCER Stage 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 an ovary, rupture of an ovarian cyst malignant ascites or positive abdominal washings Stage II Spread to adjacent pelvic structures IIA Spread to uterus or fallopian tubes IIB Spread to pelvic peritoneum IIC Confined to the pelvis, but with malignant ascites or positive abdominal washings Stage III Spread to the upper abdomen IIIA Microscopic spread to the upper abdomen IIIB Cancer nodules less than 2 cm in the abdomen IIIC Nodules more than 2 cm, or positive pelvic or aortic lymph nodes Stage IV Distant spread beyond the abdomen, liver, lung etc. |
The stage is determined at surgery. If there are cancer nodules throughout 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 all but the earliest cancers there is often some cancer remaining after surgery. This is because it spreads throughout the abdomen in little nodules, some are only barely visible and others are too small to see. The surgical goal is not to leave any nodule larger than 1cm which is about a quarter of an inch. If the residual is this small or smaller then the debulking or cytoreduction is considered to have been optimal. Sometimes this is not possible but a maximum effort should be done to try to achieve this optimal situation. This may require removal of a piece of intestine and even a colostomy in some instances.
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 even 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.
MANAGEMENT OF OVARIAN CYSTS
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 2 cm 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.
RESPONSE TO CHEMOTHERAPY FOR ADVANCED OVARIAN CANCER 100 patients with advanced cancer treated with a platinum combination chemotherapy 80 patients will have an initial complete clinical response, i.e., the cancer will be undetectable and the Ca-125 normal, but 40 patients will have persistent cancer if they are reoperated, and 40 will have no cancer detected at reoperation, but of these 20 will recur within the next 5 years. This leaves 20 patients free of cancer, but some will still recur, so 10-15 patients will remain cancer free and apparently cured. |
Those who recur or have progressive disease on chemotherapy will be treated with a variety of methods, but the outlook is not good.
SECOND LOOK SURGERY
A second look procedure is a complete surgical exploration and restaging procedure to determine the
status of the cancer upon completion of chemotherapy. In many cases, after an ovarian cancer has been
diagnosed and treated, there is no detectable cancer. X-rays, CT scans, Ca-125 and physical examination
are all normal. The question is then asked " What to do now?". If there is no more cancer then nothing
more needs to be done. If there is still cancer remaining in the abdomen, more treatment needs to be
given. At this point the only way to determine the status of the cancer is by another major surgery
because even though all the tests are negative there can still be cancer present. This is called a second
look.
The dilemma of second look surgery is that if it is positive, that is, persistent cancer is discovered,
what can be done about it? The best known treatment has already been given. The odds are poor that any
other treatment will be effective. If the second look is negative, the odds of cancer recurring are about
50%. It used to be that if the second look was negative no further treatment was given. But since the
odds of recurrence after a negative second look are so high, most oncologists still want to give more
treatment. The problem is what that treatment should be. There have been many studies to try to answer
this question, but there is no definite answer.
If the second look is positive then there is an opportunity to continue treatment. But with what? Again,
there is no demonstrated effective treatment, although many things have been tried.
When contemplating a second look procedure both the patient and oncologist must have a clear idea of why
they are going to do it and what they are going to do with the results. Second look procedures can be
difficult. If the intestines are stuck together with adhesions from the previous surgery, it can be very
difficult to even do the procedure, and the risk of a bowel injury is increased. The surgical procedure
can be long and difficult especially if there is no cancer detected. You have to look and biopsy
everything that can be biopsied, because when it is all done you have to be convinced that there was
nowhere else to look and that the negative results are as accurate as they can be. Of course, if a piece
of cancer is detected right away then the procedure is terminated; nothing more needs to be done surgically.
You can predict what the results of a second look will be. If there was large residual at completion of
the original surgery the odds of a positive second look are about 80%. If there was no residual after the
initial surgery the odds of a negative second look are 80%. If there was no residual after the initial
surgery and the second look is negative the odds of recurrence are less than about 10%. If there was
large residual initially and a negative second look the odds of recurrence are about 75%.
WHAT TO DO WHEN NOTHING IS WORKING
Most patients with advanced ovarian cancer will do well initially, but most will not be cured. For these
women and their families there will be a prolonged course of alternating hope and fear as results of
treatment are awaited and new treatments tried. Some of these treatments will result in a complete
remission of the cancer. Few remissions will be lasting. Some patients will receive investigational drugs
administered through nationwide studies. Some will try investigational techniques such as high dose
chemotherapy with bone marrow or stem cell replacement. And, some will opt for unconventional treatments,
of which there are many, all with testimonials as to their efficacy.
When ovarian cancer persists, in spite of several different treatment regimens, a decision should be made
as to what the overall goals will be. Cure is seldom a realistic goal, but if that is what is decided
then you should probably seek an entirely different approach such as a highly investigational method.
These would be available only at major cancer treatment centers. Miracles can be sought through
unconventional treatment regimens.
If cure is not a realistic goal, then neither may be longevity. If longevity is not a goal, then you can
stop worrying about the cancer and devote your emotional energy and resources to the more important
problems of daily living. You are going to live with this cancer. You may die as a consequence of this
cancer. BUT, YOU ARE NOT DEAD YET. There are still things for you to do. There are still things that your
doctor needs to do for you. There are still things your family and friends need to do for you. And, there
are still things you need to do for yourself.
Each day will require provision for comfort and function. Each day will be an opportunity to say good-bye
to those you need to say good-bye to. Each day will be an opportunity to resolve past conflicts and
reconcile yourself with your religious beliefs. Each day will be a free day. You can do with it as you wish.
How do you decide when to stop treatment? Ovarian cancer is different from other cancers. It is usually
diagnosed in an advanced stage, but responds well to initial treatment. About 15% will even be cured.
Most other cancers that are diagnosed at advanced stages are essentially untreatable. By contrast, breast
cancer is usually diagnosed at an early stage, but is unpredictable and can recur several times over many
years. For the ovarian cancer patient both the initial fear and the initial hope are both justified. Most
will do well initially, but most will do poorly in the long run.
Since the initial treatment has such a high response rate it is justified to think that treating the
recurrences will do as well. The dilemma is that as new active drugs are developed they are rapidly used
as initial treatment, leaving few choices for the recurrences. The odds of achieving a complete response
for a recurrence following first line treatment are only about 5%. The duration of this complete response
is usually less than 6 months. The possibility of cure is unknown, but is probably only a percentage
point at most. The odds of cure if the second line treatment does not work are too low to calculate.
How do you decide when to stop treatment? It depends on how you ask the question. If the question asked is:
"Is there any possibility that this cancer can be cured?"
Then the answer is "Probably not, but if there is any possibility that it can be cured then it will
require more surgery and chemotherapy or some other treatment. Whatever the possibility, it is
potentially more than zero, which is the outcome if nothing is done."
With this approach the decision is usually to agree to more treatment. If the question asked is:
"Is there any known treatment that will cure this cancer?"
Then the answer is "No and any more treatment is futile."
At this point the decisions are based more on personality and philosophy than medicine.
The decision not to try more treatment does not mean being abandoned by your doctors. You may need even
more medical care in an attempt to solve or palliate some of the effects of the cancer. Now is also the
time to make contact with a Hospice organization if there is one available. Hospice can help you stay at
home and coordinate care with your doctors.
The decision to not take more cancer treatment does not mean to choose death but rather to choose life,
for however long it is to be, free of the burden of chemotherapy etc.
TREATMENT OF OTHER TYPES OF OVARIAN CANCER
As a group the Germ cell cancers are usually diagnosed at an early stage and treated surgically, often
with removing only the involved ovary. Almost all patients are then given chemotherapy with a combination
of drugs selected specifically for this type of cancer. There are some variations in treatment between
the specific types of germ cell cancers so each case must be considered individually. In general, the
outlook is good.
The Specialized Stromal cell cancers are usually considered low grade malignancies and are usually
diagnosed at an early stage. They are diagnosed and treated surgically without postoperative
chemotherapy. Since most are diagnosed at an early stage, the outlook is good.
FALLOPIAN TUBE CANCER
Fallopian tube cancers are rare. If they involve the ovary, they are often called ovarian cancers. They
arise from the lining of the tube. They have the same microscopic appearance as the serous epithelial
ovarian cancers. This is as expected since the lining of the fallopian tube is derived from the same
embryologic tissue as is the surface of the ovary. The diagnosis of a fallopian tube cancer requires the
determination that the major portion of the cancer is within the tube rather than on the ovary.
Since there are no large series of fallopian tube cancers that have been reported, they are, by default,
treated the same as are epithelial ovarian cancers. They seem to have the same behavior and have the same
prognosis.
INTRAPERITONEAL ADENOCARCINOMA
Occasionally a cancer that is identical to that of a papillary serous ovarian cancer will occur
throughout the abdomen. These cancers are thought to arise directly from the peritoneum and are sometimes
referred to as mesothelial adenocarcinomas or as extraovarian papillary serous cystadenocarcinomas. The
mesothelium was the lining of the abdominal cavity of the fetus prior to birth. It is the same structure
that covers the ovaries; so it is not surprising that the same sort of cancer can occur from the lining
of the abdomen as occurs from the surface of the ovary. It is often difficult to determine if the cancer
arose from the ovaries or if it arose from the peritoneum. The lining of the uterus is also sometimes
involved with the same cancer so the primary site is further confounded. These cancers have been known to
occur years after the ovaries were surgically removed. In general, they are treated and behave the same
as an ovarian cancer of similar stage and grade.
William M. Rich, M.D.
Clinical Professor of Obstetrics and Gynecology
University of California, San Francisco
Director of Gynecologic Oncology
University Medical Center
Fresno, California