Skripsi Ovarium

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Ovarian Cancer Hugh R. K. Barber CA Cancer J Clin 1986;36;149-184 DOI: 10.3322/canjclin.36.3.149
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OvarianCancer
Hugh R.K. Barber, M.D.
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Introduction
A new era in the management of ovarian cancer is emerging. Although the diag nosis rates and types of treatment have re mained constant over the last 30 years, new advances in science and technology offer hope for the future. These advances in clude an understanding of immune com plexes, hybridomas and monoclonal antibodies, the serologic diagnosis of can cer, and immunoprophylaxis and immu notherapy. Ovarian cancer, which is increasing in incidence in highly industrialized coun tries, presents the most frustrating problem in gynecology. The ovary is distinctive in that it not only gives rise to a great many primary cancers but is also a site of me tastasis of other cancers. A thorough pre operative evaluation (metastatic workup) is mandatory for any patient with a suspected ovarian cancer. Ovarian tumors are difficult to diag nose; at initial diagnosis, about 60 to 70 percent have already reached stage III or IV. Moreover, the five-year survival rate for patients with invasive cancer is only 15 to 25 percent, and treatment results are no better now than those reported for Dr. Barber is Director of the Department of Obstetrics and Gynecology at Lenox Hill Hos pital and Professor and Chairman of the De partment of Obstetrics and Gynecology and Associate Dean for Cancer Programs of New York Medical College in New York, New York.
VOL 36, NO 3 MAY/JUNE1986
the previous two decades. With new mo dalities of therapy (hyperalimentation, multiple drug chemotherapy, and immuno therapy), patients are living longer and more comfortably, and an increase in the five year survival rate should follow. Unlike the situation for patients with other pelvic cancers, a high percentage of patients with ovarian cancer remain alert up to the moment of death. Despite im paired gastrointestinal functioning, these patients suffer greatly from ravenous hun ger and thirst, yet only a small amount of food or water precipitates bouts of pro longed vomiting. Women with advanced ovarian cancer pose a dilemma to thera peutic nihilists who argue that patients should be left to die dignity. We with cannot abandon these patients, driving them to seek unproven treatment methods. In our care of these women, the art of med icine must take over when the science of medicine fails. For most gynecologic cancers, the cause of death can be determined. The pic ture is less clear for patients who have died of ovarian cancer. It is widely assumed that repeated bowel obstructions result in in anition and malnutrition; these patients lit erally vomit themselves to death. This assumption, however, is difficult to verify. Some patients live on despite a large vol ume of cancer; others who have bowel ob struction die even though they are kept in good nutritional, fluid, and electrolyte bal ance. Close observation indicates that most
149
of these patients have infection and some have sepsis. Lowered immunocompetence interferes with the host's ability to respond normally to infection. The overall management of the patient with ovarian cancer has come full cycle. In the l950s, surgery was aggressive, but the resulting morbidity and mortality decreased the enthusiasm of the profession for this ap proach. For patients who survived the post operative period, chemotherapy was not sophisticated enough to ensure a predict able chance for either cure or palliation. Re cently, the improved and expanded role of hyperalimentation and the use of the Swan Ganz catheter have permitted a more ag gressive plan of management, and the im proved understanding of and new regimens for anticancer chemotherapy have in creased the survival rate. The increased use of broad-spectrum antibiotics and the mul tidisciplinary team approach have contrib uted immeasurably to the management of the patient with ovarian cancer.
and a median of 60.
Mortality
Seven years ago, the estimated incidence of ovarian cancer was four percent, and the estimated mortality was six percent. Ovarian cancer accounted for 23 percent of genital cancers among white women and 12 percent among black women. Ovarian cancer accounted for 49 percent of all gy necologic cancer deaths; the mean age of death was 65, and the median was 65.2 years. The death rates by age for cancer of the ovary show a steady increase as the risk population gets older until ages 70 to 75, followed by a slight decline in the older ages. The rates for nonwhites are lower than those for whites in each age group for ages over 20 years. The rates for all ages in white women have risen slowly and steadily through the years. The rates for ages 55 and over have shown a general increase. In the age groups 35 to 44 and 45 to 54, there is a general leveling off. The trends in age-standard ized death rates for major sites show that the rate for ovarian cancer is increasing: the death rate from cancer of the ovary has tripled in the past 40 years. In a given 10year period, more than 100,000 women die of ovarian cancer.
Incidence
Ovarian cancer is the eighth leading cancer in women and accounts for about four per cent of all cancers in females. Only cancers of the breast, colon and rectum, uterus, and lung, and leukemias and lymphomas account for more new cases of cancer in females than does cancer of the ovary. Ac cording to the Third National Cancer Sur vey, an estimated one of every 70 newborn girls (1 .4 percent) will develop cancer of the ovary. Ovarian cancer accounts for about 26 percent of all gynecologic cancer and about 52 percent of all genital cancer deaths. The specific incidence rates for ovar ian cancer show a steady rise with age, up to the age of 80 when the rate begins to drop off slightly, indicating that although the ovary is too old to function, it never gets too old to form a cancer. This obser vation should be considered when deciding whether to preserve the ovaries at the time of hysterectomy in women 40 years of age or older. The greatest number of cases of ovarian cancer are found in the age group of 55 to 59 years, with a mean age of 59.5
Epidemiology
A number of epidemiologic factors are sus pected of being linked with ovarian can cernulliparity, infertility, marked premenstrual tension, abnormal breast swelling, marked dysmenorrhea, increased number of abortions, early menopause, type A blood, irradiation of pelvic organs, ex posure to industrial products such as as bestos and talc, higher socioeconomic status, celibacy, breast cancer, resistance to mumps parotiditis, and a high-fat diet.' Cancers of the endometrium and ovary share at least two important risk factors with breast cancer: All three are associated with high-fat diets. Women who have not borne children are at an increased risk for all three types of cancer compared with
150
CA-A CANCER JOURNAL FOR CLINICIANS
women who have borne children. A woman who has either breast or ovarian cancer has an increased risk of cancer developing at the other site. Breast cancer also increases the risk of future endometrial cancer. The influencing factor in all of these sites may be ovarian hormonal activity. The relationship between ovarian can cer and repeated stimulation of the ovary by incessant ovulation has been well documented.? The opposite is also true: factors that suppress ovulation, such as pregnancy and the use of oral contracep tives, are known to protect against ovarian cancer. The increasing incidence of ovar ian cancer in many Western countries is probably related to the decreasing number of children born to successive generations of women. As black women achieve a higher so cioeconomic status, they are having fewer children and are eating a diet that is higher in fat. This is similar to the situation that is already found among white women.
Differences among Ethnic Groups

The incidence of ovarian cancer varies from one ethnic group to another. The incidence of ovarian cancer is low among the Japa nese, but is high among the Swedish peo ple. The combined mortality rates for all cell types of ovarian tumors vary widely in different countries. In the United States, the rates for white women are higher than those for nonwhites. In South Africa, the rates for white women are nearly double those for black women. American Indian women have lower relative frequencies of ovarian cancer than do other American women. Serous cystadenomas are the most fre quent distinctive histologic type of ovarian cancer in the US, as well as in England, Scotland, Canada, and Scandinavian coun tries. Serous cystadenocarcinoma has ac counted for almost half of ovarian cancers in Uganda, a country with a low overall fre quency of tumors of the ovary. Relative pro portions of individual cell types in low-risk countries are not available or are difficult
to compare because of variations in termi
nology. A report from north Thailand mdi

VOL 36, NO 3 MAY/JUNE 1986
cated that mucinous carcinomas account for half of the cancers of the ovary and that ser ous carcinomas seem to be rather rare. Re ports indicate that malignant teratomas are relatively more frequent in black women in the US and Uganda. Women of Oriental heritage have a greater proportion of germ cell tumors. Little is known about the epi demiology of less frequent cell types. Malignant granulosa cell tumors are reported in many countries but account for only a small proportionof the total numberofovarian tumors. In the US, ovarian cancer accounted for 24 percent of genital cancers among white women and 12 percent among black women. Studies of the histologic type in dicate notable racial variations. Papillary serous cystadenocarcinomas make up about one fourth of all ovarian cancers in white as well as black women. A higher per centage of these tumors, however, have been classified as localized among black women (34 percent) than among white women (26 percent). Papillary carcinomas occurred more frequently among white than black women and were diagnosed more often in the localized stage among white women (27 versus 19 percent). A much higher percentage of papillary cystadeno carcinomas of the ovary occur among black women (15 percent) than among white women (two percent); 31 percent were lo calized among white women and only 16 percent among black women. When their disease is diagnosed when localized, white patients with mucinous cystadenocarcinomas and granulosa cell carcinomas have a relatively high survival rate. The most lethal tumors were the un classified carcinomas and adenocarcino mas; only 10 and 18 percent, respectively, of the patients with these tumor types live for five years after diagnosis. About three fourths of these patients, however, were diagnosed after the disease had metasta sized to distant sites. Detection of ovarian cancer when it was confined to the ovaries occurred in only one fourth of these patients. One half to two thirds of patients had distant me tastases when first diagnosed. The only no ticeable change over time was an increase
151
in distant disease, with a corresponding decrease in regional spread. Although a high proportion of ovarian cancer patients receive no definitive treat ment, the increased use of chemotherapy resulted in a decline in the percent of un treated patients from about 25 percent for women of both races in 1950 to 1954, to seven percent for white women and 13 per cent for black women in 1970 to 1973. In addition, the proportion of patients treated with surgery and radiation therapy alone or in combination declined during the 24 years of this study,3 while a higher pro portion receive chemotherapy as an ad junct to these older treatment modalities. The five-year survival rates increased from 30 percent in 1950 to 1954, to 34 percent in 1965 to 1969 among white women and from 27 percent to 41 percent among black women. The 10-year survival rate was 30 percent for both white and black patients. Over all time periods, black women under age 55 had a survival rate that was almost identical to that of white women. For both races and for patients with all stages as well as localized disease, women under age 45 had a markedly longer survival than older women. It is interesting to compare the ob
served median survival time by age for white patients and black patients for 1960 to 1973. Among white patients, the ob served median survival time for all ages was 1.6 years; under age 45, it was more than five years; 45 to 54 years, 1.9; 55 to 64, 1.5; 65 to 74, 0.9; and 75 and over, 0.6 years. Among the black patients for all ages, however, the survival time was 0.9 years; under age 45, more than five years; 45 to 54, 2.0; 55 to 64, 0.7; 65 to 74, 0.5; and 75 and over, 0.4. Table 1 shows the median survival time for ovarian cancer patients.
Clinical Manifestations
There are usually no early manifestations of ovarian cancer; this fact alone is con sidered to be a major contributing factor to the poor therapeutic results. The usual manifestations recorded in hospital charts abdominal swelling, pain, and a mass are associated with advanced cancer. The earliest manifestations are gen erally insidious and include vague abdom inal discomfort, dyspepsia, indigestion, gas with constant distension, flatulence, eruc tations, a feeling of fullness after a light meal, slight loss of appetite, and other mild
152
digestive disturbances.4 Although the man ifestations are certainly not specific, these GI complaints are not uncommon. They are suggestive of ovarian cancer unless some other definitive explanation can be identified. Unfortunately, such complaints are usually not considered significant. Un like patients without disease or those with a benign process, patients with ovarian cancer have a less alkaline reaction of their peritoneal fluid, which may partly explain the early GI symptoms. The GI manifestations may precede other symptoms by months. It is impera tive to rule out ovarian cancer in women over age 40 who present with GI symptoms that cannot be definitely diagnosed. El derly women without pelvic complaints but with symptoms referable to the intestinal tract are more apt to consult their internist, family doctor, or primary care physician for their extrapelvic complaints. These doctors have a great opportunity to diag nose ovarian cancer at an early stage. In general, then, the following may help identify the high-risk patient: 40 years or older. Age Persistent GI symptoms that cannot be definitely diagnosed. A long history of ovarian dysfunction or malfunction. Clinical Diagnosis The early diagnosis of ovarian cancer is a matter of chance rather than a triumph of scientific approach. Means of early detec
tion, which is so important, are extremely
enlargement. In some cases, the pelvic findings may be uncertain even late in the disease. Pain in the early stage is associ
ated with a complication such as torsion or rupture. Later, pain occurs when adja cent organs or nerve sheaths are infiltrated by tumor.
Menstrual disorders may result from hormone-producing tumors. In the meno pausal patient, vaginal bleeding may oc cur. In non-endocrine-associated tumors, this has been attributed to the functioning stroma in ovarian cancer. Ascites with ma
lignant cells is a sign of advanced disease.

A variety of paraendocrine effects, such as hypercalcemia, hypoglycemia, Cushing's syndrome, and disorders such as hemolytic
anemia, may also rarely be related to the presence of ovarian cancer.
OvarianCancerMasquerading as
An UmbilicalHernia
Each year, our department receives refer rals of at least one to three patients who
limited. Although the cancerous tumor of one cc in size (about 1/16 in3), weighing about one gm, is about the smallest that can be detected by palpation or x-rays, such a tumor already contains about a billion cancer cells, each potentially capable of originating a new focus of disease. Dis covery of cancers when they are consid erably smalleri.e., microscopic in size would materially increase cure rates. In the majority of cases, the finding of a pelvic mass is the only available method of diagnosis, with the exception of func tional tumors, which may manifest endo crine activity with minimal ovarian
VOL 36, NO. 3 MAY/JUNE 1986
have been operated on for an umbilical hernia that proved to have metastatic ovar ian cancer present. The history of each is similar. The patient had a known history of an umbilical hernia. There is an increase in the size of the abdomen that aggravates the hernia. At the time of repair, the sur geon is surprised to find an ovarian cancer. The message is clear that a patient being operated on for an umbilical hernia with such a history should have a thorough rec tovaginal examination after first receiving an enema. Other tests should be ordered as needed. Some believe that all women undergoing abdominal surgery should have a preoperative pelvic vaginal examination, a recommendation that represents the height of optimal medical care. Pelvic Findings Although pelvic findings are of limited value in diagnosis, the physician should be alert to: A mass in the ovary. Relative immobility due to fixation and
adhesions. Irregularity of the tumor.
153
results, which may be the reason why truly invasive ovarian cancers rupture before they grow to a large size.
Indications for Exploratory Laparotomy

Prime indications for doing exploratory
laparotomy are: Pelvic mass that has appeared after

menopause, particularly an adnexal mass.
Adnexal mass in a woman of any age that progressively enlarges beyond five cm. Adnexal mass 10 cm or more in size (functional cysts seldom get this large). that cannot be diagnosed defini Mass tively as either fibroid or carcinoma. Table 2 shows the complete workup for ovarian cancer. Laboratory Diagnosis Neither sonography nor computed tomog
raphy(CT) scan has been helpful in early di
agnosis. Nuclear magnetic resonance (NMR) shows promise for detecting lesions smaller than are possible with either sonography or the CT scan. NMR, like sonography and CT scan, however, will probably play its great
est role in monitoring therapy. Laparoscopy
has been helpful in staging patients with

ovarian cancer, but has not been helpful in making an early diagnosis.
Carcinoembryonic antigen (CEA), lac

Nodular consistency with increased firmness. Tumors in the cul-de-sac described as a elevated, however, they play a role in mon tic dehydrogenase, Regan isoenzyme, and chorionic gonadotropins have not been help ful in making an early diagnosis; if
handful of knuckles. Relative insensitivity of the mass.

Increasing size. Bilaterality (70 percent in ovarian car cinomas, compared with five percent in benign lesions).
Diagnostic Sign of Palpation

Ovarian cancers often grow more rapidly than their blood supply, which produces variations in consistency. Some areas are hard, others soft; some are cystic, while other areas appear to be rubbery. In areas in which the tumor grows more rapidly and escapes from the blood supply, necrosis
154
itoring the response to therapy. Alphafe toprotein is elevated in endodermal sinus tu mors and may be the only markerspecific for diagnosing an ovarian tumor. The rare ex traembryonal choriocarcinoma of the ovary is associated with an elevated human cho rionic gonadotropin (HCG) 13-subunittiter. The work reported by Bast and colleagues5 on the use of monoclonal an tibodies to monitor the course of epithelial ovarian cancer may some day be perfected so that it can be used for early diagnosis of ovarian cancer. Currently, the murine monoclonal antibody OC 125 reacts with an antigen (CA 125) common to most non mucinous epithelial ovarian cancers. An
assay has been developed to detect CA 125 in the serum. Atack et al have reported that a rise or falling level of CA 125 correlated with progression or regression of disease in 93 percent of their patients.6 One of the most exciting areas of gy necologic oncology is the effort now being made to diagnose ovarian cancer with im munologic techniques. Progress is moving rapidly, and success to achieve early diag nosis by a serologic method seems assured. Tumor-Specific Ovarian Cancer Antigens The ectopic production of HCG by tumors is being explored in great detail. Since the individual starts as a single cell, it is rea sonable to believe that the cell contains the potential for producing every type of en zyme and protein needed for the differ entiation of cells into tissues and organs.
This differentiation is accomplished by a constant interplay between the repression
Modern technology
has made it pos
sible to isolate a homologous and very pure antibody from ascitic fluid. By splitting the antigen-antibody complex that is so abun dant in the peritoneal effusion, it has also
been possible to isolate an antigen that is
much purer than has been available pre viously. The ovarian cancer research team at Lenox Hill Hospital has been working with immune complexes isolated from malig nant effusions in patients with ovarian carcinoma, using precipitation with poly ethylene glycol 6000 and affinity chro matography on protein A-agarose. The iso lated complexes were dissociated by treatment with cold 8 molar urea. Antigen was separated from antibody by ion-ex
and derepression of genes. When a cell mutates and there is loss of genetic control (with derepression of normally repressed cells), enzymes and proteins that were originally produced but later held in abey ance are produced once again and start to function. This may explain reports that 40 percent of all cancers produce chorionic gonadotropin; some embryonal tumors have been found to produce chorionic gonado tropin in 100 percent of cases. This prob ably represents a retrogenetic expression from derepression of genes following the dedifferentiation of cells. Several research groups have identi fled a candidate antigenunique for ep ithelial ovarian cancerthat can produce an antibody when injected into rabbits. The absorbed antiserum has a very high spec ificity for epithelial ovarian cancer, but it may not be sensitive enough to diagnose early lesions. Radioimmunoassay studies or similar tests are necessary to screen a large number of women. However, it will be necessary to first determine whether the antigen will remain bound to the tumor and whether it will be secreted as an antigen or as an antigen-antibody complex. The prospects are promising.
VOL 36, NO. 3 MAY/JUNE1986
The ovary is distinctive in that it not only gives rise to a great many primary cancers but is also a site of metastasis of other cancers.
change chromatography, allowing the re covery of antibodies in the quantities needed for the preparation of immunogens. The relative content of tumor-associated anti bodies was determined by an enzyme linked-immunosorbent assay (ELISA) us ing plates sensitized with antigen extracts of an endometrioid carcinoma cell line es
tablished in the laboratory at the hospital.
The method for determining the tumor-as sociated antigen was adopted from the Hsu avidin: biotinylated horseradish peroxidase complex (ABC) technique.7 A highly reactive antibody preparation from a patient with endometrioid cancer of the ovary was used to prepare high purity antigen by affinity chromatography. Mice were immunized with this antigen and their spleen cells cultured in vitro and fused with standard myeloma cell line SP-2. The re sultant hybrid cells were screened for an tibody activity by ELISA and flow cytometry. The resulting hybridmyeloma,
155
100
80 -
@
C 0 U 6) Q.
60 -
40
20
-U
1960
1965
1970 Years
1975
1980
Fig 1. Incidence of ovarian carcinoma diagnosis of ovarian carcinoma.
in retained ovaries among patients admitted
with a
or hybridoma, cells were produced by a technique similar to that discovered by Milstein.6 Selected hybrids were cloned and their monoclonal antibodies investigated for their reactive spectra. Several these of antibod ies and one in particular (named FEN- 1 for the research associate who isolated it) are presently being studied by screening pa tients with ovarian tumors to assess their sensitivity and specificity for use in im
Cytogenetics In malignant ovarian tumors, the chro mosome distribution varies with the degree of invasiveness. Ovarian carcinomas differ from other gynecologic cancers in their ploidy distribution and the frequency of marker chromosomes. Wakong- Vaartaj a and Auersperg9 reported that 59 percent of the differentiated cancers of the ovary were in the hypodiploid (2n-x) group and 41 percent were in the triploid (3n group, x) whereas 100 percent of the undifferen tiated were in the triploid group. Ovarian cancers that were localized had a high dip bid mode, while those that had metasta sized had a high tripboid mode. The evi dence suggests that a spread outside the ovary is associated with a change from the dipboid to the triploid mode. The same au thors report that a high incidence of larger marker chromosomes is present in ovarian
CA-A CANCERJOURNALFORCLINICIANS
munodiagnosis and therapeutic monitoring

of ovarian cancer. The ELISA technique shows promise of being a much more sen sitive test than is the radioimmunoassay method. Teratomas containing significant vi telline component (endodermal sinus and polyvesicular vitelline tumors) have been shown to give rise to a serum alphafeto protein. The fetal antigen has also been identified in the ascitic fluid.
156
cancer. Since benign, borderline, and in vasive areas may be present in the same
tumor, it is obvious that wide sampling must be carried out to accurately determine the chromosomal content of the cancer. Early Detection and Prevention
In the last five years, ovarian cancer has become the leading killer among gyneco logic cancers. There are only two methods available to lower the mortality rate: early diagnosis and prophylaxis. Unfortunately, there is no method available for early diagnosis, and there is strong resistance to prophylaxis on the part of both the patient and the physician. How ever, when a hysterectomy is indicated in a patient older than 40, it is important to explain to her that ovarian cancer is on the increase, that it is the leading cause of death from gynecologic cancer, and that most cases are in stages III and IV when the diagnosis is made. Bilateral salpingo oophorectomy should also be advised. Thirty years ago, the incidence of ovarian cancer in the retained ovary of pa tients who were admitted with a diagnosis of ovarian cancer and had previous pelvic surgery was about three percent. Since then, the incidence has shown a steady increase: seven percent in 1962, 8.9 percent in 1967, and 20 percent in 1971. Since ovarian can cer is on the increase and is the leading cause of death from gynecologic cancer, it
woman. Patients with postmenopausal pal pable ovary syndrome should not be fol lowed and re-evaluated, but must be investigated promptly for the presence or absence of an ovarian tumor (Table 2). The only method of diminishing the mortality rate from ovarian cancer is the acceptance of more liberal indications for surgery. To wait until a solid tumor mass of up to five cm can be felt and then to expect a cure
is unrealistic. A review of the median sur vival time by age emphasizes the impor tance of vigilance (Table 1).
Classification In 1973, the World Health Organization (WHO) published a monograph establish
ing standards for the histologic typing of
ovarian cancers. This is a complete

breakdown of the common epithelial, gon adal stromal (formerly termed sex cord cells), germ cell, and metastatic tumors, as well as unclassified tumors. The clas sification system further differentiates the common epithelial tumors into not only the usual three groups of benign, borderline, and malignant, but also according to
whether the adenomatous or fibrous ele ment is dominant (Table 3). WHO reports that borderline cancer can be defined as a tumor that has some, but not all, of the morphologic features of
cancer, including in varying combinations: stratification of the epithelial cells, appar
would be interesting to know what the rate

is today (Fig. 1). There is no indication that the risk of ovarian cancer is reduced by removing one ovary. Currently, more than 800,000 hysterectomies are per formed each year, and most of these are performed in women over 40 years of age.
ent detachment of cellular clusters from

their sites of origin, and mitotic activity
and nuclear abnormalities intermediate be

tween those of clearly benign and unques tionably malignant tumors of a similar cell
Postmenopausal Palpable Ovary Syndrome Barber and Graber' reported an early sign of ovarian cancer that has proved most val uable in diagnosisthe postmenopausal palpable ovary syndrome. Palpation of what is interpreted as a normal-sized ovary in the premenopausal woman represents an
ovarian tumor in the postmenopausal
type. On the other hand, obvious invasion of the adjacent stroma is lacking. Tumors with epithelial cell proliferation or atypi cality of a minor degree should be placed in the benign category. Surface papillomas are included as a separate entity since there is increasing evi dence to suggest that they are more prone to spread than the completely encapsulated tumor, even though both are in the same
clinical stage. It is usually not difficult to determine
whether serous tumors (Fig. 2) have in

157
VOL 36, NO. 3
MAY/JUNE 1986
158
159
@ 4@-
/@Pregnancy
Luteoma Stroma
4 and Hyper
B ,,.@HyperpIasia of Ovarian
C. Mas@v@ Edema;
@ @ -.:. . .@-
. -
-.
D. SolitaryFollicle -
Cyst and Corpus ,, Luteu . _@
E._Multiple Folticle Cysts (Polycystic Ovar @f.4. .@1 E. Multiple.Luteinized Follicle - Cysts a G..Endometrio@is@@.H. Surface-epithelial Cysts Lesions L ..
. 1t@,Jr,
. ! Inclusion Cysts (Ge :

: -@:
1 @, Simple @
@
J.i'iiflan@niatory
K@_Parovar.ian1Cysts@.
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1+ @l.
vaded the stroma. Although diagnosis is generally made without difficulty in clear cell (Fig. 3) or endometrioid cancers, it is not as clear-cut as reported among the ser ous cancers. Benign, borderline, and ma lignant forms may coexist in any one tumor. This has been confirmed in work done with the electron microscope and may explain the importance of studying many sections before reporting the tumor karyotype. Mucinous tumors (Fig. 4) are com monly multilocular and parvilocular, which often makes it impossible to accurately de termine in a given patient whether glan dular structures lying within the stroma are
the result of budding from a larger gland or cyst, or an indication of invasion of the stroma. The documentation of invasion of this group may have to await the results of studies of histologic and nuclear grading as well as stromal response. Currently, if the epithelium is four cells high it is con sidered invasive.
Staging
Table 4 shows the recommended stage groupings of the Cancer Committee of the International Federation of Gynecology and Obstetrics (FIGO).
160
Ovarian Epithelial Tumors of Low Malignant PotentialBorderline Tumors

There is now agreement that a category of
low malignant potential (LMP) or border

line tumors exists. Histologically, these tu mors are intermediate between truly benign
those with invasive stage I neoplasia. Re porting on 65 cases of papillary serous tu mors that were borderline, Julian and Woodruffl2 showed that conservative sur gery is indicated when the disease is lim ited to a single ovary. The absolute five
tumors and those with invasive character istics; they constitute about 10 to 20 per
cent of all ovarian epithelial tumors. No matter how malignant the epithelial cells appear, unless they invade the stroma or are at least four cells high in the mucinous tumors, they must be classified as LMP
year survival rate was 83 percent, and the

relative five-year survival rate was 92 per
cent. Again, multiple sections of the tumor were required to define cellular uniformity of the lesion. An intraoperative diagnosis of tumor of LMP is usually followed by a hyster
ectomy, bilateral salpingo-oophorectomy, of the peritoneal
and not as invasive tumors. Metastatic le

sions (or multiple primary sites) are present in approximately 20 percent of cases, and these are found in the usual sites for ovar ian carcinoma metastases. These second ary lesions may in fact be of an invasive nature. Clinical staging of LMP tumors is sim ilar to that of invasive tumors. Eighty per cent of these tumors are reported to be limited to the ovaries (i.e., stage I), al though adequate staging procedures may well reduce this figure in the future. Pro vided the lesion is limited to the ovaries, the prognosis is excellent. It is important that these tumors be identified because they can be managed differently in the young age group and their prognosis is entirely different from the truly invasive ovarian cancer. There is a wide variation in the diagnosis of ovarian epi thelial tumors in centers where the diag nostic criteria for borderline tumors are not
and appropriate staging procedures. Stag

ing includes inspection
With new modalities of therapy, ovarian cancer patients are living longer and more comfortably. surfaces, cytologic washings of the peri
toneum, multiple peritoneal biopsies, scraping or biopsy of the diaphragm, and node sampling from the retroperitoneal area, particularly of the iliac and the para aortic area. If preserving fertility is de sired, unilateral salpingo-oophorectomy is
acceptable under certain circumstances.

The recommendation is to limit con servative surgery to young women with stage Ia disease lacking tumor rupture, ad hesions, and capsular excrescences. In this situation, even conservative therapy should be accompanied by inspection of perito neal and nodal biopsies, omental biopsy, and endometrial curettage. Unilateral sal pingo-oophorectomy is done only in young women because it entails a small but meas urable risk of microscopic disease in the remaining ovary. Biopsy of the opposite ovary, therefore, is advisable even though it may lead to adhesions and induce infer tility in up to 14 percent of patients. Wedge resection of the contralateral ovary may disclose or subsequently induce the for
well known or uniformly applied. Because

these criteria are now accepted and suffi cient information has been accumulated, much of the natural history of epithelial tumors of LMP is established. With iden tification of a uniform group of borderline tumors, a better defined category of ovar ian cancer has emerged. Progress has come about gradually. It must be re-emphasized that benign, borderline, and invasive areas may be pre sent in the same tumor. It is extremely important to get multiple sections before classifying a tumor as LMP or borderline.
It has been shown that serous tumors stage II and III borderline do almost as well as
161
mation of recurrent inclusion which cysts, should not be confused with metastatic dis
ease. If conservative therapy is done, some
@32 may
be
useful.
In
advanced
stages
(II
through
IV), hysterectomy
and bilateral
oncobogists recommend that salpingo oophorectomy and hysterectomy be per formed to remove the residual ovary after fertility is no longer required. The following can be said about ovar ian tumors of LMP or borderline malig nancy: Patients have a high survival rate. Tumors follow a typical and indolent course when they behave in a malignant fashion. is occasional spontaneous regres There sion of peritoneal implants. A minority of cases are fatal. Diagnosis must be based exclusively on
examination of the ovarian tumor with out considering whether it has spread.
salpingo-oophorectomy are performed along with cytoreductive surgery, as in the

truly invasive ovarian carcinomas. Re moval of all deposits larger than one cm in size probably increases the survival of
patients with malignant tumors. The appropriate therapy beyond sur

gery is controversial. Julian and Woodruff'2
believe that stage III serous tumors of LMP are primary low grade in situ peritoneal tumors and that adjunctive therapy is not needed. Other clinicians'@report that some stage II and III tumors of LMP do not progress after cytoreductive surgery; it makes no difference whether further ther apy is given. This point, therefore, is still unsettled. It is clear that progressive dis ease requires therapy, as for invasive
ovarian cancer. Without a randomized pro
Multiple sections from different parts of the tumor must be taken to rule out any invasive characteristics. The classification of these tumors is specific. It does not mean that the pathol ogist is undecided. It means that a clear and positive diagnosis has been made of tumors showing epithelial abnormalities and proliferation but without stromal invasion. Grading has been shown repeatedly to offer a very good indication of prognosis. Tumors in which the degree of epithelial atypia is slight and there is no invasion of the stroma behave in a benign fashion. Fox'3
has divided tumors of LMP into two groups,
spective study, however, the issue of pro gression and the appropriate therapy will remain controversial. Based on the re sponse of patients with advanced carci noma, combination chemotherapy appears to be superior to any single agent. Because the role of radiotherapy in the treatment of patients with advanced disease is unclear,
it is also difficult, when there are so few
patients, to provide firm data about the use of radiotherapy in tumors of LMP. Ovarian Mesothelioma
Woodruff's has proposed the concept that the ovary and the entire pentoneal cavity
based on the concentration of carcinoem

bryonic antigen (CEA). Those with a high
CEA have a more aggressive natural his tory. This work is still considered prelim
inary, but will be helpful in management decisions if it proves accurate. Nonepithelial tumors (germ cell and
are mesothelial structures and that what

ever stimulates the ovary to produce a neo plastic change can also affect other parts of the pentoneal cavity. Visceral and pa rietal peritoneal metastases of ovarian can
gonadal stromal tumors) do not lend them

selves to a diagnosis of LMP as well as do the common epithelial tumors. An attempt should still be made, however, to identify whether they are of LMP or are more ag gressive.
Because the survival rate of patients

with stage Ia and lb tumors For patients of LMP is how
excellent, adjunctive therapy is not needed.

with stage Ic disease,
cer, therefore, may not actually be metastases but may represent multiple pri mary cancers. Although not universally ac cepted, the concept is an exciting one that stimulates pathologists, gynecologists, and research scientists to rethink the traditional theories of pathogenesis of ovarian neo plasia. The advantages of this concept are to: Specify the epithelium of the ovary as
ever, intraperitoneal radioactive colloids

162
mesothelium and identify it as a unique

epithelial cell of mesodermal origin.
ica albuginea that is well developed at eight
to 10 weeks of embryonic life and sepa

rates the covering mesothelium from the
Identify both the epithelium and stroma as tissues of mesodermal origin and thus explain the origin of the mixed lesions of the uterus, tubes, ovaries, and peritoneal cavity. Explain the common findings of mul tiple cell types in many ovarian tumors that is, combinations of serous, mucinous, endometrioid, mesonephroid, and meso thelial cell types.
Identify the similarity between lesions
of the ovary and those arising in the en docervix, endometrium, and endosalpinx. Explain the occurrence of multiple foci of neoplasia in the ovary and upper genital canalboth systems of mesodermal origin.
Suggest a theory for genesis of ovarian mesothelioma. Woodruff'6 reviewed the literature of
underlying tissue; invasion into the matrix, therefore, can occur only through trauma. In contrast, there is no capsule in the fe male gonad, and openings develop con stantly during ovulation. Since there are so few testicular tumors that have been iden tified as malignant mesotheliomas, the conclusion must be drawn that the testis is protected from the intra-abdominal envi ronment and its associated irritants. An additional argument in favor of this is that the female patients, presenting with ascites and papillary abdominal carcino
matosis, are generally assumed to have pri
the 1800s and the early l900s and found

only seven cancers reported in series with
as many as 500 ovariotomies; in one re view of 100 patients with ovarian cysts, no cancers were reported. Since 1900, there has been an increase in the malignancy rate of ovarian tumors, and Woodruff suggests that these statistics point to one or more carcinogens that have been introduced into industrialized urban communities. In creases in population and longevity prob
ably also play a role in the increase of the
mary ovarian cancer even though the ovarian surfaces may be the least involved in the entire peritoneal cavity. It is Wood ruff's opinion that these cases classically demonstrate the spectrum of cell types de scribed for ovarian cancer and dramatically defend the validity of this concept. Al though tumors arising from the surface or lining cells of the ovary are classically re ferred to under such general terms as cys tadenocarcinoma,papillary carcinoma, and undifferentiated cancer,Woodruff presents evidence to support the thesis that
such lesions are mesotheliomas, and such a thesis can be defended embryologically, histologically, and clinically. There are cases in which the ovaries have been re
common epithelial ovarian cancer. Since women who have incessant ovu lation without the rest period provided by
pregnancy have a higher incidence of ovar ian cancer than do those with many children or those on long-term oral contraceptives, it would seem that the process of ovulation
moved in their entirety and masses later occur that act very much like an invasive
ovarian cancer. It may be assumed that the irritant or stimulus has remained and con tinues to affect the mesothelial surface, causing mesothelial proliferations fol lowed by the development of cancer. Diagnosis and Management Adnexal Mass of an
with recurrent breaks in the mesothelial sur face covering of the ovary subjects the ovary
to greater risk for the introduction of car cinogens compared with the undisturbed mesothelial surface of the ovary that is at rest
and not ovulating. There is a marked mitotic proliferation on the surface of the ovary at the site of ovulation. In a five-year period at Johns Hopkins Hospital, there were 240 cases of ovarian cancer but no malignant epithelial tumors of the testis. This raises some interesting
speculation: The testis has a capsule or tun
Age is an important consideration in the management of a patient with an adnexal mass or suspected ovarian tumor. A mass in the very young and the very old is pre sumed to be abnormal. The best manage ment consists of a careful workup and
exploratory laparotomy. There is no time

or place for observation and procrastina
163
VOL. 36, NO 3 MAY/JUNE1986
tion with patients
in these age groups.
Management of an adnexal mass diag

nosed during pregnancy or in patients be tween 20 and 40 years may arouse
tient should have a thorough workup, and management should be carried out without delay. Women 65 years and older are more
likely than younger women to be in ad vanced stages of ovarian cancer at the initial
controversy. The patients have been di

vided into three age groups: birth to 20, 20 to 40, and over 40 years. Birth to Age 20 Although ovarian tumors account for only one percent of new growths in children
diagnosis, and they constitute about 42 per cent of this group. In the stage-unknown
category, more than 50 percent are 65 or
older. Data suggest that elderly women are

treated more conservatively than younger patients. Yancik et al'7 report that for stages
under 16, they remain the most frequent

genital tumors of childhood and adoles cence. Although ovarian tumors may occur at any age in childhood and adolescence, they tend to be most common at puberty
III andIV disease, the five-year relative sur vival rates for elderly women are almost one
half the rate observed for women under 65.
Although the prognosis of all patients with advanced ovarian tumors is poor, it is even
worse as age progresses.
(between age 10 and 14). The genital or gans migrate from the abdomen to the pel
vis at the time of puberty. In the prepubertal child, the genital organs are located in the abdomen. The most common tumors seen in thisage group are germ celltumors, particularly cystic teratomas (dermoids). Among the malignant tumors, dysgermi
Management
The goal of treatment for ovarian cancer should be to remove the entire cancer; if this is not feasible, it is important to re move as much of the cancer as possible without causing an inordinately high mor bidity or mortality. The incision should be
noma is the most common. The key to

treatment is to be conservative. Any spread
beyond the ovary, however, demands a more aggressive approach. Age 20 to 40

In this age group, controversy may arise
vertical. There is no place for a Pfannen

stiel incision, because it is impossible to accurately stage the cancer through such
an incision; the disease is then all too often

understagednd therefore a undertreated. A
over management of an adnexal mass. A

more aggressive approach is followed for patients who are close to 40. Questions arise, however, as the age moves towards 20. In this age group, germ cell and gon
small incision also increases the risk of

rupture of the cancer, with the potential of
spread.
The liberal use of hyperalimentation, antibiotics, and improved methods for monitoring these patients (Swan-Ganz catheter) has permitted a much more ag gressive surgical and chemotherapeutic at tack than was formerly employed. Some
adal stromal and occasionally common ep

ithelial cell tumors occur. Treatment should be individualized according to the type of
tumor, stage of disease, and age of the

patient. In the younger patient, conserva
tism, unless it jeopardizes the patient's

chances for a cure, is desirable.
of these patients develop sepsis followed by a shock lung syndrome. Increased

knowledge about diagnosis and treatment
has helped to improve the results in those

patients treated aggressively. It is sometimes difficult to crossmatch blood for transfusions for patients with ovarian cancer; they may have an antibody
Age 40 and Older Patients 40 years and older are at high risk,
because they are either premenopausal or postmenopausal. Metastatic cancer to the ovaries is more common in these patients.
that complicates the crossmatch. Since some of these patients have never had a
transfusion, the antibody is not related to antibodies to human leukocyte antigens
CA-A CANCERJOURNALFOR CLINICIANS
Observation is not indicated, but the pa

164
(HLA) present on white blood cells or platelets. It appears that patients develop
antibodies because there is an antigen pre sent, perhaps on the red blood cells, that is not recognized as self, and consequently, an immune response is stimulated. The re sult is an autoimmune disorder, although
dicate that metastatic disease may be found

in the omentum even in an apparently early encapsulated ovarian cancer. Chemo therapy should be given if indicated.
Stages Ila and lIb

Here, too, after aspiration for cytology, the treatment of choice is total hysterectomy,
not an autoimmune disease. The antibody can be temporarily suppressed with corti sone, thus permitting a crossmatch. Like
patients with an autoimmune disease, these patients have an increased sense of well being during the administration of the cor tisone.
bilateral salpingo-oophorectomy, omen tectomy, and appendectomy; @32 instilla

tion is optional. Adhesions surrounding the
tumor should be biopsied to determine the presence or absence of cancer and to fur ther document the extent of disease. Che
motherapy is given as indicated.
Treatment of Epithelial Cancers Surface epithelial and ovarian stromal tu

mors represent about 90 percent of ovarian cancers. Few, however, occur in women
Stage Ill
If possible, the surgical approach is the same as that used for stage I and II can cerstotal hysterectomy, bilateral sal pingo-oophorectomy, appendectomy,and omentectomy. Chemotherapy is given.
under the age of 35; most develop in pa tients over 40. Conservative surgery is not
indicated for these older patients; treatment includes total hysterectomy, bilateral sal pingo-oophorectomy, omentectomy, and
appendectomy. Chemotherapy is given for

patients with stages II through IV cancers. Instillation of radioactive phosphorus (P32) is optional.
Stage IV
The ideal management is to remove as much cancer as possible through total abdominal hysterectomy, bilateral salpingo-oophorec tomy, appendectomy, and omentectomy.
StagesIa to Ic
Following aspiration for cytology, total hysterectomy, bilateral salpingo-oophorec tomy, omentectomy, appendectomy, and the optional instillation of @32 also the is recommended treatment for patients with stages Ia to Ic disease. Caution must be exercised using @32 women who have in had previous surgery, since bowel com plicationsincluding perforationhave occurred. All patients should have any free fluid aspirated and cytologically examined according to the Papanicolaou technique. Although there is considerable controversy about the value of omentectomy, it is help ful in that it can occasionally detect islands of tumor cells, advancing the classification from a seemingly stage I tumor to stage III. These are the stage III patients who are cured. In addition, the omentum interferes with even distribution of @32 is best and removed if p32 is administered. Reports in
VOL.36,NO. 3 MAY/JUNE 1986
Chemotherapy is given. The Eftect of Spill or Rupture of an Ovarian Tumor Accidental rupture of the smooth-surfaced, freely movable cyst will probably have lit tie unfavorable effect on prognosis. The
exception may be the mucinous cystade noma or carcinoma with a fluid content that varies from stringy, sticky mucus to a secretion the consistency of wet glue. This adhesive property creates pseudomyxoma peritonei following rupture or spillage from the cyst. Rupture of a soft vascular ovarian
tumor that is densely adherent and directly

infiltrated suggests a poor prognosis. Prog nosis is determined by the extent of disease and is adversely affected by rupturing or spillage from the tumor. Biopsies of any adhesions may reveal cancer cells, mdi
165
eating more disease than anticipated, and

may explain the reason for the rupture of
the cyst. To evaluate whether rupture has any effect on the survival rate, FIGO has added a subcategory to stage I (i.e., stage Ia[2], capsule ruptured), which will eventually provide hard data to help answer this ques tion. Role of Radioactive Isotopes The five-year survival figures for patients
with stage I ovarian cancer treated by total hysterectomy, bilateral salpingo-oophorec
vicular areas; retrograde extension to the inguinal nodes is very infrequent. The iliac nodes are involved about one quarter as often as in cancer of the cervix. The natural
history of the disease, therefore, contrain

dicates node dissection. The only possible
exception may be in the management of a

patient with a germinoma. Node biopsy (pelvic and para-aortic) is definitely indi cated in second-look operations. Node sampling helps stage the cancer more accurately, particularly if para-aortic
nodes are tested. Indications for Removal of the Bulk of Ovarian Tumor The following are the indications for re moving the bulk of ovarian tumor: help ease the patient's psycholog To ical reactionpatients who leave the op erating room with the same size mass as when they entered know that nothing could be done and that the prognosis is poor. From a psychological standpoint, there fore, it is important to try to reduce the tumor mass. improve the patient's response to To
radiation therapy and chemotherapy. reverse immunosuppression, To quired tolerance, and immunologic ac en
tomy, omentectomy, appendectomy, and the instillation of p32 are impressive and
range from 85 to 90 percent. Not all series confirm these spectacular results. In ad dition, since radioactive phosphorus emits
only beta rays, it usually causes very little bowel reaction; by limiting the dose to 15 millicuries, damage to the bowel is avoided. Radioactive phosphorus can control ascites
associated with small implants, but is in effective in large cancer nodules. The use of radioactive gold (which emits gamma as well as beta rays) has been abandoned
because of associated dense adhesions, bowel obstruction, and late bowel necro sis. The increased use of chemotherapy prophylactically may eliminate the need for
radioactive substances. If the protocol includes a second-look procedure, radioactive substances should be used with caution because of the ad hesions and bowel changes secondary to its use.
hancement. The volume of tumor is important in considering patients for therapy. Radiation
therapists feel strongly that nodules over two cm will not react predictably, because the middle of the nodule contains anoxic cells that respond poorly to radiation ther apy. These cells recover and grow. Radia
Node Dissection as Part of Planned Definitive Therapy

The consensus is against node dissection. Ovarian cancer usually spreads, over the surface of the peritoneum and the bowel, to the upper abdomen. Since the ovary arises embryologically about T10, it is not surprising that if nodal involvement oc curs, it will be in the retroperitoneal nodes of the upper abdomen around the duo
tion therapy is not the choice for treatment for the common epithelial ovarian cancer. Anticancer drugs reduce a constant per centage of tumor cells that are in cycle. For example, the same dose that kills 99
percent of 100,000 leukemia cells will kill 99 percent of 100 ovarian cancer cells. Therefore, 1,000,000 cells can be reduced to 10,000; 10,000 further reduced to 100; 100 cells to fewer than 10 cells; and finally 10 cells to zero. This shows why reduced volume of tumor is so important in at tempting to achieve cure. The immune response fails for many
denum, kidney, and celiac axis. Spread then

continues to the mediastinal and supracla
166
reasons, and it is important to reverse some of the factors that inhibit a good immune response. The tumor itself is immunosup pressive. Removing a bulk of tumor over comes a great deal of immunosuppression, allowing the host's own immune response
Role of Extended Surgery and Pelvic Exenteration

In patients with advanced disease, the can cer is usually widely disseminated over the pentoneal surfaces of the pelvis, upper ab domen, and omentum. Both ovaries are frequently involved due to either metas tases or bilateral primary growths. Ad
to function more efficiently. Acquired im munologic tolerance may occur if a large amount of antigen is released by large tu mors, overwhelming the host's immuno logic response. Following the removal of
such a large tumor mass, the host exhibits resistance to the reimplantation of the pa tient's own tumor cells, suggesting that the intrinsic failure of the immune response was not the cause of the original lack of immune reaction. Rather, the temporary paralysis observed was due to the inability of the system to cope with so big a chal lenge. Immunologic enhancement, a humoral response, results from either enhancing or blocking antibodies present in the serum. These antibodies block the antigenic sites on the surface of the tumor and prevent
vanced ovarian cancer is not surgically treatable. This concept, however, may be
revised if and when immunotherapy is ef fective as standard treatment. Since the tumor mass must be reduced below a certain volume before this form of treatment is effective, in the future pa tients may be treated in stepwise fashion first by surgery, then radiation therapy and
chemotherapy, and finally by immuno therapy. The second-look operation may play a role in finding patients with reduced tumor masses who are good candidates for
immunotherapy.
On theoretical grounds, the natural

history of ovarian cancer contraindicates these radical surgical procedures. In rare cases, however, when tumor recurrence is late and limited entirely to the pelvis, more
the killer lymphocytes from attacking the tumor. Removal of a bulk of the tumor removes a great number of antibodies that have formed complexes on the surface of the tumor. This argument has been ad vanced to show that a tumor is destroyed
by a cell-mediated mechanism rather than by a humoral mechanism. Immunoselection suggests that cells within a tumor are presumed to be de scendants of a single transformed cell. The bulk of the cells, therefore, have the same
radical surgery may be chosen. Endome

trioid cancer, for example, which appears to be less aggressive than other epithelial ovarian cancers, especially in its potential
for metastases, may lend itself to this ap proach. Long and Taylor'8 reported that
only 30 percent of their cases were bilateral and 45 percent showed metastases to the
upper abdomen. In general, patients with

advanced ovarian cancer should rare cases. not
antigen. Through mutation, however, some develop more antigen and attract a greater number of specific antibodies. They are then eliminated while the cells with few antigens continue to grow. The tumor, therefore, grows relatively slowly at first and often appears to be restrained, but pro gressively acquires more autonomy and greater invasive properties. Antigen modulation occurs when an antibody is formed and present, causing
the cell to stop synthesizing tumor anti
undergo extended surgery or pelvic exen

teration except in extremely
Plan for Evaluating an Adnexal Mass In the First Trimester of Pregnancy A unilateral, encapsulated, freely movable
mass of uniform consistency and less than 10 cm can be kept under observation until the second trimester of pregnancy. At that
gens. This renders ineffective an immu nologic reaction against tumor cells. Immunoselection and antigen modulation have not been documented in humans.
time a functional cyst such as a corpus luteum will regress. Surgical intervention is indicated if a complication arisesfor example, twisting or rupture. A hard, knobby, fixed mass of varie
167
gated consistency, bilaterality, or signs of fluid are indications for surgical interven tion, no matter what the trimester of preg
Treatment of Nonepithelial Cancer Nonepithelial lesions make up 10 percent of all ovarian tumors and are the most com mon gynecologic tumor in children and ad olescents. In childhood, one in 10 ovarian tumors is malignant, arising generally from germ cells. The cancer progresses rapidly and is susceptible to torsion, due to the long infundibulopelvic ligament.
nancy. Management of Ovarian Cancer in The Pregnant Patient

Fortunately, ovarian cancer is rare in preg nancy. Fewer than 10 percent of all ovarian cancers occur in women under 35 years of age; the incidence is only about one in
every 18,000 pregnancies (Table 5). Gen emily, the management of ovarian cancer
in a pregnant patient is the same as that
Germ Cell Tumors The management of germ cell tumors (Fig. 5) must be based on knowledge of their natural history. The dysgerminomas re semble sexually undifferentiated germ cells of the early gonad. Some patients have subnormal gonadal development and pseu
dohermaphroditism, but these findings are not caused by the tumor, and the patient's
for a nonpregnant patient. If the tumor is

low-grade and confined to only one ovary,
the treatment of choice consists of unilat

cmi oophorectomy and bisection of the op posite ovary. The pregnancy is allowed to go to term. If, however, the ovarian cancer
has extended beyond the ovary from which it arose, total hysterectomy, bilateral sal pingo-oophorectomy, omentectomy, and appendectomy are recommended. Chung and Birnbaum'9 found that fewer than 40 cases of ovarian cancer compli cating pregnancy had been reported be tween 1963 and 1972, and they added an
additional 10 cases during pregnancy and
four cases after pregnancy. Beischer et al20 recorded 164 gonadal tumors diagnosed during pregnancy or in the puerperium at the Royal Women's Hospital in Melbourne during the years 1947 to 1969. More than 50 percent were either adult cystic tera tomas or mucous cystadenomas, and only four (2.4 percent) were malignant. They commented on the difficulty of establish ing a definite diagnosis during pregnancy and concluded that the size of the tumor was not a reliable criterion of malig nancy. Novak and co-workers2' reported on
100 examples of ovarian neoplasia asso ciated with gestation. There was a total five-year salvage rate of 76 percent, which is obviously much greater than with ovar ian tumors in general, although there are certain patients alive with late recurrence. Thisexcellent survivalate r seeminglyre
ambiguous sexual status is not altered after removal of the lesion. In a patient over the age of 35, with a tumor that has spread beyond the ovary, or in those with testic ular feminization, the ideal treatment is total hysterectomy, bilateral salpingo oophorectomy, omentectomy, appendec tomy, and biopsy of para-aortic nodes with postoperative irradiation to the pelvis and para-aortic nodes as indicated. We rec ommend cytologic examination of aspir ated fluid, although some investigators challenge its value in patients with dys germinoma. In a young woman with a unilateral, encapsulated dysgerminoma who wants to
retain childbearing capability, conservative management is indicated; only five to 10 percent of these lesions are bilateral, and survival rates approach 90 percent. The
treatment of choice is unilateral salpingo oophorectomy, biopsy of the other ovary and of the para-aortic nodes, as well as
cytologic examination of pelvic fluid. The
patient should be followed every two to

three months for the first three years and
flects the low-grade potential of many of the tumors encountered during pregnancy.
168
every six months thereafter. Ideally, she should undergo a second-look operation about eight months after the initial pro cedure was performed. Endodermal sinus tumors, embryonal teratomas, and choriocarcinomas of the
ovary are highly malignant.
Management
is generally total hysterectomy and bilat eral salpingo-oophorectomy, but no strong argument can be made for this treatment over a more conservative approach. Prior to the use of combination chemotherapy,
the survival rate for the more aggressive
the granulosa cell tumors. Since both are characterized by late recurrence, total hys
terectomy and removal of the remaining ovary are recommended when the patient does not want to have more children.
compared with the more conservative ap proach was close to zero. These tumors are not generally radiosensitive, but triple che motherapy has shown some encouraging
results. A second-look operation is rec
Gonadoblastoma Gonadoblastoma, a rare ovarian tumor, is composed of germ cells (dysgerminoma) and gonadal stromal cells (granulosa or Sertoli-Leydig). Sex chromatin studies usually show a negative nuclear pattern (46 XY) or a sex chromosome mosaicism (XO/XY). Most patients are intersexual,
with a phenotypic femalehabitus,men a orrhea, and possibly virilization. Although the malignancy rate is very low, the gonads
ommended for patients on a regimen of three or four drugs who survive more than six months. The solid adult teratoma is a benign
lesion and commonly occurs in patients
over 35 years of age. Conservative treat ment is not indicated despite the fact that the lesion is benign in patients over age
35. The cystic teratoma, which accounts for 50 percent of ovarian tumors in child
should still be removed because they do not contribute to reproduction or menstrua tion. When a Y chromosome is identified
in these patients, it is important to remove the gonads because they have an increased incidence of malignancy.
hood, has a malignancy rate below the two percent reported in adults and is bilateral in fewer than 10 percent of patients. Con servative management is recommended in
children and adolescents. Mesenchymal Tumors (Gonadal Stromal)
MetastaticOvarianCancer
Approximately 10 percent of ovarian can cers are metastatic, and the survival rate is very low. Most arise from the bowel, breast, or thyroid. Since cancer of the co lon is on the increase among women and
Female gonadal stromal lesions (formerly called sex cord tumors) are often referred
to as feminizing tumors, although a certain number are nonfunctioning. The granulosa tumor (Fig. 6), the most important in this category, is bilateral in five percent of pa tients. Diagnosis is not infrequently made following rupture with resultant hemoperi toneum. In women over 35 years of age,
is the second most common cancer, the incidence of metastases to the ovary from
the colon is also increasing. Multiple sec
tions of the ovaries must be taken, since it has been found that approximately 25
percent of colon cancer patients have me tastases to the ovary. Metastatic breast can cer is rarely detected clinically because the patient usually dies from widespread dis
treatment involves total hysterectomy and

bilateral salpingo-oophorectomy. In chil dren and adolescents, the tumor is usually
unilateral and encapsulated, and unilateral salpingo-oophorectomy is sufficient treat ment.

Male sex cord lesions, formerly grouped together as arrhenoblastoma, are now termed Sertoli-Leydig cell tumors. The designation arrhenoblastoma has
ease before the ovaries have become large enough to produce symptoms. However, it has been found in performing prophylactic
oophorectomies that more than 40 percent of patients will have metastases to the ovary
if multiple sections are taken.

KrUkenberg tumors (Fig. 7), for ex
been abandoned, because not all of these

tumors produce masculinization. These tu mors are managed in the same manner as
ample, usually arise in the GI tract and metastasize to the ovary, although this tu mor may also occur primarily in the ovary. Probably arising in germinal epithelium
having mUllerian potentialities, KrUken
VOL 36,NO. 3 MAY/JUNE 1986
169
berg tumors are often bilateral and typi

cally solid; the ovary retains its normal
shape. A few cases have been reported in children. Krukenberg tumors are charac terized histologically by large, swollen, signet ring-like cells that lie in clumps
within areas of mucoid degeneration, and these are scattered through an endomatous stroma-like matrix. Only tumors meeting
entire peritoneal cavity is treated The by a downward moving strip starting from above the diaphragm and completed below the obturator foramina, using 2,250 rad
and 10 fractions midplane to all but the
these criteria should be so designated. Ovarian metastases should be removed whenever feasible. Since bilateral ovarian tumors may represent metastatic disease, a thorough exploration should be per formed. Radiation Therapy
External radiation therapy has been phased out as a modality of therapy for the man agement of common epithelial ovarian cancer. These tumors spread over the sur face of the upper abdomen including the kidneys and liver. To avoid nephritis and hepatitis, lead shields are used over these
upper and lower strips. liver shielding is used, but poste No rior renal shielding is used throughout. Patients were treated prone, two fields per day with an isocentric technique on
cobalt-60. In this hospital's experience, it
is common for a field less than 40 cm in length to cover the peritoneal cavity ade quately from the floor of the pelvis to the domes of the diaphragm.
All poorly differentiated stage I tumors
are irradiated, along with stages II and III

with no gross residual disease or a small amount of pelvic residual tumor. More ex
tensive disease receives chemotherapy as initial treatment. The Princess Margaret

group reports that about 40 percent of all
patients with cancer of the ovary have been

cured. They state that patients with stage
structures for protection; this selects these cases out for failure. In addition, radiation therapists claim that they cannot irradiate patients with nodules larger than two cm or those with ascites and expect a cure. Cells in the center of the nodule get anoxic and become sick, but do not die; sometime later, they start to grow. Delivering a dose that would eliminate these cells would re quire three times the dose needed to erad
icate well-oxygenated cells. Since many of
Ia well-differentiated cancers do not need adjuvant therapy after appropriate surgery.

Patients with stage Ia moderately and/or
poorly differentiated cancers, however, do

receive radiation therapy.
these cancers are stage III, delivering a

dose of this magnitude damages the bowel.
External therapy has a place in the treatment of germ cell and gonadal stromal tumors. These tumors are more responsive to external radiation therapy than are the common epithelial tumors and have a nat ural history and pattern of metastases that make them suitable for treatment with ex ternal radiation therapy.
A prospective randomized trial is un derway at the Princess Margaret Hospital in Toronto.22 The physicians have struc tured a program from the moving strip
technique that is slightly different from that
Chemotherapy
Whether chemotherapy will improve the five-year survival rate for ovarian cancer is difficult to estimate, but it has made life more comfortable for a great number of these patients and has increased their sur
vival time. Each center has its own criteria, but, in general, patients with metastases and ascites have been given chemotherapy. The indications are becoming more liberal. Chemotherapy, given in a well-controlled
normally employed. The central figures for abdominal-pelvic irradiation at the Hos pital are as follows: prescribed midplane abdominal The dose was 2,250 rad in 10 fractions (plus a pelvic boost), compared with 2,800 rad and 3,300 rad in eight fractions reported by others. The physical cost of this lower
dose treatment is small, but the benefit is
manner, does not produce as much mor

bidity as occurred with radiotherapy it was given to the upper abdomen. when
large.
170
Following response to chemotherapy function. The patient should be well-hy and in the absence of palpable disease, re drated and have a good urinary output. Cy clophosphamide at a dose of one g IV has peat surgery may be undertaken as a sec ond look. Usually an arbitrary time has been added to the regimen. Hexamethyl melamine eight mg/kg/day per os has been been chosen (for example, after 10 cycles used alone or in combination with the above of drug therapy or after one year). With drugs. It may produce peripheral neuro the newer combinations of drugs, the time for re-exploration should be less than when pathy. The drug should be stopped if any neurologic symptoms develop. a single drug regimen is employed. When these multiple drug regimens work, the re Young et a123reported on a randomized trial comparing a four-drug combination sponse is dramatic, and by the first four treatments tumor masses have greatly re hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa gressed or disappeared entirely. It may be necessary, therefore, to rethink the plan for CAF)with the oral alkylating agent, melphalan. Treatment with the four-drug timingthesecond-lookrocedure. tmay p I combination was associated with a signif be better to do the second look after four cycles of treatment when the tumor can no longer be palpated or identified by the lab oratory procedure. There is a The author usually uses cyclophos well-documented phamide as either continuous inter a or relationship between ovarian mittent regimen. The intermittent regimen is preferable in that the bone marrow is cancer and repeated restored before the volume of cancer cells stimulation of the ovary; increases. The continuous regimen for cy conversely, factors clophosphamide is200 mg intravenously that suppress ovulation (IV)for five daysfollowed 50 mg orally by offer protection. twice a day. The hemoglobin, white blood count, differential, and platelet counts are done every two to three weeks. Treatment is interrupted if the white blood cell count icantly increased overall response rate (75 versus 54 percent), more complete remis drops below 3,000 mm3, the polyps below sions (33 versus 16 percent), and longer 1,500 mm3, or the platelets below 100,000 mediansurvival (29versus 17months), but mm3. The intermittent regimen is 3.5 to more severe toxicity than occurred with five mg/kg/day for 10 days, or 40 to 60 mg/kg as a single dose.The regimen is melphalan. Patients with minimal residual disease had a significantly higher overall repeated every four weeks. Melphalan is given at a dose of 0.2 response rate than patients with extensive residual disease (84 versus 53 percent). mg/kg/dayforfivedays and repeated at Young et al23 concluded that the four-drug four-week intervals. The blood count and regimen is more effective than melphalan platelets arefollowed above. as in the management of advanced adenocar Combination chemotherapy has re cently been shown to produce better results cinoma. than a single alkylating agent. The com Despite promising this report, thefive year survival rate remains dismal for ovar binations are Adriamycin 50 mg per M2 IV ian cancer patients. The use of combina and cisplatin 50 mg per M2 IV at three tion drug therapy needs further controlled week intervals. Because Adriamycin is investigation. Although the plan of treat toxic theheart, to thesepatients must be evaluated carefully with electrocardio ment outlined here is being followed by an graphic studies and cardiac ejection fac increasing number of practitioners, enough tors. Because cisplatin is toxic to the kid criticism has been directed at it that caution should be exercised in using it as a model ney, patients should be evaluated prior to for treatment of the common epithelial treatment to make sure they have good renal
VOL. 36, NO 3 MAY/JUNE1986 171
ovarian cancer. On the other hand, al though there are side effects and compli cations from the multiple drug regimen, it is evident that patients following this reg imen are living longer and more comfort ably. Currently, the most commonly used combinations of anticancer drugs for ovar ian carcinoma are cyclophosphamide, Adriamycin, and cisplatin. Although it is acceptable to treat pa tients with commOn epithelial ovarian cancer with a single alkylating agent, a multiple-drug regimen should be given for treatment of germ cell and gonadal stromal tumors. Work being done on the use of anti emetic agents has revealed that there are
An antiemetic
therapy
that has been
helpful on the author's service is: Dexa

methasone 20 mg IV administered slowly over a period of five minutes; followed by Benadryl 50 mg IV; followed by Reglan two mg/kg IV by slow infusion for four doses: two hours before cisplatin, 30 min utes before cisplatin, four hours after cis platin, and six hours after cisplatin.
Immunotherapy
Immunization implies a method of protec tion rather than an active form of treat ment. Up until the present, all forms of immunotherapy have been nonspecific and unpredictable in their action. With new technology and the introduction of mono clonal antibodies, however, greater spec ificity has been introduced. Immunotherapy is reported to have started with Coley at Memorial Hospital. Observing that a sarcoma regressed in a patient with erysipelas, he cultured the streptococcus from the patient and used attenuated cultures to inoculate patients who had sarcoma. Some responded and others did not. Bacillus Calmette-Gurin (BCG) and corynebacterium parvum, several polynu cleotides, levamisol, and interferon have been used as immunopotentiators either alone or in combination with other con ventional forms of therapy for ovarian can cer. Since they are nonspecific, however, the results are totally unpredictable. A great deal of attention is being di rected to vaccines that are specific for a given tumor. Progress is being made, and it is clear that nonspecific immunization will soon be replaced y vaccines b that are specific. The author and Hollinshead of George Washington University Medical Center have an ovarian cancer vaccine in a phase I study.
There are usually no early manifestations of ovarian cancer; advanced disease is heralded abdominal swelling, pain, and a pelvic mass.
by
proposed sites of action for the different anti-emetic drugs. It has also been shown
that different drugs act in different areas to produce their emetic action. The emetic centerthe cortex, periphery, and un known areas of the cerebrumis associ ated with emesis. A variety of drugs have been trieddimenhydrinate (Drama mine), prochlorperazine (Compazine), chlorpromazine (Thorazine), dexametha sone, diphenhydramine hydrochloride (Benadryl), and metoclopramide hydro chloride (Reglan). Combinations of these drugs are usu ally effective, but if one or more do not work it is important to try others. One of the psychologically dramatic effects of chemotherapy derives from the anticipa tion of its effects. Some patients start vom iting the day before therapy; others merely think about the person who administers the chemotherapy and begin to vomit. It is im portant to find the drug combination that best fits the needs of the individual patient and to pursue it vigorously.
172
In Vitro Testing of Ovarian Carcinoma

Chemosensitivity testing is done to im prove therapy by means of an individual (selective) cytotoxic chemotherapy; a bioassay technique facilitates selec drug
tion. This may be described as a quanti tation of differential sensitivity of human tumor stem cells to anticancer drugs. In
using this technique, the evaluator should expect no more than is achievable with
studies of sensitivity of bacteria and anti biotics. The current definition of sensitiv ity is an operational one. It has been shown, however, that there is a fairly high corre lation between in vivo and in vitro sensi tivity response. In the last 25 years, various test meth ods and evaluation procedures have been
somewhat by the amount of tumor avail able and the difficulties of cloning. Al though the cloning efficiency of tumor cells is low, it is comparable to that observed in
normal bone marrow granulositic and
erythroid progenitors in vitro. The respon

sible physician should work with a single cell suspension containing a sufficient number of viable tumor stem cells.
To select a chemotherapy regimen for

a given patient, clinicians currently rely on
their own experience or choose well-proven

regimens of recent prospective randomized
developed for chemosensitivity testing. The

distinction can be made between long-term
therapy studies. Test systems are now being developed, however, and are available for
predictive testing. The methodology for sensitivity testing for cancer chemotherapy
culture methods (that is, more than 30 hours), short-term culture methods (less
than 30 hours), and those that take less than three hours. The in vitro and in vivo correlations now attainable offer the prom ise of an additional method of predicting response to a given anticancer drug. It was long assumed that a cancer started from a single clone of cells. If this were true and the clone was particularly sensitive to the chemotherapeutic agent or agents used, the tumor should be eradi cated within a given period of time. It would appear, however, that if tumors do arise as a single clone, it is not uncommon for clonal divergence to occur. This would allow one line to remain sensitive to the drugs being
One of the most exciting areas of gynecologic oncology is the effort being made to diagnose ovarian cancer with immunologic techniques.
includes in vitro and in vivo methods and models. The in vitro methods (both long term and short-term methods) include
monolayer cultures, organ cultures, free

floating slices cultures, single cell suspen sion, and fragment cultures. The in vivo models include cultivation in animals (the fusion chambers) and heterotransplanta tion (immunologically deprived animals, nude mice, or rats).
used while the other divergent lines may not be sensitive. There is increasing evi dence, especially for ovarian cancer, that
a tumor may be the result of multiple clones. Ifthis isso,it would be necessaryoiden t tify not only the major clone that the tumor cell is sensitive to, but also the other lines that may be less antigenic and would, therefore, grow more slowly. This problem
The evaluation of test samples requires experience. The following methods are available to detect the effects of cytotoxic
substances on tissues or cells: morphologic evaluation; cell count; enzyme assays; tracer
eventually may be solved through the use

of in vivo and in vitro chemosensitivity testing. Salmon and colleagues24 have been the leaders in chemosensitivity testing. They have reported that the logistics and time constraints of their assay may present ma jor problems. They have continued to per fect their technique, however, and many of the early problems have been elimi
incorporation studies, such as audioradio graphy; and radioactive biochemical methods. At this time, however, animal
transplantation tumors cannot exactly sim ulate actual clinical problems. A further limiting factor in all pre therapeutic tests is the unknown reaction of the organism to a given chemotherapy. This may include the vascularity of tumor, the amount of necrosis, the type of cell
173
nated. The number of drugs and variations

and duration of drug exposure
VOL. 36, NO. 3 MAY/JUNE1986
are limited
present, and the patient's metabolic status. The success of a chemotherapeutic agent depends mainly on the effects of the drug on both the tumor cells and host cells. The action of cytotoxic drugs on hematopoiesis is the main limiting factor in establishing the dose level. Some authors suggest that the therapeutic index should be deter mined. The chemosensitivity oftumorcellss i determined at the same time as the reaction of bone marrow cells to cytostasis. It can
to three weeks for tumor colony assays, and up to several months for in vivo test models. Evaluation by autoradiography re quires several days. Rapid advances are being made in chemosensitivity assays. Ideally, drugs that are active in vitro may also be active in vivo, and a maximum cytotoxic concentration can then be pre dicted. It can then be stated that the bio logic basis of the assay is sound.
be concluded, therefore, that if the cells of

the bone marrow react more strongly than tumor cells, then the disadvantages of the side effects will outweigh the benefits of therapy. This does offer prognostic value
Flow Cytometry
Flow cytometry has the potential to make a significant contribution to monitoring the response of the tumor to chemotherapy. By plotting a frequency of fluorescence inten sity, the relative DNA content of cells can be displayed. The relative number of cells in each phase of cell cycle can be deter mined. DNA analysis can help to deter mine the best time to administer chemotherapy. By staining bone marrow cells with a DNA stain, the percent of ab normal cells in the S phase can be moni tored. A schedule can be determined to administer an S phase-specific drug, max imizing the kill of only abnormal S phase cells. It is possible to verify the long-term success of treatment. DNA analysis can monitor effects of chemotherapy by deter mining the relative number of cells in a tumor population at regular intervals. Aneuploid cell populations in each phase of the cell cycle can be identified. These cells,ontainingn abnormal amount of c a DNA, can appear as separate populations on a DNA histogram. The clonogenic as say and the flow cytometer may comple ment one another or the flow cytometer may render the clonogenic assay obsolete.
that
There is no indication the risk of ovarian cancer

is reduced by removing
one ovary.
for a pretherapeutic test. It may well be, however, that comparing the rate of uptake of label tumor systemsand the bone by marrow systems is testing merely the rel ative rate of division of the two cell sys tems; it does not really test the tumor's drug resistance. For all methods, the disadvantage re mains the heterogeneity of the cell popu lation in human tumors; it is not known, therefore, whetherthe pretherapeutic in vestigations are carried on in cells that are representative for the respective tumor. There are methods that give a predomi nance of stem cells. The goal of further efforts, therefore, must be to develop bet ter methods of cell preparation and iden tification in order to obtain as many representative and viable tumor cells as possible. Therearecertain criteria necessaryor f routine clinical use of a predictable test. It should be available in a short time, simple, well producible, and as inexpensive as pos sible. The results can now be available after eight to 10 hours, compared with a few days for monolayer and organ cultures, two
174
Second-look laparotomy is defined as an operation that is carried out after a stated interval following initial and/or adjunctive therapy in a patient without clinical evi dence of disease or disease that can be identified by any method. Two groups of patients fall into this category. The first includes patients with known disease that
could not be adequately removed at sur gery but regressed after additional therapy; there is no longer any evidence of disease either clinically or by laboratory or tech-@ nologic examination. The second includes patients in whom all disease was removed at the time of the original operation, who received prophylactic chemotherapy for a stated interval of time, and who had no identifiable disease on examination. The
chemotherapy given prior to the second

look operation. The length of survival after second-look operations where disease is
found vanes directly with the volume of

tumor remaining at the time of surgery and the amount of tumor left behind at the sec
ond operation.
A guarded approach should be used to report the results of second-look opera tions. Occasionally, although no disease can be seen, there may be unexpected pos itive cytology on washings or unsuspected tumor cells that are found on biopsy. Dis ease may be found in the retroperitoneal area. The physician undertaking the treat ment of ovarian cancer at the onset as well as at the time of the second-look operation should be prepared to handle surgical prob lems relating to the bowel. There is a very limited role for mon itoring the management of ovarian cancers with the use of laparoscopy. If disease is found, it has significance. If disease is not seen, however, it may merely mean that the disease is in the retroperitoneal area and that the only way to identify it is by surgically exploring that area. The following represents the minimal amount of surgery necessary for an ade quate second-look operation. Ideally, this operation should consist of separate wash ings from the pelvis and upper abdomen, and a thorough exploration of all the peri toneal surfaces. The large and small bow els should be carefully inspected, as well as their mesenteries, and the area between the liver and diaphragm on the posterior peritoneum should be carefully evaluated. The diaphragm should either be biopsied or scraped for cytologic examination. The anterior and posterior peritoneum should be carefully explored. Palpation of the tissue is almost as im portant as the microscopic examination. The tissue often has a moist appearance and feels greasy; on careful palpation, however, the tissue feels sandy or gritty.
type of procedure for patients who have

progression of disease during chemother apy or whose disease is identified by any method at the time of scheduled surgery, is called a second operation or an explor atory laparotomy rather than a second-look operation. The most important question concern ing the second-look operation is whether it is possible to offer the patient a second chance for cure if disease is present. If there are enough data available, it should be possible to make that determination. The second-look operation was pop ularized by Wangensteen and colleagues,25 who used it for patients who had cancers arising in the stomach and colon and who had a response to treatment and were asymptomatic at the time of second oper ation. About half of these patients were known to have disease present. The sal vage rate of the second-look operation was only nine percenta small percentage, but a great gift of life to those fortunate few. The second-look operation gives the surgeon the opportunity for exploration, to remove all residual tumor or reduce the tumor mass and improve the patient's chances with a new regimen of treatment, to outline the site of tumor and determine the status of residual tumor, and to plan a program of treatment for the patient. Pa tients with stages I and II who have had all disease removed and have received pro phylactic chemotherapy have fewer recur rences than do patients with stages III and IV disease treated therapeutically for re sidual disease after initial treatment. The most important prognostic factors in the second-look operation are the stage of cancer at the initial procedure, the amount of residual tumor left at the initial operation, and the number of courses of
VOL. 36, NO 3 MAY/JUNE 1986
A second-look operation that is correctly

performed is difficult; indeed, it may be a tougher operation than the initial proce dure. It should consist of cytologic cx amination of the fluid from the pelvis and theupperabdomen;biopsies ofthebladder
175
flap, cul-de-sac, pelvic side walls, lumbar gutters, transverse colon, and mesenteries of the small and large bowel; and biopsies and scrapings of the diaphragm. It is im portant to explore the retropentoneal space. This surgical step may result in an ileus as well as a low-grade temperature. This should be anticipated and accepted, how ever, knowing that a more thorough ex amination has been performed. The retroperitoneal space can be ex plored by splitting the peritoneum lateral to the large bowel on the ascending and descending sides and evaluatingthe areas with washings and biopsies; alter natively, an incision may be made lateral to the infundibulopelvic ligament. The in fundibulopelvic ligament is a retroperito neal structure, and the lymphatics follow along the course beneath the peritoneum. Disease is inclined to follow the infundi bulopelvic ligament up to the level of the duodenum and pancreas. The exploration should be continued along the para-aortic area and must include washings as well as biopsies. Although it is important to explore the entire para-aortic area, the area from the bifurcation in the aorta up to the level of the duodenum is usually not involved with disease. There are instances, however, when disease is present along the external and common iliac arteries and ascends along the para-aortic and paravenacaval areas. It is particularly important to biopsy by the duodenum and pancreas, because disease is known to occur at this level and push the peritoneum anteriorly. Radiation ther apy combined with chemotherapy occa sionally provides palliation that is usually of short duration. There are no hard data that prove that the second-look operation has added to the long-term survival of these cancer patients. There are data, however, that show that patients live longer and more comfortably. When enough data are accumulated and analyzed, it is hoped that they will show an increased long-term survival rate. For the responsible gynecologic surgeon treat ing ovarian cancer, there is no option other than to perform a second-look procedure. The message for the physician must be that
176
since there is no test sensitive enough to identify very small nodules of tumor, the operation must be doneand done cor rectly.
Ovarian Cancer in Children: Guide to a Difficult Decision

Ovarian cancer in children is a difficult and challenging problem for the clinician. In children, the ovary is the most common site in the reproductive system for tumors, and one of every 10 tumors is malignant. Ovarian tumors may occur at any time in childhood or adolescence, but they tend to be more frequent at puberty, between the ages of 10 and 14 years. This supports the theory that release of a control mech anism or pituitary stimulation of a latent factor in the ovary is the triggering device. In children, certain problems caused by ovarian tumors are more significant than in adults. In children, ovarian cancer is associated with increased cachexia and as cites, and larger tumors cause relatively greater pressure symptoms and dyspnea than in adults. Also, evolution is more rapid in childhood ovarian cancer, due to the limited space for tumor expansion. Ovar ian cancers in the youngwhose immu nologic defenses are least efficient generally have a high degree of virulence. The effects of cancer therapy on the child's development must also be considered.
Diagnosis
Ovarian neoplasms in the early stages may produce few symptoms. The degree of symptomatology and physical signs are in direct relation to the tumor's rapidity of growth, location, degree of malignancy, potential for hormone production, and pos sible complications, such as torsion, rup ture, hemorrhage, or infection. Since ovarian tumors in children are abdominal and have their embryological origin from the level of T10, it is not surprising that pain and mass in the abdomen are com mon. Pain may be due to the relatively small pelvic and abdominal cavity, which causes the tumor to stretch the peritoneum and produce pressure on adjacent organs.
@ @ @ @ @ -
..@ . -
%_, ..
...-.. @.k -@-L -% S.. 4%@@b . . @
*..b@
.@
S.
-., 5,.,. @ @ -..4% @ . ,@ .,,,
..,.. @. .\@... .a,,..... @:
@
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.5.. :.. .. .t .., .. .. . .%@
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Fig. 2. Papillary serous cystadenocarcinoma.
Fig. 3. Clear cell carcinoma-mesonephric.
Torsion is more commonly encountered in

children than in adults, because of the long,
thin infundibular ligament present in the

adolescent girl. A general physical exam including pelvic and rectal examination is essential.
Rectal examination often indicates that the

pelvis is free of tumor, but a negative find ing does not rule out an ovarian tumor,
since it frequently presents as an abdom inal mass in the early stages. In most chil dren, it is impossible to palpate normal ovaries; if palpation detects an enlarged ovary, therefore, the ovary is abnormal.
Baseline blood counts, platelets, uri nalysis, and blood chemistries must be ob Fig. 4. Mucinous cystadenocarcinoma.
tained. A pelvic and abdominal sonography should be ordered, and a flat plate of the abdomen may help determine whether a dermoid cyst is present. If time permits,
intravenous pyelograms and x-ray studies of the GI tract are indicated. Radiologic
Ultrasonic methods and CT scan have

recently been introduced. There is reluc tance to use CT scan in the young patient
studies of the bone age may be useful in

patients suspected producing tumor. of having a hormone
because of the amount of radiation that the patient receives. NMR has no radiation ef
fect and may be an important diagnostic method. The role of laparoscopy in ab dominal and pelvic problems remains to be
A hormone assay profile including CEA, human chorionic gonadotropin, and

alphafetoprotein may be very valuable in diagnosis; the alphafetoprotein titer has
determined for this age group.

The clinical picture and physical find ings usually point to the diagnosis. Dif ferential diagnosis includes: appendiceal abscess, intussusception, obstruction, sal pingitis, hematometra, pyelonephritis, Wilms' tumor, neuroblastoma, and retro
been found to be elevated in extra-em bryonal endodermal sinus tumors and in certain embryonal carcinomas. Although
rare, hormone-producing tumors have a clinical picture related tothehormone they produce.
peritoneal sarcoma.
177
Treatment
It is difficult to accept a diagnosis of ovar ian cancer in a child and even harder to accept the surgery that deprives a child of reproductive potential. Although therapy must be appropriate for the patient and ex tent of disease, the internal reproductive organs should generally be radically extir pated when a cancer has spread beyond the ovary. If a tumor is encapsulated and freely movable, or if there is any doubt about either the tumor type or whether a cancer is present, then it is usually best to perform a unilateral salpingo-oophorectomy. The pelvis should be aspirated and the fluid sent for a cell block. If the tumor proves to be
should be instilled as in the adult with the dose lowered to 10 millicuries. Common epithelial ovarian cancers that occur in this age group are usually the mucinous type.
Germ Cell Tumors
Germ cell tumors almost always occur in children and adolescents, rather than in adults. A knowledge of the natural history guides the surgeon in treating this group of tumors. Dysgerminomas are highly ra diosensitive and have a bilateral rate of five to 10 percent. Although controversial, therapy of an encapsulated, unilateral dys germinoma in a young girl is unilateral salpingo-oophorectomy. This treatment is based on the assumption that there are no tumors in the opposite ovary, no positive Palpation of para-aortic nodes, and no positive cells in what is interpreted as the pelvis. Some investigators dispute the value a normal-sized ovary in the of cytology in these tumors, since they premenopausal woman rarely shed cells. These patients should be represents an ovarian tumor followed every two months for the first two in the postmenopausal years, with chest x-rays given every six woman. months. If there is any evidence of spread, total hysterectomy and bilateral salpingo oophorectomy are advised. Whether or not malignant, the abdomen may be opened to administer postoperative radiation ther and the remaining reproductive organs ex apy depends on the individual. There is a cised. In certain low-grade cancers, uni great reluctance on the part of physicians lateral salpingo-oophorectomy is adequate. to give postoperative radiation therapy to the prepubertal or pubertal child. This de cision, however, must be weighed against Tumors of Epithelial and the remaining other modalities of therapy Stromal Origin and the chances for cure. Although epithelial tumors make up 90 The role of second-look operation for percent of ovarian tumors, they are rarely dysgerminoma merits discussion. If the seen in children, particularly prior to pu mass isgreaterhan 15 cm indiameter t at berty. However, if a seemingly encapsu the time of the original operation; if the lated, unilateral mucinous or serous pathology report indicated a triad of ana cystadenocarcinoma is found in a child in plasia, medullary structure, and numerous the absence of positive cells in the pelvis, mitoses; and if residual tumor is left, post unilateral salpingo-oophorectomy with bi operative radiotherapy and/or combination section and negative biopsy of the opposite chemotherapy is indicated. If no residual ovary is sufficient treatment. If there is any tumor is palpable after completion of ther evidence of spread beyond the ovary, a apy, abdominal exploration is indicated at eight to 10 months. At the second-look total hysterectomy, bilateral salpingo operation, any recurrent or residual tumor oophorectomy, appendectomy, and omen tectomy (if an omentum has been devel should be removed in toto, if possible. oped) should be performed. The role of @32 These tumors exhibit troublesome clinical has not been determined, but if used, it and pathologic phenomena of very late re
178
VOL.36, NO 3 MAY/JUNE1986
179
I.
Diagnosis
@IignancyRat
Traatmnt
currence in the opposite ovary. It is pru dent, therefore, to remove the intact ovary after the patient's reproductive destiny has been fulfilled. Embryonal teratoma, choriocarci noma, endodermal sinus tumor (Fig. 8),
180
and polyvesicular vitelline tumor are highly malignant. When the tumor is unilateral and encapsulated, treatment by unilateral oophorectomy is as effective as total hysterectomy and bilateral salpingo oophorectomy. Few survive when surgery
Germ C.ILT
Genfimornas
I
Extra
embryonic
Yolk I Tropoblasdc (Chodocercinome) (Endod
Embryonil I. Adult Teretornat Tretomes
Fig.5. Classificationgerm cell of tumors.
is the only treatment, and radiotherapy has little to offer because these tumors are relatively radioresistant. The role of combination chemotherapy remains to
chromatinnegative.he most frequently T encountered karyotypes are 46XY and 45
XO/46 XY. Hyaline bodies that simulate Call-Exner bodies are typically present, and
foci of calcification are common. The cal cifications may be seen on x-ray studies of the pelvis and abdomen. The malignant potential is determined by the germ cell present. About half of the gonadoblastomas are associated with dys
be established; reports indicate, however, that increased survival rates may follow
conservative surgery (unilateral salpingo
oophorectomy), and combination chemo therapy (vincristine combined with Adri

amycin and cisplatin). This is but one of the regimens that have been used to treat these tumorsfor example, vincristine, actinomycin D and Adriamycin. Cyclo phosphamide in the postmenarchal girl may destroy the ova that are present. More than one half of ovarian tumors in children are benign cystic teratomas; these can be excised simply, with the ova ries preserved in most cases. In the occa sional cancer arising in cystic teratomas, unilateral oophorectomy is indicated if there is no evidence of spread. Gonadoblastoma Gonadoblastomas are composed of both germ cells and gonadal stromal cells. Most patients are intersexual and have primary
germInoma and are therefore relatively be nign. Occasionally, endodermal sinus

tumors, chonocarcinoma, and embryonal carcinoma may represent the germ cell type present in the tumor, and the cancer rate
is then increased. Since these tumors are

commonly found in the intersexual patient, bilateral oophorectomy is indicated. Gonadal Stromal Tumors
Some gonadal stromal tumors have the po tential to produce either an estrogenizing or a masculinizing effect. The only im portant malignant tumor of the female cell type is the granulosa cell cancer, which is usually unilateral and has a recurrence rate
beyond five years; metastasis or recurrence

is typically confined to the pelvis. Since
181
amenorrhea. About 90 percent of cases are

VOL.36,NO 3 MAY/JUNE 1986
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.@,
.-@-
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. .. ..
. @,. . . .
.. .-.@j .@V!'@
...
@
-,:
:.:-.@
@
-@-:
!...
Fig.6. Granulosa cell tumor.
Fig. 8. Endodermal
sinus tumor.
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-.
. ..
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@I
@ :@:
S..., ,@
.;.I I
,@ r
well as the natural history of late recur rence, total hysterectomy and bilateral salpingo-oophorectomy should be per formed after the patient has completed her family. Gynandroblastomas represent about 10 percent of gonadal stromal tumors and are composed of cells from both male and fe male cell types in about equal proportion. Management is the same as for granulosa tumors.
Sarcoma of the Ovary

Fig. 7. Krukenberg tumor.
the tumor has a low grade of cancer, con servative surgery in the form of unilateral oophorectomy is indicated when the tumor is unilateral and encapsulated. Among the male cell types, the Ser toli-Leydig cell tumors (a.rrhenoblastoma) are the most significant and generally oc cur in women of childbearing age. When functioning endocrinologically, they de feminize and then masculinize the patient. If malignant, they usually spread within the pelvis, and rarely to distant organs. Indications for conservative surgery are the same as for granulosa cell tumors. Since there is lack of correlation between the his tologic findings and the clinical course, as
182
Sarcoma of the ovary is relatively rare and is found most often in children. It is usually primary but may be the result of secondary malignant change in a fibroma or teratoma. The tumor is highly malignant, and pa tients rarely survive five years - If the tumor is encapsulated and unilateral, there is no advantage of radical over conservative sur gery. If there is evidence of spread, how ever, a total hysterectomy and bilateral salpingo-oophorectomy is indicated. Com bination chemotherapy should be given, although its value remains to be deter mined. Since the chemotherapeutic agents have the greatest effect on epithelial tissue and the sarcomas contain a great deal of stromal tissue, it is important to add pro gestational agents in this regimen; proges tational agents have an effect on stromal tissue.
Other Ovarian Tumors

There are tumors that are not specific for
the ovaryfor example, Burkitt's lym phoma. Treatment with cyclophosphamide

may be adequate to control Burkitt's lym phoma, unless the ovary is greatly enlarged or complicated by torsion or hemorrhage.
frustrating of all gynecologic diseases. Total surgical extirpation of disease is the only hope for cure; for now, early diagnosis more chance than scientific is
method.
Thanks to better public and profes sional education, ovarian cancer is now
If the lymphoma is unilateral and encap sulated, unilateral oophorectomy is indi cated; removal of an ovarian lymphoma
should be followed by chemotherapy. Metastatic Ovarian Cancer
being diagnosed at an earlier stage. The earlier the diagnosis, the greater the chance for cure. It is becoming obvious that ovar ian cancer is a disease of the GI tract, and physicians treating ovarian cancer should
be prepared to deal with bowel-associated problems. The practice of tapping women with ascites for diagnosis as well as doing
Metastases to the ovaries do occur in chil dren; there are reports of Krukenberg tu
mors with a primary lesion in the upper GI tract. As much of the tumor as possible, primary as well as metastatic, should be removed surgically. Summary Early diagnosis is the most effective means
Since there is no test sensitive enough to identify very small nodules of tumor, a second-look operation should be performed.
an exploration merely to obtain a biopsy
of reducing the currently high mortality rate associated with ovarian cancer. The palpation of what appears to be a normal
size ovary in a premenopausal woman sug
gests an ovarian tumor in a postmenopau

sal woman. Ovarian cancer should be ruled
should be discouraged. Unless the physi cian is prepared to carry out the optimal surgical approach for the patient, it is cru
cial that the patient be referred to either a
out in any woman 40 years of age or older who has persistent, unexplained GI symp toms. Ninety percent of all ovarian tumors are of epithelial origin. Treatment consists
of total hysterectomy, bilateral salpingo
center or to a physician who is actively

engaged in the day-to-day care of cancer
patients. With the combined use of all the avail able treatment methods, patients with
ovarian cancer are now living longer and
oophorectomy, omentectomy, and appen dectomy. Instillation of @32optional. In is stages lIb, III, and IV tumors, chemo therapy is advised; in stages I and ha, the use of prophylactic chemotherapy must be judged on an individual basis. In children, ovarian cancer that is be yond the localized stage is one of the most
more comfortably. There is also indication

that their long-term survival will be in creased. The one message that is important for both patients and physicians is that the
gloom and doom of the 1960s and 1970s can now be replaced by a spirit of opti mism.
VOL 36,NO.3 MAY/JUNE986 1
183
References
I. Barber HRK: Ovarian Carcinoma:Etiology,

Diagnosis and Treatment, ed 2. New York, Masson Publishing USA, Inc, 1982. 2. Casagrande iT, Lowe EW, Pike MC, et al: Incessant ovulation nd ovarian cancer. Lan a cet 2:170172,1979. 3. Cancer Patient Survival Report Number 5, 1976. Washington, DC, US Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health. 4. Wynder EL, Dodo H, Barber HRK: Epide miology of cancer of the ovary. Cancer 23:352 370, 1969. 5. Bast RC Jr. KIug TL, St. John E, et aI: A radioimmunoassay using a monoclonal anti body to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883, 1983. 6. Atack DB, Nisker JA, Allen HH, et al: CA
14. Taylor HC: Malignant and semimalignant

tumors of the ovary. Surg Gynecol Obstet 48:702, 1929.
15. WoodruffJD: The pathogenesisof ovarian

neoplasia. Johns Hopkins Med 1 144:117120,
1979. 16.WoodruffJD: Historyof ovarianneoplasms:

Facts and fancy. Obstet Gynecol Annu 5:33 1 344, 1976. 17. Yancik R, Ries LG, Yates JW: Ovarian can cer in the elderly: An analysis of surveillance, epidemiology, and end results program data. Am I Obstet Gynecol 154:639, 1986.
18. Long ME, Taylor HC Ir: Endometrioidcar cinoma of the ovary. Am I Obstet Gynecol
90:936950,1964.
125surveillanceand second-looklaparotomyin
ovarian carcinoma. 154:287, 1986. Am J Obstet Gynecol
19. Chung A, Birnbaum SJ: Ovarian cancer associated with pregnancy. Obstet Gynecol
41:211, 1973. 20. Beischer NA, Buttery BW, Fortune DW, et
7. Hsu SM, Raine L, Fanger H: A comparative study of the peroxidase-antiperoxidasemethod

and an avidin-biotin complex method for study
al: Growth and malignancyof ovarian tumors

in pregnancy. Inst NZJ Obstet Gynecol 11:208 220,1971.
Ovarian tumors in pregnancy: An ovarian tumor assay antibodies. Am I Clin Pathol 75:734 registry review. Obstet Gynecol 46:401, 1975. 738, 1981. 22. Bush RS, Dembo AJ: Current status of treat 8. Milstein C: Monoclonalantibodies. Sci Am ment for patients with ovarian cancer, in New 243:6674,1980. man CE, Ford CHJ, Jordan IA (eds): Ovarian 9. Wakong-VaartajaT, Auersperg N: Cytoge Cancer. New York, Pergamon Press, 1980, pp netics of gynecologic neoplasms. Clin Obstet 115 136. Gynecol 13:813830,1970. 23. Young RC, Chabner BA, Hubbard SP, et 10. Barber HRK, Graber EA: The PMPO syn al: Advanced ovarian adenocarcinoma: A pro drome (Postmenopausal palpable ovary syn spective clinical trial of melphalan (L-PAM) drome). Obstet Gynecol 38:921923, 1971. versus combination chemotherapy. N EngI I Med 11. Serov SF, Scully RE, Sobin LH: Histolog 299:12611266, 1978. ical Typing of Ovarian Tumors. International HistologicClassification TumorsNo.9. World 24. Salmon SE, Hamburger AW, Soehnlen B, of Ct al: Quantitation of differential sensitivity of Health Organization, Geneva, 1973, RQoSadag. human-tumor stem cells to anticancer drugs. N 12. Julian CO. Woodruff ID: Biologic behavior Engl I Med 298:13211327, 1978. of low-grade papillary serous carcinoma of the ovary. Obstet Gynecol 49:860867, 1972. 25. Wangensteen OH: Further experience con 13. Fox H: Advances in the histopathology of cerning the principle of the second-look pro ovarian tumors, in Newman CE, Ford CHJ, cedure in alimentary tract cancers. Discussion Jordan JA (eds): Ovarian Cancer. New York, before AmSurgAssoc 1950. Ann Surg 132:561, Pergamon Press, 1980, pp 928. 1950.
ing polypetide hormones with radioimmuno
21. Novak ER, Lambrou CD, Woodruff ID:
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Ovarian Cancer Hugh R. K. Barber CA Cancer J Clin 1986;36;149-184 DOI: 10.3322/canjclin.36.3.149

This information is current as of November 10, 2010

and a median of 60.

CA-A CANCER JOURNAL FOR CLINICIANS

Differences among Ethnic Groups

nology. A report from north Thailand mdi

lignant cells is a sign of advanced disease.

anemia, may also rarely be related to the presence of ovarian cancer.

Indications for Exploratory Laparotomy

laparotomy are: Pelvic mass that has appeared after

has been helpful in staging patients with

Carcinoembryonic antigen (CEA), lac

handful of knuckles. Relative insensitivity of the mass.

Diagnostic Sign of Palpation

has made it pos

Fig 1. Incidence of ovarian carcinoma diagnosis of ovarian carcinoma.

in retained ovaries among patients admitted

munodiagnosis and therapeutic monitoring

ovarian cancers. This is a complete

would be interesting to know what the rate

ent detachment of cellular clusters from

and nuclear abnormalities intermediate be

whether serous tumors (Fig. 2) have in

VOL 36, NO. 3

CA-A CANCER JOURNAL FOR CLINICIANS

VOL 36, NO 3 MAY/JUNE1986

Cyst and Corpus ,, Luteu . _@

. ! Inclusion Cysts (Ge :

CA-A CANCER JOURNAL FOR CLINICIANS

Ovarian Epithelial Tumors of Low Malignant PotentialBorderline Tumors

low malignant potential (LMP) or border

year survival rate was 83 percent, and the

and not as invasive tumors. Metastatic le

and appropriate staging procedures. Stag

acceptable under certain circumstances.

well known or uniformly applied. Because

salpingo-oophorectomy are performed along with cytoreductive surgery, as in the

patients with malignant tumors. The appropriate therapy beyond sur

based on the concentration of carcinoem

are mesothelial structures and that what

gonadal stromal tumors) do not lend them

Because the survival rate of patients

excellent, adjunctive therapy is not needed.

ever, intraperitoneal radioactive colloids

mesothelium and identify it as a unique

ica albuginea that is well developed at eight

to 10 weeks of embryonic life and sepa

the 1800s and the early l900s and found

exploratory laparotomy. There is no time

VOL. 36, NO 3 MAY/JUNE1986

tion with patients

in these age groups.

Management of an adnexal mass diag

controversy. The patients have been di

older. Data suggest that elderly women are

under 16, they remain the most frequent

noma is the most common. The key to

beyond the ovary, however, demands a more aggressive approach. Age 20 to 40

vertical. There is no place for a Pfannen

an incision; the disease is then all too often

over management of an adnexal mass. A

small incision also increases the risk of