Pelvic Malignancies
Guy I. Benrubi, M.D.
Guy I. Benrubi, M.D. is Professor and Associate Chair of the
Department of
Obstretrics and Gynecology at the University of Florida Health Science Center /
Jacksonville.
The most common malignancy in women, other than basal cell carcinoma of the skin, is
breast cancer. Breast cancer currently is being diagnosed in approximately 200,000 women
every year. This number can be compared to the total number of new pelvic malignancies
that are being diagnosed annually, nearly 75,000, involving the endometrium, ovary,
cervix, vulva, vagina, tubes, as well as gestational trophoblastic disease, and pelvic
sarcomas. Approximately 20,000 to 25,000 women will succumb to these pelvic malignancies
every year. Half of all pelvic malignancies arise in the endometrium, about one-third
arise in the ovary, approximately 14,000 to 15,000 arise in the cervix, and 3,000 arise in
the vulva. Tubal and vaginal primary cancers are very rare. Only 300 cases are diagnosed
in each site on a yearly basis. Additionally 3,000 patients per year are diagnosed with
gestational trophoblastic disease. The number of pelvic malignancies which will be
diagnosed during the next decade will increase because of demographic changes in the
general population. Ovarian, endometrial and vulvar cancers tend to occur primarily in the
postmenopausal years and as the "baby boom" generation is now entering this
stage of life, these malignancies will be seen more frequently. Physicians who provide
primary care services to women in this age group should be familiar with the risk factors
for developing these diseases and how to appropriately screen or identify early
malignancies in these patients.
Endometrial Cancer
Endometrial cancer is the most common pelvic malignancy in women. Two-thirds of these
cancer result from an inappropriate balance of estrogen versus progesterone in the
patient. One-third of endometrial cancers are not related to estrogen. A woman's risk of
developing endometrial cancer in her lifetime is two percent. However, this risk is
markedly increased in those women who have a long-time exposure of unopposed estrogen. The
primary cause of over exposure of estrogen is obesity. Androstenedione which is made in
the adrenals is converted by fat cells into estrone. This is further converted into
estradiol and estradiol has a deleterious effect on the endometrium. Other patients who
have this increased unopposed estrogen effect are women who are anovulatory, women who are
nulliparous, women who have late menopause and early menarche. Conditions which are
protective against endometrial cancer include the use of oral contraceptives because of
the progestational component of those medications; women who have multiple pregnancies;
patients with late menarche and early menopause, and smokers. There is a substance in
cigarette smoke which inhibits the estrogen uptake at the receptor level. Because of this,
the risk of endometrial cancer in smokers is decreased. However, they also have an
increased incidence of osteoporosis as well as poor complexion and wrinkled skin.
There is no good screening test for endometrial cancer. However, the disease is usually
diagnosed at an early stage because it has very specific and dramatic symptoms early on,
which make the patient go to the physician's office and be appropriately evaluated. The
most common early symptom of endometrial cancer is abnormal vaginal bleeding. In the post
menopausal period all bleeding is abnormal. Although most bleeding in post menopausal
patients is due to atrophy, all post menopausal bleeding should be considered neoplasia
until proven otherwise. In the reproductive age group, the most common cause of abnormal
bleeding is dysfunctional uterine bleeding. However, as the patient approaches age 40,
endometrial cancer should be ruled out. The diagnosis of endometrial cancer is easily made
by using office endometrial biopsy techniques which can be accomplished quite readily,
without great discomfort using a Pipelle endometrial biopsy system.
As in every cancer, once a diagnosis is made and the patient is informed of the
diagnosis, the next step should be staging. Endometrial cancer is surgically staged.
Therefore, the staging procedure is also the first step in the treatment of the disease.
The staging procedure involves an exploratory laparotomy with a total abdominal
hysterectomy, bilateral salpingo-oophorectomy, pelvic and periaortic lymph node sampling
and peritoneal cell washings. Once this material is turned over to the pathologist,
depending on the presence of certain risk factors for recurrence, adjuvant therapy may be
given including radiation therapy, chemotherapy, hormonal therapy, or a combination of any
or all of the above. The risk factors which should be evaluated include grade of tumor,
type of tumor, depth of myometrial invasion, presence in either the tubes or the ovaries,
involvement of the cervix, involvement of the pelvic or periaortic lymph nodes and
presence of malignant cells in the peritoneal cell washings. The individual combination of
risk factors that would then necessitate adjuvant therapy are too detailed to review in
this communication. Suffice it to say that there is quite a bit of controversy as to which
adjuvant therapy should be used, and in what settings.
Because endometrial cancer is usually diagnosed at an early stage, the results of
therapy are quite good. In those patients who are afflicted by a disease which is well
differentiated, limited to the endometrium with no involvement of the myometrium or any
other structures, and negative pelvic and periaortic lymph nodes, the cure rates can be as
high as ninety-eight percent without adjuvant therapy. Fortunately, most patients who have
estrogen related disease tend to fall in this category.
Ovarian Cancer
The second most common malignancy of the female reproductive tract is ovarian cancer.
Approximately sixty-five percent of all ovarian cancers are epithelial in origin and the
comments of this discussion will be limited to these type of tumors. Approximately five
percent of all epithelial cancer is genetic in origin with a high percentage of patients
that have a genetic predisposition having either BRCA1 or BRCA2 gene abnormality. BRCA1
and BRCA2 are anti-cancer genes and if there are mutations in these genes which alter
their wild behavior, then the patient has a very high incidence of ovarian and breast
cancer. However, ninety-five percent of all epithelial ovarian cancers are not related to
genetic abnormalities. The life-time risk of a woman in the United States developing
ovarian cancer is approximately 1.5 percent. There are certain risk factors which increase
the chance of developing this malignancy. The epidemiologic risk factors are somewhat less
well-defined in ovarian cancer than they are in endometrial cancer. Diet may be a strong
component, as Japanese women tend to have a lower incidence. However when Japanese move to
the United States, in subsequent generations, the incidence approaches the same as that of
Caucasian women. Another theory is that during ovulation, when the epithelial capsule of
the ovaries ruptures, there is invagination of epithelium into the stroma of the ovary
which then results in epithelial ovarian cancer. If this hypothesis were to be correct,
then women who have multiple ovulations would be at increased risk for ovarian cancer. In
fact, women who are nulliparous tend to have a higher incidence of ovarian cancer than
women who are multiparous. The presumption is that multiparous women tend to have fewer
overall lifetime ovulations with a decreased ovarian cancer risk. Similarly, women who are
on oral contraceptives tend to have a lower incidence of ovarian cancer, and three years
of oral contraceptive use decreases the incidence of epithelial ovarian cancer by fifty
percent. Conversely, women who are on ovulation induction agents may double their risk of
ovarian cancer, although the precise risk rates has not been totally elucidated.
Another hypothesis states that there may be an external factor that enters the
peritoneal cavities of women and then becomes an inducer of ovarian cancer. Whether this
external factor may be talc or some other substance, is still not totally clear. However,
if this theory were to be correct then women who have undergone tubal ligations or
hysterectomies should have a decreased incidence of ovarian cancer. This has now been
corroborated in several studies.
There is no good screening test for ovarian cancer and unfortunately the symptoms of
the disease are quite protean. Consequently, the disease is usually diagnosed at a very
late stage, primarily IIIB or IIIC. The disease is staged surgically and the diagnosis is
usually not made until the staging laparotomy. Most frequently, the patient presents with
either a pelvic mass, or a pelvic mass with ascites, and at the time of surgical
intervention the diagnosis is made and staging laparotomy also ensues.
One of the tenets of therapy for ovarian cancer is aggressive cytoreduction. In order
for cytoreduction to make any clinical sense, the tumor that is being cytoreduced should
have a response to chemotherapy that is somewhere between zero and one hundred percent.
Although this sounds facetious, it actually makes clinical sense. If a tumor has zero
percent response to chemotherapy then cytoreduction obviously makes no sense because any
amount of tumor that is debulked would immediately return to the original volume within a
very short time. If the tumor is one hundred percent responsive to chemotherapy then
cytoreduction makes no sense because the tumor could be treated by chemotherapy alone.
Ovarian cancer is one of the few, solid tumors where cytoreduction seems to be an
appropriate therapy. With new agents, the response of ovarian cancer to chemotherapy is
approximately eighty percent which means that there is initially a good chance of
remission with this disease, especially if optimally cytoreduced.
When an ovarian cancer diagnosis is made at the time of laparotomy, a surgeon should
make the maximal effort to remove the ovaries, uterus and any gross tumor which is
possibly resectable, as well as the omentum. A pelvic and periaortic lymph node sampling
is not necessary if the patient has stage III disease and the decision has already been
made to use chemotherapy. However, in stage I disease, particularly stage IA disease,
pelvic lymph node sampling and multiple peritoneal biopsies should be carried out to rule
out occult metastases to these areas which would then convert the tumor from a stage I to
a stage III. Once cytoreduction is accomplished, the patient should be started on an
adjuvant course of chemotherapy with most clinicians agreeing that a combination of taxol
and platinum is the most efficacious method. Some clinicians use platinum in the form of
carbo-platinum, others use it in the form of cis-platinum, but most agree that the
platinum-taxol combination is the one that should be used. This involves treatment with
six courses of chemotherapy, with a space of three to four week between treatments. At the
end of the six courses of induction chemotherapy, agreement as to the next step is
lacking. Many, if not most, clinicians at this time stop additional treatment once
induction chemotherapy is completed, and then follow the patient expectantly monitoring
with examinations, CA125 blood tests, and possibly imaging studies. Retreatment starts
once clinical evidence of disease returns. Other clinicians have used additional therapies
for consolidation, including whole abdominal radiation, high-dose chemotherapy with bone
marrow transplantation, and investigational agents. None of these therapies have been
proven to be any more efficacious than waiting and treating when clinical symptoms
reappear.
Because of the unfortunate nature of this disease which precludes early diagnosis, the
ten year survival rate for stage III ovarian cancer at this time is only eight percent.
However, there have been some major successes in terms of progression free interval in
this disease during the last ten years, particularly with the use of taxol. It is not
uncommon for women to be disease free over a four to eight year period prior to ultimately
succumbing to their disease.
Cervical Cancer
Cervical cancer is the third most common malignancy of the female reproductive tract.
The fact that approximately 14,500 women every year are diagnosed with cervical cancer in
this country, and that approximately 6,000 to 7,000 women die from this disease, should be
a personal affront to every physician. If every woman were to have a cervical cytological
smear once a year with adequate evaluation and follow-up, this disease essentially should
be eradicated. The fact that this disease is still among us is clearly a failure of our
health care system in this country.
The current theory of cervical cancer is that it arises when a patient has an infection
with a carcinogenic type of human papilloma virus. There are currently over 70 types of
human papilloma virus which have been identified, only some of which are carcinogenic in
the female lower reproductive tract. The E6 and E7 proteins which are made by this
carcinogenic HPV types prevent the proper functioning of anti-cancer genes in patients.
When oncogenes are turned on by a carcinogen, then lower genital track neoplasia results.
Therefore, HPV infection is a necessary but not sufficient cause of carcinogenesis of the
lower reproductive tract including cervix, vagina, vulva, perineum, and perianal area. A
cofactor for carcinogenesis seems to be cigarette smoke. The most common epidemiologic
risk factors for cervical cancer are, total number of sexual partners in a life time, and
age at the onset of first intercourse. The second factor seems to be more significant. In
other words, if a woman has intercourse at age 12, she has a much higher chance of
cervical cancer than if a woman had initial intercourse at age 50 despite the number of
sexual partners. That is because of the dynamic nature of the transformation zone of the
cervix in the teenage years.
There is a superb screening test for cervical cancer and it is unique in that the
object of the Papanicolaou smear is not to diagnose early cervical cancer but to diagnose
preinvasive disease, therefore, to allow eradication of any disease prior to invasion.
Preinvasive disease can be 100% cured by office means such are: LEEP, laser and cryo
therapy. Once the disease becomes extensive more invasive procedures are required.
Cervical cancer is clinically staged and is a disease which primarily spreads by
lymphatics and by direct extension. It tends to remain in the retroperitoneal area and
kills by blocking the ureters at the parametrial level. If the disease is limited to the
cervix and the upper vagina, and if the patient is a good surgical candidate, she can be
treated with a radical hysterectomy, pelvic lymphadenectomy, and periaortic lymph node
sampling. In more advanced stages, or if the patient is not a good candidate for surgery,
the therapy consists of whole pelvic radiation and intracavitary cesium application. For
early stage disease, the cure rates approach eighty percent. For stage II the cure rate
drops to fifty percent, and for stage III to approximately twenty-five percent. It is,
therefore, obvious that the disease should be diagnosed in its preinvasive stage and
treated successfully prior to invasion.
Vulvar Cancer
Vulvar cancer is very similar in it's epidemiology to cervical cancer except that it
occurs much later in life. The average age for vulvar cancer is approximately 60. Vulvar
cancer should be a disease which is easily diagnosed because it is essentially a skin
malignancy apparent to vulvar inspection. Unfortunately, very frequently, these
malignancies are delayed in their diagnosis because of patient delay as well as physician
delay. The American Cancer Society has tried to reverse this unfortunate situation by
encouraging patients to undergo vulvar self-exams as they are being encouraged to do
breast self-examinations. The therapy of this disease has undergone drastic change in the
last two decades. Currently, vulvar cancer is approached by doing a wide, radical excision
of the lesion using at least a one centimeter to a one centimeter and a half margin. The
groin nodes on the involved side are also dissected to rule out metastasis. In central
lesions bilateral groin node dissections are carried out. In patients with nodal disease
adjuvant pelvic radiation is given. In early stage disease, vulvar cancer can be very
successfully treated with cure rates at above ninety percent. It is therefore apparent
that education would be the best method of preventing this disease from causing death or
disfigurement.
Summary
With aggressive education of both physicians and public, and screening, many pelvic
malignancies can be eliminated or markedly decreased in their incidence and consequent
morbidity and mortality. Unfortunately, ovarian cancer treatment and early identification
still remain elusive and future screening modalities offer the best hope for decreasing
the morbidity from this disease.
- Additional Reading
- Gallup D, Talledo O. Surgical Atlas of Gynecologic Oncology. Saunders,
Philadelphia, 1994.
- Rubin S, Hoskins W. Cervical Cancer and Preinvasive Neoplasia.
Lippincott-Raven, Philadelphia, 1995.
- Rubin S, Sutton G. Ovarian Cancer. McGraw-Hill, New York, 1993.
January, 1999/ Jacksonville Medicine
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