Borderline Tumor

n 1929, Taylor first described a subset of epithelial ovarian tumors that he termed semimalignant. These lesions have a more favorable outcome than do other ovarian cancers, but they were not separately classified by the International Federation of Gynecology and Obstetrics (FIGO) and the World Health Organization (WHO) until the early 1970s. Go to Ovarian Cancer for more complete information on this topic.
Tumor subtypes

The 2 major histologic tumor subtypes are serous and mucinous, with serous being more common. Serous tumors are presumed to originate from the germinal epithelium. Mucinous tumors do not have a clearly defined origin. Substantial information indicates that many tumors may actually originate from the appendix; thus, this organ should be removed at the time of surgery.
Presenting symptoms of borderline ovarian tumors

Borderline tumors, as with other ovarian tumors, are difficult to detect clinically until they are advanced in size or stage. In one study, the most common presenting symptoms were abdominal pain, increasing girth or abdominal distention, and abdominal mass. Approximately 23% of patients were asymptomatic.
Etiology and associated factors

The etiology of this disease remains unclear because of the small number of cases and the lack of randomized, controlled studies. Based on molecular studies, some mucinous borderline tumors of the ovary may actually represent metastasis from the appendix. Although none of these has been shown to be statistically significant, factors reportedly linked with borderline tumors include the following:

Oral contraceptive use Menarche Age at first pregnancy Age at first delivery Menstrual history Smoking history Family history of ovarian cancer

Incidence of borderline ovarian tumors

One woman in 55 (1.8%) develops some form of ovarian cancer in her lifetime. Approximately 90% of these cancers are tumors of epithelial origin. If benign lesions are included, epithelial tumors account for 60% of all ovarian tumors.

In the United States, borderline tumors make up approximately 15% of all epithelial ovarian tumors. The mean age of occurrence is approximately 10 years younger than that of women with frankly malignant ovarian cancer. In Sweden, the incidence of borderline tumors may be increasing, according to a study. The frequency of these tumors in the population increased from 1 case to 5.3 cases per 100,000 women years from 1960-1964 to 2000-2005. The authors suggested that this change may have been due to a rise in diagnostic activity, as well as by a lack of protective effect of oral contraception use.[1] Comprehensive staging of borderline ovarian tumors is of significant prognostic value and is performed surgically. As opposed to its true malignant counterpart, epithelial ovarian carcinoma, borderline ovarian cancer is often found at an early stage. Without comprehensive surgical staging, the prognosis for an individual patient is difficult to predict. Borderline ovarian tumors are staged according to the FIGO classification of ovarian cancer. Many clinicians group stages II-IV together for prognostic consideration. Another common component of staging is the description of the type of implants, as these have significant prognostic value. Preoperatively, borderline tumors are often presumed to be either benign or malignant ovarian masses; however, as with other ovarian masses, staging is performed surgically. Many sources recommend complete staging if a borderline tumor is found. Current guidelines include biopsy specimens of the pelvic peritoneum (cul-de-sac, pelvic wall, and bladder peritoneum), abdominal peritoneum (paracolic gutters and diaphragmatic surfaces), omentum, intestinal serosa and mesentery, and retroperitoneal lymph nodes (pelvic and para-aortic).
Inaccurate staging

One study found that only 12% of patients were adequately staged at initial operation. Of these patients, 78% were operated on by general obstetrician/gynecologists, 10% by gynecologic oncologists, and 6% by general surgeons. When gynecologic oncologists were asked about surgical staging for borderline tumors, 97% recommended some type of staging procedure, although opinions varied significantly about which samples should be taken.[2] In a study of stage I disease, all recurrences appeared in patients who were inadequately staged. Many, if not all, of these patients probably did not actually have stage I disease. Pathologic diagnosis is difficult to confirm by frozen section. Borderline tumors are correctly diagnosed 58-86% of the time by frozen section, depending on the experience of the pathologist and the site of the operation (eg, tertiary care vs community hospital). However, in one study at a tertiary referral center, benign disease was excluded in 94% of cases subsequently diagnosed as borderline tumor. Thus, the proper operation and staging procedures

could have been performed during the initial operation in most cases, even though the diagnosis by frozen section was not completely accurate.
Staging versus laboratory findings

The diagnosis of borderline ovarian cancer is based on surgical staging. From the available data, there is no accurate way to predict the final pathology of ovarian tumors from laboratory or imaging studies alone.

Prognosis in Borderline Ovarian Cancer

Patients with borderline tumors have an excellent overall prognosis. These women have a 60% chance of having stage I disease when diagnosed. Postoperative treatment for any stage is controversial; therefore, recommending reoperation for surgical staging alone is difficult.[3, 2] This being said, adequate staging is essential for determining the prognosis. Approximately 95% of borderline ovarian tumors have diploid deoxyribonucleic acid (DNA). This finding is almost always associated with an excellent prognosis. If the tumor is aneuploid, the recurrence rate is high. Some authors suggest treating these as low-grade invasive carcinoma (also called micropapillary carcinoma). Conflicting data exist with respect to overexpression of various oncogenes and tumor suppressor genes. Although TP 53 positivity and HER2 overexpression in invasive cancer have been associated with a worse prognosis, the same gene profile has conferred a survival advantage in borderline tumors.

Recurrence and Survival

Patients with stage I disease confirmed by comprehensive staging have a recurrence rate of approximately 15%. The 5-year survival rate for such patients approaches 100%. However, the 10year survival rate is 90-95%, depending on histologic findings. In patients with stage II-IV disease, the prognosis is different; an increased stage is associated with a worse prognosis and only age at diagnosis and the presence of invasive implants are shown to influence prognosis. In reported series, women who had serous tumors with noninvasive peritoneal implants demonstrated a mean 20% recurrence rate and a mean 7% death rate. In patients with recurrence, a median time to diagnosis of 3.1 years was reported if the recurrence was of the borderline type. In patients whose recurrence was invasive carcinoma, the median time to diagnosis was 8.3 years. It is believed that the former was a recurrence but that the latter was probably a new primary tumor. The cancer antigen 125 (CA-125) level was normal in 65% of the recurring cases (see the section Biomarkers and DNA Cytometry). Death was noted only when invasive carcinoma was noted in the recurrence.

In patients with serous borderline tumors with invasive implants, the relapse rate was 31-45%, according to a study by Gershenson et al.[4] The median time from diagnosis to recurrence was 24 months, although the time to progression of disease was significantly longer in patients who had no macroscopic disease remaining at the time of initial operation.[4] Additionally, patients who received postoperative platinum-based chemotherapy had a significantly worse progression-free survival rate. However, the authors of this study believed that this finding might have been due to selection bias. Gershenson and colleagues' research indicated that the following factors had no effect on progression-free survival:

Age Stage Type of surgery Postoperative treatment Coexistence with noninvasive implants Number of invasive implants

No statistically significant differences are found in survival between mucinous and serous tumors. Mucinous tumors are most often stage I at time of diagnosis, and it is quite unusual to find extraovarian disease in tumors of mucinous origin.

Future Fertility
Given the excellent prognosis of patients with stage I disease and its occurrence in women of reproductive age, fertility-sparing surgery is of great interest.[3, 2] In patients diagnosed with stage I disease who were treated with fertility-sparing surgery of any type, a higher recurrence was found in patients who had a cystectomy, with or without contralateral oophorectomy (58%), as opposed to patients treated with oophorectomy (23%). However, only half of these patients underwent complete staging. When comprehensive staging was performed, no statistical difference was found in recurrence in confirmed cases of stage I disease. Thus, fertility-sparing surgery is an acceptable option in confirmed stage I disease. This again emphasizes the need for comprehensive staging in all cases. Of patients who attempted pregnancy after fertility-sparing operations, a 50% conception rate was achieved among 24 patients who were studied. At the endpoint of the study, 16 live births, 4 spontaneous abortions, 3 ectopic pregnancies, and 2 ongoing pregnancies were found. No fetal anomalies were reported. All authors, nevertheless, indicate that this is an area that needs further research because, in the literature, only 48 patients were found to have conceived after having conservative surgery for borderline tumors. In another study, which looked at 25 women who underwent fertility-sparing surgery, no recurrences took place in the study period, although the range of follow-up varied widely (4-157

mo). Of the 6 patients who attempted to become pregnant, 5 were successful, resulting in 5 live births, as well as 1 patient who underwent assisted reproductive techniques but had a miscarriage. A separate review found 254 pregnancies in 206 patients; the investigators calculated the overall pregnancy rate at 48%, based on the published numbers of women trying to conceive.[5]

Biomarkers and DNA Cytometry

Cancer antigen 125

CA-125 levels are not shown to aid in the diagnosis or follow-up care of patients with borderline tumors. However, preoperatively, it can be useful in counseling the patient as to what to expect in the operating room. Go to Gynecologic Tumor Markers for more complete information on this topic.
DNA cytometry

Although not routine, static DNA cytometry can be performed on biopsy specimens. As previously stated, about 95% of borderline ovarian tumors have diploid DNA, which is almost always associated with an excellent prognosis. With the advent of microarray technology, the characterization of the tumor genome can now be studied. Some preliminary work concerning the invasive forms of ovarian cancer is starting to emerge. However, little has been done on borderline ovarian cancer, mostly because of its low incidence and good prognosis. Some data suggest that invasive tumors discovered at low stages and borderline tumors, especially those with invasive implants, share genetic expression profiles. However, the significance of this has not been determined.

Doppler Ultrasonography
Preoperative transvaginal color Doppler ultrasonography has been used to assess the possibility of malignancy in ovarian masses. The rate of detection of intratumoral blood flow in borderline tumors (90%) is similar to that of malignant neoplasms (92%). The resistance and pulsatility indexes are also significantly reduced in carcinoma and borderline ovarian tumors compared with those of benign tumors. Although ultrasonography is useful in identifying the mass, this medium is not currently able to predict the final pathology of the tumor. It is neither sensitive nor specific enough to be used as a screening tool in the normal populations.

Foci Identification

Computed tomography (CT) scanning should be considered preoperatively to identify possible foci of metastasis. CT scanning can also be useful when following the patient in the future. Again, as with ultrasonography, there are no distinguishing characteristics that clearly identify a borderline ovarian tumor.

MRI Characteristics
In a retrospective study looking at MRI characteristics of known borderline tumors, Bent et al found that serous borderline tumors were significantly smaller than mucinous borderline tumors.[6] However, the investigators were not able to identify any key imaging characteristics that would distinguish borderline tumors from other ovarian tumors.[6]

Histology and Cytology

According to Dietel and Hauptmann, the histology of borderline tumors is characterized by the following features:

Epithelial multilayering of more than 4 cell layers Not more than 4 mitoses per 10 high-power field (HPF) Mild nuclear atypia Increase in nuclear/cytoplasmic ratio Slight to complex branching of epithelial papillae and pseudopapillae Epithelial budding and cell detachment into the lumen No destructive stromal invasion - A major component in differentiating malignant from borderline tumors

Mucinous tumors look grossly similar to their benign counterparts, having large, multilocular cysts with smooth surfaces. The epithelial layer is characterized by stratification of 2-3 layers. Nuclear atypia, enlarged nuclei, and mitotic figures are observed. Approximately 25% of borderline tumors have cell proliferations on the outer surface of the lesion, with no evidence of growth from the inner surface. Of these, approximately 90% develop peritoneal implants. Only 4% of cases with peritoneal implants do not have surface proliferation.
Implants

Peritoneal implants are described as invasive or noninvasive. Noninvasive implants are glandular or papillary proliferations with cell detachments. Psammoma bodies, cellular atypia, and desmoplastic fibrosis are observed in some instances. The appearance of invasive implants is similar, but they have epithelial cells infiltrating the stroma.

Treatment Parameters

The accepted initial treatment of borderline ovarian tumors is surgical removal of the tumor and the performance of biopsies. However, the postoperative management protocol is far from clear. To date, no medical therapy has been shown to clearly improve outcomes. No consensus has been reached concerning treatment of patients with stage II-IV disease. Although these women still have high 5-year survival rates compared with their counterparts with true malignant ovarian cancer, an increased stage is associated with a worse prognosis. However, stage (II vs III vs IV), type of surgery, postoperative treatment, postoperative platinum-based chemotherapy, and even the number of noninvasive implants have no effect on progression-free survival. Only age at diagnosis and the presence of invasive implants are shown to influence prognosis.

Chemotherapy
Various chemotherapy regimens have been used, but evidence is insufficient to determine exactly which therapy is indicated for borderline ovarian tumors. Many authors have used platinum-based agents, but with varying results. Some authors recommend platinum-based therapy for patients with invasive peritoneal implants because of their worse prognosis. Standard chemotherapy regimens for invasive ovarian cancer are used if any medical therapy is given. In patients without metastatic disease, chemotherapy is not indicated. An important area of research is postoperative chemotherapy. Little advantage has been reported after postoperative chemotherapy, but the number of patients studied has been small and the chemotherapeutic regimens used have been varied. The general consensus is that borderline tumors with noninvasive implants do not require any further therapy and should be observed. However, the benefit of treating tumors with invasive implants has been discussed. To date, no randomized data show a benefit.

Tumor Excision
Given the excellent prognosis for borderline ovarian tumors, hysterectomy and contralateral oophorectomy are not necessary (if the ovary appears normal) if the patient wishes to preserve fertility. If the patient is beyond childbearing age, then hysterectomy is a reasonable option. Removal of a normal, contralateral ovary should be based on existing data regarding ovarian physiology.[3] When a complex ovarian mass is discovered, surgery is often, if not always, indicated. Complete excision of the disease must be achieved if at all possible. Comprehensive staging should be a part of every operation. Although stage may or may not affect future treatment, it is of significant prognostic value and therefore is of value to the clinician and to the patient. In one study, 77% of patients with invasive peritoneal implants also had noninvasive implants. Comprehensive debulking and staging decreases the chance of a sampling error that could result in an inaccurate diagnosis and prognosis.

In most instances, surgery is curative for patients with confirmed stage I disease. If the tumor is unilateral and adjacent to normal tissue, unilateral cystectomy can be performed; however, inspection of the capsule for signs of rupture should be performed before resection. If no normal adjacent tissue is present, oophorectomy or salpingo-oophorectomy should be performed. If the contralateral ovary is normal in appearance, a biopsy should not be performed on the adjacent ovary because of the risk of ovarian failure (if fertility is an issue). Owing to the high association between surface proliferations and peritoneal implants, exploration of the peritoneum should be extensive and thorough. If possible, carefully evaluate and remove the implants. The type of implant (ie, invasive, noninvasive) should be noted by pathology, as it has significant prognostic value. Contraindications to surgery include medical reasons (ie, the patient is too great a surgical risk secondary to other medical problems) or patient refusal. Otherwise, the masses should be surgically removed.

Complications of Borderline Ovarian Cancer

Most of the complications of borderline ovarian cancer are caused by the operation itself, subsequent therapy, or recurrence. In one series of 28 borderline tumorrelated deaths, 2 patients died of radiation-associated complications, 9 of chemotherapy-associated complications, 8 of bowel obstruction, and 8 of invasive carcinoma. This led the authors to suggest that most patients with borderline tumors died with the disease rather than from the disease. References
1. Skrnisdttir I, Garmo H, Wilander E, Holmberg L. Borderline ovarian tumors in Sweden

2.

3. 4.

5.

6.

1960-2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer. Oct 15 2008;123(8):1897-901. [Medline]. Lin PS, Gershenson DM, Bevers MW, Lucas KR, Burke TW, Silva EG. The current status of surgical staging of ovarian serous borderline tumors. Cancer. Feb 15 1999;85(4):905-11. [Medline]. Cadron I, Leunen K, Van Gorp T, Amant F, Neven P, Vergote I. Management of borderline ovarian neoplasms. J Clin Oncol. Jul 10 2007;25(20):2928-37. [Medline]. Gershenson DM, Silva EG, Levy L, Burke TW, Wolf JK, Tornos C. Ovarian serous borderline tumors with invasive peritoneal implants. Cancer. Mar 15 1998;82(6):1096-103. [Medline]. Swanton A, Bankhead CR, Kehoe S. Pregnancy rates after conservative treatment for borderline ovarian tumours: a systematic review. Eur J Obstet Gynecol Reprod Biol. Nov 2007;135(1):3-7. [Medline]. Bent CL, Sahdev A, Rockall AG, Singh N, Sohaib SA, Reznek RH. MRI appearances of borderline ovarian tumours. Clin Radiol. Apr 2009;64(4):430-8. [Medline].

OVARIAN CANCER
ORIGIN OF OVARIAN CANCER CLASSIFICATION OF OVARIAN CANCERS SCREENING FOR OVARIAN CANCER FAMILIAL OVARIAN CANCER RISK FACTORS FOR OVARIAN CANCER SYMPTOMS SURGERY FOR OVARIAN CANCER STAGING MANAGEMENT OF OVARIAN CYSTS TREATMENT OF BORDERLINE OVARIAN CANCER TREATMENT OF EPITHELIAL OVARIAN CANCER TREATMENT OF OTHER TYPES OF OVARIAN CANCERS SECOND LOOK SURGERY WHAT TO DO WHEN NOTHING IS WORKING FALLOPIAN TUBE CANCER INTRAPERITONEAL ADENOCARCINOMA Ovarian cancer is a nonspecific term for a variety of cancers that originate in the ovary. There are about 20 microscopically distinct types. They can be classified into three large groups, epithelial cancers, germ cell tumors, and specialized stromal cell cancers. There are three groups because the ovary contains collections of cells with three distinct origins and functions. ORIGIN OF OVARIAN CANCERS During embryonic development when the fetus is at about eight weeks post conception the organ systems are being formed. There is on each side of the fetal abdominal cavity an area that is destined to become the ovary. Into this area special cells migrate from the yolk sac which are destined to become the ova or eggs. These cells are also called germ cells or sex cells. Also in these two areas are cells that are specialized for the manufacture of steroid hormones. Covering all of this is the mesothelium which in the adult is recognized as the peritoneum, the lining of the abdominal cavity. The abdominal cavity is a large space lined with peritoneum in which are contained all of the intestines, the liver and in women, the uterus, tubes and ovaries. Thus, the future ovary is covered with mesothelium and contains germ cells and steroid producing cells. At birth and through adult life the ovary will function as a producer of ova and the steroid hormones, estrogen and progesterone . During each menstrual cycle a germ cell will mature into an egg contained in a follicle, or cyst. While maturing the egg, the ovary produces estrogen. The follicle cyst is covered with the epithelium that once was the mesothelium. At ovulation, the follicle breaks and out comes the egg. The remnant of the follicle cyst produces progesterone, and is called the corpus luteum. The epithelial covering gives rise to the epithelial ovarian cancers; the germ cells to the germ cell

tumors and the steroid producing cells to the specialized stromal cell cancers. About 80% of ovarian cancers are epithelial. About 20% are of germ cell origin and what little is left are of specialized stromal cell origin.
CLASSIFICATION OF OVARIAN CANCERS Epithelial serous mucinous endometrioid clear cell papillary serous Brenner cell undifferentiated adenocarcinomas and sarcomas teratomas mature teratomas immature teratomas struma ovarii carcinoid dysgerminoma embryonal cell carcinoma endodermal sinus tumor primary choriocarcinoma gonadoblastoma stromal cell cancers granulosa cell tumor theca cell tumor Sertoli-Leydig cell tumor hilar cell tumor

Germ cell

Specialized

In addition, there are others that are very rare. The ovary is also a site for metastasis from other cancers, especially the intestinal cancers and breast cancer. Cancers metastatic to the ovary are referred to as Krukenberg tumors. The germ cell tumors are of note because they commonly occur in young women; 50% are in women younger than 21 years of age. They are also of note because these can be very aggressive and virulent cancers, which however, with chemotherapy can be prevented from recurring. They are also noteworthy because the teratomas have the potential to form complete adult type tissues. The common name of a mature teratoma is "dermoid." It can contain hair, teeth, bone and brain tissue. Often they are full of skin. They are not malignant but very rarely can have a secondary malignancy such as a melanoma or a squamous cell cancer of skin. Some contain thyroid tissue and can cause hyperthyroidism. Teratoma means monster which is an apt name for these ovarian tumors full of teeth and hair. If the tissue is immature or fetal in appearance then they are malignant. The specialized stromal cell tumors are rare but of interest because they can produce hormones. Granulosa and theca cell tumors are often mixed and can produce estrogen. If it occurs in a young girl it can produce premature sexual development which will also stop the bones from growing and thus cause short stature. Sertoli-Leydig cell tumors produce male hormones and will cause defemininization then masculinization with male pattern baldness, deep voice, excessive hair

growth and enlargement of the clitoris. The specialized stromal cell cancers are usually not aggressive cancers and usually involve only one ovary. The majority of ovarian cancers are the epithelial adenocarcinomas and are what most people mean when they say ovarian cancer. Like adenocarcinomas elsewhere they are graded and include a spectrum of disease from benign cysts to low grade borderline cancers to grade I, II, and III cancers. These cancers are often cystic and spread easily throughout the abdomen on all the peritoneal surfaces. This is not surprising since their origin is the same as that of the peritoneum. The peritoneum itself can give rise to an identical cancer long after the ovaries have been removed. The remainder of this article is primarily concerned with epithelial ovarian cancers. SCREENING FOR OVARIAN CANCER There have been many attempts to screen for ovarian cancers. None have been shown to be worthwhile. Screening means looking for a cancer in a person who has no symptoms and who has no physical findings suggestive of a cancer. That means those who are well and normal. The two methods used to try to screen for ovarian cancers are the Ca-125 blood test and ultrasound examinations. The reason that screening is not advised is because: 1. The incidence of ovarian cancer is low. Of the approximately 40,000,000 women in this country who are of an age to be at risk there are only about 20,000 cancers diagnosed each year. This is only about 1 in 2,000. Since two thirds of the cancers are at an advanced stage at diagnosis that leaves only about 1 woman in 10,000 who would be both asymptomatic and have no physical findings. So, the incidence of finding an unsuspected ovarian cancer is very low on an annual basis. 2. There is no recognized progression from an early premalignant change to an early cancer to an advanced cancer. Screening will only be helpful if you can find a change before it turns into a cancer or find a very early cancer before it progresses to an advanced cancer. Unlike premalignant changes on the cervix that can be found with the Pap test, there is no such progression to cancer in the ovary that is known at this time. 3. The positive and negative predictive values of both the Ca-125 test and ultrasound techniques are too low. There are too many reasons for a positive test other than cancer. If the Ca-125 is elevated in a screened population where there is expected to be only 1 cancer in every 2,00010,000 women, then it will be elevated for some other reason about 99 to 1 times. The positive predictive value is less than 1%. This means that for every 100 positive tests only one will be due to cancer. Likewise, a negative test is wrong half of the time in women with ovarian cancer and is therefore essentially meaningless. The Ca-125 is a good test to follow the results of treatment in a person already diagnosed with ovarian cancer but is of no value to use to go looking for cancers. 4. There is no easy way to evaluate an abnormal test. All you can do is say that your cancer test is positive but that it is probably wrong by a factor of 99 to 1, and maybe you should just forget about it. Or, you could repeat it in several months and pick the best two out of three results. Or, if you wish to pursue it, you will eventually have to remove the ovaries to prove that there is no cancer.

Unlike the abnormal Pap test that can easily be evaluated as many times as you wish there is no easy way to evaluate an abnormal Ca-125 or ultrasound test. 5. There is no recognized professional organization that has evaluated this problem that recommends screening. It may be possible someday but not now. Those with a documented familial ovarian cancer syndrome where the lifetime risk of developing ovarian cancer is about 50% are advised to have annual physical examinations and consider an annual pelvic sonogram. Those who have set up ovarian cancer screening programs for women with a family history of ovarian cancer have not reported any substantial benefit. Even if you decided to undergo regular Ca-125 and pelvic sonogram testing, how often should it be done? Every year seems not very adequate for ovarian cancer. How long should it be done? For the next 30 years? FAMILIAL OVARIAN CANCER It has been reported that from 1% to 5-10% of ovarian cancers are thought to be due to an inheritable syndrome. For those that are, the other female members of the family have a lifetime risk of about 50% of developing ovarian cancer. If there are several members in several generations with ovarian cancer then this may represent a familial syndrome. In general the lifetime risk of developing ovarian cancer is about 1.7%. If there is one first degree relative with ovarian cancer then the risk is about 3-5%. If there are two or more relatives with ovarian cancer then the risk is about 7%. Familial ovarian cancers tend to occur at an early age, before 50 years, and tend to be advanced serous epithelial cancers. Those with a familial syndrome are advised to have their ovaries removed by age 35. There are no recommendations for women who have one or more relatives with ovarian cancer but no documented familial syndrome. They should also consider surgery since there is no good way to follow them and they may be at the beginning of a gene mutation. The gene responsible for familial ovarian cancer is thought to be the same as the one for some breast cancers. There is a commercially available test for this gene, but its usefulness is undetermined. There are several familial ovarian cancer registries and, if you are concerned about a familial syndrome, you should consult one of these. M. Steven Piver, M.D. Director, Gilda Radner Familial Ovarian Cancer Registry. Roswell Park Cancer Institute. Buffalo, New York 14263. Beth Y. Karlan, M.D. Director Ovarian Screening Program. Department of Obstetrics and Gynecology. Cedars-Sinai Medical Center. University of California Los Angeles School of Medicine. 8700 Beverly Blvd ,Los Angeles, Ca 90048.

Henry T. Lynch, M.D. Department of Preventive Medicine. Creighton University School of Medicine. 2500 California Plaza. Omaha, Nebr. 68178. RISK FACTORS FOR OVARIAN CANCER Epithelial ovarian cancers tend to be a cancer of affluent societies where expected life spans are long. An increased risk factor, other than age, is nulliparity or delayed childbearing. A decreased risk is seen with multiparity and with prolonged use of birth control pills. The mechanism for this protective effect is thought to be that the number of ovulations is reduced. Each ovulation requires the breakage of the ovarian follicle and the repair to the ovarian surface. Reparative processes means increased cell divisions, or mitoses. Each mitotic event is a time of risk for a mutation to occur. There have been some unsubstantiated claims that the use of talcum powders contaminated with asbestos can cause ovarian cancers. Dietary factors are difficult to determine but if present are very weak in their association. One study has even associated yogurt with an increased risk. More recently there has been a purported increased risk with the use of fertility drugs. The cause of ovarian cancer is unknown. SYMPTOMS There are no symptoms of early ovarian cancer. Occasionally an ovarian cyst will be detected on a routine gynecologic examination. A cyst can break and bleed and that will also cause enough symptoms to cause the woman to seek help. Otherwise, the cancer is usually far advanced before it is diagnosed. The symptoms will be due to a build up of fluid in the abdomen called ascites. Some women will present with several gallons of ascitic fluid. Ovarian cancer spreads on the surfaces of the intestines and can cause obstruction. Sometimes it will spread into the lining of the lung cavity causing fluid to accumulate which can cause shortness of breath. Often there will be a several month history of digestive problems that are not specific. Xrays of the abdomen, upper GI studies and barium enemas will fail to find the cancer because these tests evaluate the inside of the intestines and the insides are always normal. The problem is on the outside of the intestines. Only when the fluid is detected by an ultrasound test or a CT scan or a mass is felt will the diagnosis be considered. The diagnosis is made at exploratory surgery. SURGERY FOR OVARIAN CANCER The goals of surgery are to establish a diagnosis, determine the stage and remove as much cancer as possible.
SURGICAL STAGES OF OVARIAN CANCER Stage I IA IB IC Limited to the ovaries One ovary involved Both ovaries involved One or both ovaries involved, but with cancer on

the surface of an ovary, rupture of an ovarian cyst malignant ascites or positive abdominal washings Stage II IIA IIB IIC III IIIA IIIB IIIC IV Spread to adjacent pelvic structures Spread to uterus or fallopian tubes Spread to pelvic peritoneum Confined to the pelvis, but with malignant ascites or positive abdominal washings Spread to the upper abdomen Microscopic spread to the upper abdomen Cancer nodules less than 2 cm in the abdomen Nodules more than 2 cm, or positive pelvic or aortic lymph nodes Distant spread beyond the abdomen, liver, lung etc.

Stage

Stage

The stage is determined at surgery. If there are cancer nodules throughout the abdomen then it is obviously a stage III cancer. If only one ovary is apparently involved then there has to be an extensive search for microscopic cancer on the other abdominal structures and in the lymph nodes. An early stage is assigned only after a more advanced stage has been excluded. In all but the earliest cancers there is often some cancer remaining after surgery. This is because it spreads throughout the abdomen in little nodules, some are only barely visible and others are too small to see. The surgical goal is not to leave any nodule larger than 1cm which is about a quarter of an inch. If the residual is this small or smaller then the debulking or cytoreduction is considered to have been optimal. Sometimes this is not possible but a maximum effort should be done to try to achieve this optimal situation. This may require removal of a piece of intestine and even a colostomy in some instances. In addition to stage, the grade is also important. There is a grade designated grade 0. This refers to an epithelial adenocarcinoma of low malignant potential, also called a borderline cancer. These cancers tend to be indolent and although they may be stage III, not recur for many years even without treatment. Grade I adenocarcinomas are easily identified as being from a glandular origin. Grade III cancers are difficult to identify as glandular; they are also called poorly differentiated. Grade II cancers are intermediate in appearance. Grade I cancers are expected to behave the best, grade III the worst. MANAGEMENT OF OVARIAN CYSTS Any woman with an enlarged ovary is considered to have an ovarian cancer and is operated, except those women who are found to have a simple cyst less than 10 cm in size and who are ovulatory or early pregnant. These women can be followed conservatively and reexamined in four weeks. If the cyst is gone or getting smaller, then it can be followed until it is gone. They had a functional cyst. Every ovulating woman gets a cyst every cycle. This follicle cyst is usually about 2 cm when it breaks and releases the egg. Sometimes the follicle cyst does not break and persists and gets larger. It will eventually break on its own, but if detected during this time a cancer will also have to be considered. It should be allowed to go away on its own. Or, the follicle cyst ruptures and becomes a corpus luteum cyst. This will also go away by itself. Persistent ovarian cysts will have to be

operated to exclude or diagnose a cancer. An ultrasound test can often distinguish between a simple cyst and a complex cyst. A simple cyst is just a fluid filled structure. A complex cyst has internal structures or solid areas within it. A simple cyst can be followed. A complex cyst or solid tumor should be operated. TREATMENT OF BORDERLINE OVARIAN CANCER There is a special category of epithelial ovarian cancers called borderline or cancers of low malignant potential based on the microscopic appearance of the cancer. They are expected to behave as very low grade cancers, that is, to be very slow growing. Signs of recurrence may not develop for fifteen or twenty years. Most will never recur. Most are stage I, but can be stage III when diagnosed. They are usually not treated after surgery. If they recur then they are reoperated. The treatment of advanced stage disease with residual is controversial. The inclination is for chemotherapy; the dilemma is that it cannot be demonstrated to work. TREATMENT OF EPITHELIAL OVARIAN CANCER The initial treatment is surgery which will consist of removal of the uterus, tubes and ovaries as well as any large nodules of cancer. There are exceptions when only one ovary is removed. This conservative surgery is indicated in the following situation. 1. The patient has a strong desire for further childbearing and is otherwise fertile. 2. The cancer is stage IA. Grade 0, I, or sometimes II epithelial cancer. 3. The cancer is a stage I germ cell cancer or a specialized stromal cancer. In this situation a unilateral oophorectomy is indicated. The low grade epithelial cancers require no further treatment, although these women are advised to have the remaining ovary removed when childbearing is completed. The germ cell cancers are usually on only one side. All will receive aggressive chemotherapy and most will do well. The specialized stromal cell cancers are usually unilateral and not aggressive cancers, so the other ovary can be retained until no longer needed. Otherwise, all ovarian cancer patients receive a maximal surgical effort so that the residual is small. This will give them a better chance for a complete response to chemotherapy. If a segment of intestine has to be removed, then that is done. Sometimes this will result in a colostomy. If all the large pieces of cancer can be removed then a maximum effort is indicated. All the cancer can seldom be removed, but if no piece larger than 1-2 cm remains after surgery then that is considered to be an optimal cytoreduction surgery. After surgery almost all patients will require additional treatment. The whole abdomen needs to be treated. Sometimes this can be accomplished by radiation. This is not a popular treatment in this country because of the possible major side effects and because chemotherapy seems to work as well. Another way to radiate the abdomen is to instill a radioactive substance into the abdomen. The radioactive isotope of phosphorus, called P-32, is used. This is a one time instillation and the entire abdominal contents receive a dose of several thousand RADs to a depth of several millimeters. It is used only when good distribution is assured and only microscopic amounts of cancer are present.

Chemotherapy consists of receiving the drugs soon after surgery and it is repeated every 3 or 4 weeks if all is going well. There are usually six courses of treatment. How do you know if it is working? If there is any measurable cancer, then you can tell if it is getting bigger or smaller. If there was ascites initially which has not recurred then that is good evidence of success. If the Ca125 was elevated and reverts to normal then that is evidence of a good response. If the Ca-125 rises or the ascites returns or a new cancer is detected then that indicates failure of the chemotherapy. Stage IA and IB, grade I cancers usually require no further treatment. The 5 year survival is about 95%. All stage IC and all grade III cancers receive treatment, either with chemotherapy or P-32. The prognosis for these early stage cancers is usually good, with cure rates of 65-80%. Stage II and stage III cancers with minimal or microscopic residual receive chemotherapy. The most popular regimen at this time is a platinum and Taxol combination. The 5 year survival rates are 30-50%. For those with Stage III and IV cancers with bulky residual, the near term response is good, but the long term outlook is poor.
RESPONSE TO CHEMOTHERAPY FOR ADVANCED OVARIAN CANCER 100 80 40 40 20 20 10-15 patients with advanced cancer treated with a platinum combination chemotherapy patients will have an initial complete clinical response, i.e., the cancer will be undetectable and the Ca-125 normal, but patients will have persistent cancer if they are reoperated, and will have no cancer detected at reoperation, but of these will recur within the next 5 years. This leaves patients free of cancer, but some will still recur, so patients will remain cancer free and apparently cured.

Those who recur or have progressive disease on chemotherapy will be treated with a variety of methods, but the outlook is not good. SECOND LOOK SURGERY A second look procedure is a complete surgical exploration and restaging procedure to determine the status of the cancer upon completion of chemotherapy. In many cases, after an ovarian cancer has been diagnosed and treated, there is no detectable cancer. X-rays, CT scans, Ca-125 and physical examination are all normal. The question is then asked " What to do now?". If there is no more cancer then nothing more needs to be done. If there is still cancer remaining in the abdomen, more treatment needs to be given. At this point the only way to determine the status of the cancer

is by another major surgery because even though all the tests are negative there can still be cancer present. This is called a second look. The dilemma of second look surgery is that if it is positive, that is, persistent cancer is discovered, what can be done about it? The best known treatment has already been given. The odds are poor that any other treatment will be effective. If the second look is negative, the odds of cancer recurring are about 50%. It used to be that if the second look was negative no further treatment was given. But since the odds of recurrence after a negative second look are so high, most oncologists still want to give more treatment. The problem is what that treatment should be. There have been many studies to try to answer this question, but there is no definite answer. If the second look is positive then there is an opportunity to continue treatment. But with what? Again, there is no demonstrated effective treatment, although many things have been tried. When contemplating a second look procedure both the patient and oncologist must have a clear idea of why they are going to do it and what they are going to do with the results. Second look procedures can be difficult. If the intestines are stuck together with adhesions from the previous surgery, it can be very difficult to even do the procedure, and the risk of a bowel injury is increased. The surgical procedure can be long and difficult especially if there is no cancer detected. You have to look and biopsy everything that can be biopsied, because when it is all done you have to be convinced that there was nowhere else to look and that the negative results are as accurate as they can be. Of course, if a piece of cancer is detected right away then the procedure is terminated; nothing more needs to be done surgically. You can predict what the results of a second look will be. If there was large residual at completion of the original surgery the odds of a positive second look are about 80%. If there was no residual after the initial surgery the odds of a negative second look are 80%. If there was no residual after the initial surgery and the second look is negative the odds of recurrence are less than about 10%. If there was large residual initially and a negative second look the odds of recurrence are about 75%. WHAT TO DO WHEN NOTHING IS WORKING Most patients with advanced ovarian cancer will do well initially, but most will not be cured. For these women and their families there will be a prolonged course of alternating hope and fear as results of treatment are awaited and new treatments tried. Some of these treatments will result in a complete remission of the cancer. Few remissions will be lasting. Some patients will receive investigational drugs administered through nationwide studies. Some will try investigational techniques such as high dose chemotherapy with bone marrow or stem cell replacement. And, some will opt for unconventional treatments, of which there are many, all with testimonials as to their efficacy. When ovarian cancer persists, in spite of several different treatment regimens, a decision should be made as to what the overall goals will be. Cure is seldom a realistic goal, but if that is what is decided then you should probably seek an entirely different approach such as a highly

investigational method. These would be available only at major cancer treatment centers. Miracles can be sought through unconventional treatment regimens. If cure is not a realistic goal, then neither may be longevity. If longevity is not a goal, then you can stop worrying about the cancer and devote your emotional energy and resources to the more important problems of daily living. You are going to live with this cancer. You may die as a consequence of this cancer. BUT, YOU ARE NOT DEAD YET. There are still things for you to do. There are still things that your doctor needs to do for you. There are still things your family and friends need to do for you. And, there are still things you need to do for yourself. Each day will require provision for comfort and function. Each day will be an opportunity to say good-bye to those you need to say good-bye to. Each day will be an opportunity to resolve past conflicts and reconcile yourself with your religious beliefs. Each day will be a free day. You can do with it as you wish. How do you decide when to stop treatment? Ovarian cancer is different from other cancers. It is usually diagnosed in an advanced stage, but responds well to initial treatment. About 15% will even be cured. Most other cancers that are diagnosed at advanced stages are essentially untreatable. By contrast, breast cancer is usually diagnosed at an early stage, but is unpredictable and can recur several times over many years. For the ovarian cancer patient both the initial fear and the initial hope are both justified. Most will do well initially, but most will do poorly in the long run. Since the initial treatment has such a high response rate it is justified to think that treating the recurrences will do as well. The dilemma is that as new active drugs are developed they are rapidly used as initial treatment, leaving few choices for the recurrences. The odds of achieving a complete response for a recurrence following first line treatment are only about 5%. The duration of this complete response is usually less than 6 months. The possibility of cure is unknown, but is probably only a percentage point at most. The odds of cure if the second line treatment does not work are too low to calculate. How do you decide when to stop treatment? It depends on how you ask the question. If the question asked is: "Is there any possibility that this cancer can be cured?" Then the answer is "Probably not, but if there is any possibility that it can be cured then it will require more surgery and chemotherapy or some other treatment. Whatever the possibility, it is potentially more than zero, which is the outcome if nothing is done." With this approach the decision is usually to agree to more treatment. If the question asked is: "Is there any known treatment that will cure this cancer?" Then the answer is "No and any more treatment is futile." At this point the decisions are based more on personality and philosophy than medicine.

The decision not to try more treatment does not mean being abandoned by your doctors. You may need even more medical care in an attempt to solve or palliate some of the effects of the cancer. Now is also the time to make contact with a Hospice organization if there is one available. Hospice can help you stay at home and coordinate care with your doctors. The decision to not take more cancer treatment does not mean to choose death but rather to choose life, for however long it is to be, free of the burden of chemotherapy etc. TREATMENT OF OTHER TYPES OF OVARIAN CANCER As a group the Germ cell cancers are usually diagnosed at an early stage and treated surgically, often with removing only the involved ovary. Almost all patients are then given chemotherapy with a combination of drugs selected specifically for this type of cancer. There are some variations in treatment between the specific types of germ cell cancers so each case must be considered individually. In general, the outlook is good. The Specialized Stromal cell cancers are usually considered low grade malignancies and are usually diagnosed at an early stage. They are diagnosed and treated surgically without postoperative chemotherapy. Since most are diagnosed at an early stage, the outlook is good. FALLOPIAN TUBE CANCER Fallopian tube cancers are rare. If they involve the ovary, they are often called ovarian cancers. They arise from the lining of the tube. They have the same microscopic appearance as the serous epithelial ovarian cancers. This is as expected since the lining of the fallopian tube is derived from the same embryologic tissue as is the surface of the ovary. The diagnosis of a fallopian tube cancer requires the determination that the major portion of the cancer is within the tube rather than on the ovary. Since there are no large series of fallopian tube cancers that have been reported, they are, by default, treated the same as are epithelial ovarian cancers. They seem to have the same behavior and have the same prognosis. INTRAPERITONEAL ADENOCARCINOMA Occasionally a cancer that is identical to that of a papillary serous ovarian cancer will occur throughout the abdomen. These cancers are thought to arise directly from the peritoneum and are sometimes referred to as mesothelial adenocarcinomas or as extraovarian papillary serous cystadenocarcinomas. The mesothelium was the lining of the abdominal cavity of the fetus prior to birth. It is the same structure that covers the ovaries; so it is not surprising that the same sort of cancer can occur from the lining of the abdomen as occurs from the surface of the ovary. It is often difficult to determine if the cancer arose from the ovaries or if it arose from the peritoneum. The lining of the uterus is also sometimes involved with the same cancer so the primary site is further confounded. These cancers have been known to occur years after the ovaries were surgically removed. In general, they are treated and behave the same as an ovarian cancer of similar stage and grade.

William M. Rich, M.D. Clinical Professor of Obstetrics and Gynecology University of California, San Francisco Director of Gynecologic Oncology University Medical Center Fresno, California