eMedicine Specialties > Obstetrics and Gynecology > Gynecologic Oncology

Ovarian Cancer

Author: C William Helm, MB, BCh, MA, FRCS(Edin), FRCSE, Associate Professor, Division of Gynecologic Oncology, James Graham Brown Cancer Center, University of Louisville
Coauthor(s): Robert P Edwards, MD, Professor, Department of Obstetrics, Gynecology, and Reproductive Science, University of Pittsburgh; Vice-Chair, Clinical Affairs, Director, Ovarian Cancer Center of Excellence, Magee-Womens Hospital of University of Pittsburgh
Contributor Information and Disclosures

Updated: Sep 8, 2009

Introduction

Malignant lesions of the ovaries include primary lesions arising from normal structures within the ovary and secondary lesions from cancers arising elsewhere in the body. Primary lesions include epithelial ovarian carcinoma (70% of all ovarian malignancies), germ-cell tumors, sex-cord stromal tumors, and other more rare types. Metastases to the ovaries are relatively frequent, with the most common being from the endometrium, breast, colon, stomach, and cervix.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Ovarian Cancer.

Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is the sixth most common cancer in women and the second most common female genital tract malignancy after endometrial cancer. In the United States, EOC is diagnosed in approximately 22,000 women each year with 15,000 women dying from the disease. Around the world, more than 200,000 women are estimated to develop ovarian cancer every year and about 100,000 die from the disease. The lifetime risk of a woman developing EOC is 1 in 70.

Predisposing factors

EOC can occur in females as young as 15 years, but the mean age is 56 years. In the United States, incidence of ovarian carcinoma is approximately 15 cases per 100,000 women per year for women aged 50-54 years, rising to 35 cases per 100,000 women for women aged 70-74 years. EOC occurs most commonly in white women in the industrialized countries of northern and western Europe and North America and least commonly in India and Asia. Asian women have low risk unless they relocate to North America or Europe. Scandinavian and Norwegian women have the highest risk.

The risk of EOC is increased in women who have not had children and possibly those with early menarche or late menopause. Two theories attempt to explain this. The incessant ovulation theory suggests that repeated ovarian epithelial trauma caused by follicular rupture and subsequent epithelial repair results in genetic alterations within the surface epithelium. The gonadotropin theory proposes that persistent stimulation of the ovaries by gonadotropins, coupled with local effects of endogenous hormones, increases surface epithelial proliferation and subsequent mitotic activity.

Although treatment with agents that induce ovulation in women with infertility has been suggested to increase the incidence of EOC, this is unproven.

Women with a history of breast cancer have an increased risk of EOC. Lactose consumption and the use of talcum powder on the vulva and perineum may be associated with increased risk. A steady decreased risk is observed with increasing parity and with use of the combined oral contraceptive pill.

From 5-10% of cases of ovarian cancer occur in an individual with a family history of the disease. Only a small percentage of these patients have an inherited genetic abnormality, and the risk of this occurrence increases with the strength of the family history. Hereditary EOC occurs at a younger age (approximately 10 y younger), but the prognosis may be somewhat better.

Assessment of women for their risk of ovarian cancer necessitates obtaining a careful family history of both male and female relatives, including those relatives without cancer. If possible, obtain verification of the histologic diagnoses. The counsel of a trained geneticist is ideal. Significant problems are involved in the counseling of women and their families with regard to genetic testing and its implications. Carriers of mutations may be detected through laboratory analysis of the genetic structure of white blood cells.

Disorders of the genes associated with breast cancer, BRCA1 and BRCA2, and more rarely, genes within the Lynch II syndrome complex, are associated with ovarian cancer. Mutations in these genes are inherited in an autosomal dominant pattern, with the mutated gene coming from either parent.

Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal EOC, the likelihood of a female relative having an affected BRCA1 or BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in relatives postmenopausally. Individuals with a BRCA1 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 15-45% risk of developing EOC. Those with a BRCA2 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 10-20% risk of developing EOC. Families with BRCA2 mutations are at risk for developing cancer of the prostate, larynx, pancreas, and male breast.

Individuals with Lynch II syndrome (hereditary nonpolyposis colorectal cancer syndrome) have a higher incidence of ovarian, endometrial, breast, and other malignancies, including ureter, kidney, pancreas, small bowel, and stomach. Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2.

Epithelial Ovarian Cancer - Prevention and Screening

Ovarian cancer does not lend itself to screening because it has a relatively low prevalence within the general population and no proven precursor lesion exists that can be detected and treated to prevent the cancer from occurring.

Currently, the National Cancer Institute (NCI) recommends that high-risk women should seek advice from their physician and consider having annual ultrasonographic examination, annual cancer antigen 125 (CA125) testing, and be considered for oophorectomy or participation in a clinical trial. The NCI recommends no screening methodology for women at normal risk for epithelial ovarian cancer (EOC), but these women also should be considered for research protocols seeking improved detection methods.

Cancer antigen 125 and other tumor markers

CA125 is a glycoprotein antigen detected by using mouse monoclonal antibody OC125 raised from an ovarian cancer cell line. CA125 is not specific for EOC and is elevated in other benign and malignant conditions, including menstruation; endometriosis; pelvic inflammation; liver, renal, and lung disease; and cancer of the endometrium, breast, colon, pancreas, lung, stomach, and liver. It also is elevated in 6% of women who do not have EOC. Although CA125 is elevated in 83% of women with EOC, it is elevated in only 50% of those with stage I disease.

CA125 is not useful when used alone as a single one-time test for ovarian cancer screening, but it may have increased value when serial measurements are performed over time and if it is incorporated into a risk of ovarian cancer algorithm. Other markers have been investigated, including lysophosphatidic acid, tumor-associated glycoprotein 72 (TAG 72), OVX1, and macrophage colony-stimulating factor (M-CSF). Newer experimental markers have been identified through various laboratory techniques. These markers include mesothelin, human epididymis protein 4, kallikrein, and haptoglobin-alpha.


Ultrasonography

Ultrasonography is a noninvasive technology that can detect abnormalities in ovarian size and morphology. For screening, transvaginal ultrasonography gives better views than the transabdominal approach because the probe can be positioned closer to the ovaries and the examination can be performed with an empty bladder. Improvements in ultrasonic discrimination include 3-dimensional technology and the simultaneous use of intravenous agents.

Several scoring systems have been developed to differentiate benign from malignant lesions based on ovarian volume and the complexity of the cyst, including thickness of the cyst wall, number of cysts, papillary projections into the cyst, thickness of septa, surface excrescences, and presence of ascitic fluid. In many cases, a cyst that has complex features is only benign and, overall, ultrasonography is not good at discriminating benign cysts from malignant cysts.

Clinical trials of screening

Currently, studies are trying to improve the accuracy of screening for early-stage ovarian cancer. Most are targeting perimenopausal or postmenopausal women or those with a family history of EOC.

Many studies are using a combination of ultrasound, serum CA125 testing, and other tumor markers. Large prospective trials include the United Kingdom Collaborative Trial of Ovarian Cancer Screening, a European trial of ovarian cancer screening, and the National Institutes of Health Prostatic, Lung, Colorectal and Ovarian (NIH-PLCO) cancer study. The primary outcome measure of the latter study is mortality from ovarian and fallopian tube cancer on 10-year follow-up.

Proteomic research

Considerable interest has developed in the characterization of computer-analyzed protein patterns in the blood as a way of improving screening for ovarian cancer. Such methods are currently undergoing intensive research and clinical validation, and they may hold hope for the future.

Prevention

The risk of developing EOC is significantly reduced by bearing children, using the combined oral contraceptive pill, undergoing tubal ligation, and undergoing bilateral oophorectomy.

Evidence suggests that taking the oral contraceptive pill for at least 5 years reduces the relative risk of developing EOC to 50% of the risk for a woman who has never taken it.

The epithelial lining of the ovaries is embryologically identical with the lining of the peritoneal cavity, and similar cancers can develop from the peritoneum. Thus, while oophorectomy prevents a pure EOC from developing, a small risk still exists for developing carcinoma of the peritoneum, a disease that behaves similarly to EOC.

For patients who are known carriers of BRCA1 or BRCA2 mutations, bilateral oophorectomy may be performed as soon as childbearing is complete, and probably before the patient is aged 35 years. This reduces the chance of developing EOC, but it does not prevent carcinoma of the peritoneum.

For women with BRCA1 and BRCA2 mutations who opt to not undergo early oophorectomy, the task force of the Cancer Genetics Studies Consortium recommends transvaginal ultrasound, timed to avoid the middle of the menstrual cycle, together with serum CA125 levels performed every 6-12 months in women aged 25-35 years. Use of the oral contraceptive pill is associated with lower risk of EOC in these women.

Epithelial Ovarian Cancer - Presenting Features and Diagnosis

Epithelial ovarian cancer (EOC) presents with a wide variety of vague and nonspecific symptoms, including bloating, abdominal distension or discomfort, pressure effects on the bladder and rectum, constipation, vaginal bleeding, indigestion and acid reflux, shortness of breath, tiredness, weight loss, and early satiety. The patient may feel an abdominal mass.

A case-control study showed that symptoms independently associated with the presence of ovarian cancer were pelvic and abdominal pain, increased abdominal size and bloating and difficulty eating or feeling full.² Another study reported that gastrointestinal symptoms such as nausea and vomiting, constipation, and diarrhea, or other digestive disorders were associated with later-stage disease.³ Presentation with swelling of a leg due to venous thrombosis is not uncommon. Paraneoplastic syndromes due to tumor-mediated factors lead to a variety of presentations.

Diagnosis

Presence of advanced ovarian cancer is often suspected on clinical grounds but can be confirmed only pathologically by removal of the ovaries or, when disease is advanced, by sampling tissue or ascitic fluid.

Ultrasonography is the most useful initial investigation in a patient found to have a pelvic mass. This may define the morphology of the pelvic tumor. In addition, it can determine whether large masses are present in other parts of the abdomen, including in the liver. This technique can also be used to evaluate the kidneys for evidence of ureteric obstruction and to detect ascites.

CT scan with oral and intravenous contrast is generally not as good as ultrasonography for helping characterize pelvic masses, but it can detect intra-abdominal disease, including liver metastases, and help evaluate for pelvic sidewall disease. Some have suggested that this modality plays a role in assessing operability of the tumor.

Tumor markers such as CA125 are not good discriminators of benign lesions from malignant lesions in premenopausal women but have better accuracy in postmenopausal women.

Positron emission tomography (PET) scanning does not have an established role in the diagnosis of primary ovarian malignancy. Its use is still being evaluated, but the PET scan plays a useful role in some patients by detecting the pattern and sites of recurrent disease. PET scanning is not very useful for patients with mucinous cancers.

Pathology

EOC tumors are found as partially cystic lesions with solid components. The surface may be smooth or covered in papillary projections (see Media file 1), and the cysts contain fluid ranging from straw-colored to opaque brown or hemorrhagic.

Five main histologic subtypes, which are similar to carcinoma, arise in the epithelial lining of the cervix, uterus, and fallopian tube: (1) serous (from fallopian tube), (2) endometrioid (endometrium), (3) mucinous (cervix), (4) clear cell (mesonephros), and (5) Brenner. Some variation is observed in the patterns of spread and disease distribution within the various histologic subtypes.

Spread pattern

EOC most often spreads initially within the peritoneal cavity (see Media files 2-3). Metastatic disease often is found on the peritoneal surfaces, particularly on the undersurface of the diaphragms, the paracolic gutters, the bladder, and the cul-de-sac. Other common sites are the surface of the liver, the mesentery and serosa of the large and small bowel, in the omentum, the uterus, and para-aortic and pelvic lymph nodes.

EOC is staged according to Federation International de Gynecologie et Obstetrique (FIGO) (ie, International Federation of Gynecology and Obstetrics)⁴ rules as follows:

• Stage I - Growth limited to the ovaries
  • IA - Growth limited to 1 ovary, no ascites present containing malignant cells, no tumor on the external surface, capsule intact
  • IB - Growth limited to both ovaries, no ascites present containing malignant cells, no tumor on the external surfaces, capsules intact
  • IC* - Tumor either stage IA or IB, but with tumor on surface of 1 or both ovaries with capsule ruptured, with ascites present containing malignant cells, or with positive peritoneal washings
• Stage II - Growth involving 1 or both ovaries with pelvic extension
  • IIA - Extension and/or metastases to the uterus and/or tubes
  • IIB - Extension to other pelvic tissues
  • IIC* - Tumor either stage IIA or IIB, but with tumor on surface of 1 or both ovaries, with capsule(s) ruptured, with ascites present containing malignant ovaries, or with positive peritoneal washings
• Stage III - Tumor involving 1 or both ovaries with histologically confirmed peritoneal implants outside pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastasis equals stage III; tumor limited to true pelvis, but with histologically proven malignant extension to small bowel and omentum
  • IIIA - Tumor grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces, or histologically proven extension to small bowel mesentery
  • IIIB - Tumor of 1 or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative
  • IIIC - Peritoneal metastasis beyond the pelvis larger than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes
• Stage IV - Growth involving 1 or both ovaries with distant metastases; if pleural effusion is present, positive cytology must be apparent to allot a case to stage IV; parenchymal liver metastasis qualifies as stage IV disease

*In order to evaluate the prognostic impact of the different criteria for allotting cases to stage IC or IIC, knowing if rupture of the capsule was spontaneous or caused by the surgeon is of value. Also of value is knowing if the source of malignant cells detected was peritoneal washings or ascites.

Epithelial Ovarian Cancer - Treatment

Treatment of ovarian cancer is undertaken after consideration of many factors, including the extent of disease spread, symptoms, and patients' wishes and fitness to undergo treatment.

Surgery

Surgery is the initial treatment of choice, provided patients are medically fit. Patients who are not fit for surgery may be given chemotherapy and considered for surgery later. The aim of surgery is to confirm the diagnosis, define the extent of disease, and resect all visible tumor. The role of cytoreduction was demonstrated by Griffiths in 1975 and has been confirmed by many others.

The incision for surgery should be midline abdominal. In young women with early-stage disease, a transverse incision may be considered. Careful inspection and/or palpation of the abdominal contents should be performed, including all peritoneal surfaces, the liver, large and small bowel and mesentery, stomach, appendix, kidneys, spleen, retroperitoneal spaces, and all pelvic structures.

Appropriate surgery, depending on whether or not disease is visible outside the ovaries, is described below. It is essential that where no disease is visible outside the ovaries, the patient be adequately surgically staged because the incidence of microscopic metastases is significant. Surgery for patients with stage IV disease should be individualized, particularly when disease is in the liver and above the diaphragm. Patients who are in stage IV because of small-volume disease in the liver, abdominal wall, or lung should undergo cytoreductive surgery if medically fit.

• No visible disease outside of an ovary
  • Aspirate ascitic fluid for cytology studies.
  • Perform peritoneal washings* for cytology if ascites is not present.
  • Remove the ovary and ovarian tumor intact.
  • Perform diaphragmatic scraping or biopsy for cytology studies.
  • Obtain peritoneal biopsy specimens.
  • Perform a subcolic omentectomy.
  • Obtain bilateral para-aortic and pelvic node samples.
  • Obtain biopsy samples of adhesions or other suspicious areas.
  • If the patient does not desire future fertility, perform a total abdominal hysterectomy and excise the opposite ovary.
  • Remove the appendix if mucinous tumor is present.
• Macroscopic disease outside of the ovary
  • All visible tumor should be removed. This may require extensive surgery, including bowel resection, excision of peritoneal implants, liver resection, omentectomy, and splenectomy.
  • The extent of bowel resection should depend on the role this plays in achieving maximal cytoreduction.

*Fluid must have been in contact with broad surfaces of the peritoneum above the liver, the paracolic gutters, and the pelvis. All specimens may be placed in the same container with heparin at a concentration of 1U/mL of aspirate and sent for cytology studies.

Role of laparoscopy

According to guidelines developed by the American College of Obstetricians and Gynecologists, laparoscopy may be used for diagnostic purposes in a patient with low risk for ovarian cancer and to remove cystic masses. The mass must be 10 cm or smaller as viewed by a sonogram, must have a distinct border and no solid parts, and must not be associated with ascites. The serum CA125 level must be normal (<35 U/mL), and the patient must have no family history of ovarian cancer. If a chance exists that ovarian cancer may be present, surgery is best arranged in conjunction with a specialist in gynecologic cancer surgery. The patient can then undergo all necessary surgery for her cancer under a single anesthetic, without delay.

As part of initial treatment of EOC, laparoscopic surgery may be performed for early stage disease when no disease is visible outside of the ovaries. Its use in more advanced disease, when spread is visible outside the ovaries, is more limited due to the scope of cytoreductive surgery necessary and the risk of port-site recurrence. Laparoscopy also has a role in second-look inspection and in the staging of apparently early-stage disease found by chance during another surgery.

Chemotherapy

Only a small percentage of women with EOC can be treated with surgery alone. These include patients with stage IA grade 1 and stage IB grade 1 serous, mucinous, endometrioid, and Brenner tumors. Clear-cell carcinomas are associated with a significantly worse prognosis in stage I, and patients with this histologic subtype should be considered for chemotherapy at all stages.

Patients not treated with chemotherapy should be monitored closely at regular intervals with clinical examination, serum CA125 estimation, and ultrasonography if an ovary is still present. Surgery to remove the uterus and residual ovary should be considered when the patient no longer desires to remain fertile.

Higher-risk early-stage disease includes all histologic subtypes with stage IA and stage IB grade 2 and all stage I grade 3. These patients should be treated with front-line chemotherapy with a taxane/platinum combination for a minimum of 3 courses. They should consider participating in clinical trials.

All patients with stage II cancer and greater should receive front-line chemotherapy and should strongly consider participation in clinical trials.

Until January 2006, standard therapy for all patients with advanced disease following surgery was a taxane/platinum combination, usually carboplatin and either paclitaxel or docetaxel for a minimum of 6 courses. Carboplatin given at an area under the curve (AUC) of 6-7.5 mg/mL/min (using the Calvert formula for calculating total dose of carboplatin: Total dose (mg) = target AUC x (GFR + 25), where GFR = glomerular filtration rate, taken to be the creatinine clearance in mL/min and AUC in mg/mL/min.

The normal range of AUC for treatment of ovarian carcinoma varies from 5-8. Patients who have received extensive prior chemotherapy or radiation should start with an AUC of less than 5. Paclitaxel and docetaxel are usually dosed at 175 mg/m² and 60-75 mg/m² respectively. Cisplatin at 50-75 mg/m² can be substituted for carboplatin. Docetaxel in combination with carboplatin has been shown to provide equivalent survival rates with less neurotoxicity but greater neutropenia. 

Intraperitoneal chemotherapy

Use of chemotherapy agents instilled into the peritoneal cavity has the theoretical advantage that much higher concentrations can be obtained locally without the risk of adverse systemic effects; however, the agents are unable to penetrate more than a few millimeters. At least 3 randomized studies comparing chemotherapy regimens, including the intraperitoneal route with the intravenous route, have shown a survival advantage for the arms receiving intraperitoneal chemotherapy. 

The most recent Gynecologic Oncology Group protocol #172 published in January 2006 showed that following optimal cytoreductive surgery women with advanced EOC randomized to receive part of their chemotherapy with cisplatin and paclitaxel intraperitoneally had a median progression-free interval and median overall survival approximately 5 months and 16 months greater than those women receiving standard intravenous chemotherapy. Thus, intraperitoneal chemotherapy should be strongly considered for the treatment of front-line disease following surgery where 5mm or less-residual disease exists and perhaps, for more advanced cancers. 

This route of chemotherapy may cause more side effects for the patient and administration requires the placement of a subcutaneous tube into the peritoneal cavity (an intraperitoneal port); this is associated with a number of complications including infection, blockage, retraction out of the peritoneal cavity, and discomfort. Nevertheless, randomized studies show a survival benefit and disease-free survival benefit and the National Cancer Institute has suggested that all women with optimally cytoreduced disease should at least be offered intraperitoneal treatment.

Neoadjuvant chemotherapy

This is given to patients with disease that is initially considered inoperable or if the patient is unfit for surgery at the time of diagnosis. If the patient has a good response to 3 or more cycles of chemotherapy, interval debulking surgery may be performed followed by further chemotherapy. Overall, patients treated with this approach likely have an inferior outcome to patients undergoing initial maximal cytoreductive surgery followed by chemotherapy.

Radiation therapy

Radiation has not been widely accepted as a routine treatment modality in the initial treatment of patients with EOC, despite reports of efficacy for higher-risk stage I and II disease and in stage III disease where small-volume residual disease is present after surgery. In selected cases, pelvic diseases may respond to palliative dosing regimens with minimal toxicity.

Second-look laparotomy

Second-look laparotomy is a surgical procedure performed within a few weeks following initial treatment of EOC when no disease is evident on clinical examination, by CA125, or radiology. The aim is to inspect the abdominal cavity for disease and, when no macroscopic disease is found, perform peritoneal washings and extensive biopsies for pathologic assessment for microscopic disease. Some years ago this surgery went out of fashion in many centers because no effective treatment was available for those found to have disease present following front-line therapy, and, thus, the evaluation did not improve prognosis. Of those patients who had completely negative findings at second-look surgery (a complete pathologic response), 56% had recurrence by 5 years and 60% by 10 years. In the Gynecologic Oncology Group Study #172, despite the improvement in overall survival rate, 65% of these patients developed recurrence within the time period of the study.⁵

Efforts are now underway to find effective methods of delaying or preventing recurrence following front-line therapy. The best way to determine that a woman is pathologically disease-free is a second surgery because regular clinical investigations are far from accurate. It may be possible to perform this evaluation adequately using the laparoscope in many instances.

Consolidation chemotherapy

Ovarian cancer has a very high response rate when treated front-line; despite this, most patients develop recurrent cancer. Many have shown interest in research into treatments to prevent or prolong the interval of recurrence (such as consolidation therapy). A Gynecologic Oncology Group protocol was discontinued when a statistical improvement in disease-free survival was demonstrated in patients receiving 12 months versus 3 months of additional monthly paclitaxel after initial therapy. However, questions remain about this study, which was not completed as designed. Since no consensus on management in this situation exists, patients should be encouraged to participate in clinical trials of consolidation therapy.

Estrogen replacement therapy after treatment of epithelial ovarian cancer

The safety of estrogen replacement therapy (ERT) after treatment for EOC has not been tested in a randomized trial, but current evidence suggests that the benefits of ERT outweigh the risks.

Younger women with endometrioid subtypes are of concern because these tumors theoretically are estrogen-sensitive. If estrogen is used in such patients, a progestogen probably should be given with it.

Epithelial Ovarian Cancer - Prognosis and Recurrent Disease

Five-year survival rates for epithelial ovarian carcinoma by FIGO stage (survival percentage rounded to nearest whole number) are as follows:

• Stage IA - 87%
• Stage IB - 71%
• Stage IC - 79%
• Stage IIA - 67%
• Stage IIB - 55%
• Stage IIC - 57%
• Stage IIIA - 41%
• Stage IIIB - 25%
• Stage IIIC - 23%
• Stage IV - 11%
• Overall survival rate - 42%

Recurrent disease

In the majority of patients presenting with advanced EOC, the disease recurs, and the prognosis for these patients is poor. The goal of further therapy is to achieve a response to treatment and to prolong meaningful quality survival.

Treatment of recurrent disease may involve surgery, chemotherapy, and radiation. Participation in clinical trials should be considered. If a localized mass is present, surgery may play a role prior to the initiation of further chemotherapy. Response is more likely in patients who previously had a good response to first-line therapy and who had a long interval between the completion of initial therapy and the time of recurrence.

Patients whose previous response to platinum agents was good and who have gone at least 6 months since completing initial therapy may be re-treated with a taxane together with carboplatin or cisplatin. Patients with platinum-resistant disease who respond poorly to treatment with platinum agents initially and have a short interval to recurrence, do poorly. These patients particularly should be offered participation in clinical trials, if available. Agents with some activity in this situation include topotecan, etoposide, liposomal doxorubicin, and docetaxel and altretamine. Single-agent therapy is usually given for recurrent disease, although combination therapy is becoming more popular and several combinations have been reported. Anti-angiogenesis agents, such as bevacizumab and hormonal agents such as tamoxifen and anastrozole, may have a role to play.

Samples of recurrent tumor or ascitic fluid can be sent to one of several laboratories for chemotherapeutic assay. This assay involves culturing tumor cells in media containing a range of chemotherapy agents. This allows chemotherapy agents to be offered to patients with the greatest potential for activity, and, conversely, this allows drugs associated with extreme resistance to be avoided.

Patients who were initially sensitive to platinum-containing chemotherapy have overall response rates of 30-60%, with an overall survival of 12-48 months, whereas patients resistant to chemotherapy have expected response rates of 12-32%, with an overall survival of 7-12 months.

The finding of elevated CA125 in the serum in the absence of clinical or radiographic disease is a relatively common situation in patients with EOC following initial treatment. Treatment of these patients is controversial.

Radiation

Radiation has a palliative role in recurrent disease for symptomatic and persistent masses. Emerging evidence suggests that radiation may improve the prognosis for women with recurrent disease that can be surgically debulked to microscopic disease only. However, morbidity may be high, and each case should be considered individually.

Hyperthermic intraperitoneal chemotherapy

The instillation into the peritoneal cavity of chemotherapeutic agents in a solution heated to between 40°C and 43°C was first introduced in an attempt to induce longer survival in patients with gastric carcinomas that had spread to the peritoneal cavity. Considerable experimental evidence shows that not only is heat alone tumoricidal, but it also increases the activity of many different chemotherapeutic agents, several of which have activity in ovarian cancer. Over the last 25 years, many reports have surfaced on the use of such therapy in combination with debulking surgery in diseases such as malignant mesothelioma, appendiceal cancer, and colorectal cancer.

In 2003, findings from a randomized controlled trial on patients with peritoneal carcinomatosis from colorectal cancer was published. The trial demonstrated a significant prolongation of life in patients undergoing surgical debulking with hyperthermic chemotherapy in comparison with patients treated with standard palliative surgery and chemotherapy. Although the patients in the experimental arm did better, the study design did not allow for determination as to what role each modality (surgery, chemotherapy, hyperthermia) played in this.

Ovarian cancer is a good theoretical target for surgical debulking combined with hyperthermic chemotherapy because it combines 3 separately useful modalities: surgical debulking, intraperitoneal chemotherapy, and heat. No randomized, phase III studies have been performed in ovarian cancer cases and more research is warranted.

Epithelial Ovarian Cancer - Tumors of Low Malignant Potential

Tumors of low malignant potential (LMP) (borderline tumors) are a distinct variety of epithelial ovarian cancer (EOC) that behave in a much less aggressive fashion. These tumors cause great anxiety to patients, and the concept of LMP sometimes is difficult to explain. They comprise approximately 20% of malignant ovarian tumors. The mean age of diagnosis is younger than for invasive EOC, at approximately 48 years, and no large peak of incidence is observed.

These tumors are staged identically to EOC, using the FIGO system (see Staging), but unlike with EOC, the majority of tumors are stage I at presentation (IA, 51%; IB, 6%; IC, 18%; II, 8%; III, 15%; IV, 2%).

Presenting features

LMP can cause a range of symptoms similar to EOC, including increasing abdominal girth, an abdominal mass, abdominal pain, abnormal uterine bleeding, urinary symptoms, and gastrointestinal symptoms. They may be asymptomatic and found after routine examination or ultrasound examination.

Pathology

All histologic subtypes of EOC have serous, mucinous, endometrioid, clear cell, and Brenner LMP variants, with the essential feature being that no invasion occurs. Mucinous and serous types are most common (see Media files 4-5). Invasion is difficult to interpret in mucinous tumors, and the requisite microscopic feature is epithelial stratification exceeding 3 cell layers with associated nuclear atypia. Ovarian tumors require very careful pathologic examination, with sufficient numbers of sections taken to ensure adequate assessment. Particular care must be taken with frozen section interpretation of large mucinous tumors at the time of surgery.

LMP tumors can metastasize throughout the abdominal cavity and elsewhere. Metastases can be differentiated microscopically as those without invasion and those with invasion.

Surgery

Surgery begins with a full assessment of the pelvis and abdominal contents as for EOC and is carried out as described in Surgery for ovarian cancer.

Patients who are premenopausal and desire preservation of fertility can be treated with unilateral oophorectomy alone. In selected cases, ovarian cystectomy may be enough for stage IA serous tumors of LMP. Hysterectomy and removal of the other ovary can be performed if the patient no longer desires to remain fertile.

When complete surgical staging is performed in patients with LMP tumors, some patients with disease originally thought to be confined to the ovaries are found to have disease that has spread. However, the value of this has not been defined in early-stage disease.

In advanced disease, patients should undergo cytoreductive surgery, as for invasive EOC, to remove all visible tumor.

Adjuvant therapy

Chemotherapy and radiation therapy are not indicated for LMP tumors following complete resection for stage I and II disease. In cases where disease has spread from the ovaries at the time of surgery, and particularly where implants are found to be invasive, chemotherapy can be considered, but data establishing its efficacy are absent.

Follow-up after initial treatment

Regular follow-up care includes clinical examination and serum CA125 estimation, especially if the original tumor was serous and/or the CA125 was elevated. If a patient retains 1 or both ovaries, annual ultrasound examination may be indicated.

Treatment of recurrence

LMP tumors do not recur in the majority of patients. When they do, initial debulking surgery usually is indicated. Chemotherapy has no proven role.

Prognosis

Overall survival rate at 5 years according to FIGO is shown below. Others have reported better survival rates with 5-year, 10-year, 15-year, and 20-year survival for patients with serous LMP as 97%, 95%, 92%, and 89%, respectively.

Five-year-survival rate for LMP tumors by FIGO stage (survival percentages rounded to nearest whole number) are as follows:

• Stage IA - 93%
• Stage IB - 90%
• Stage IC - 91%
• Stage IIA - 88%
• Stage IIB - 86%
• Stage IIC - 100%
• Stage IIIA - 29%
• Stage IIIB - 75%
• Stage IIIC - 62%
• Stage IV - 30%
• Overall survival rate - 86%

Malignant Germ Cell Tumors

Malignant germ cell tumors (GCTs), which include dysgerminoma, endodermal sinus tumor, malignant teratoma, embryonal carcinoma, and choriocarcinoma, are thought to derive from primitive germ cells in the embryonic gonad. GCT of the ovary is much rarer than GCT of the testis in males, and much of the development of the management approach has been based on experience with male GCT.

Common characteristics of these tumors include rapid growth, a predilection for lymphatic spread, frequent mixtures of tumor types, and a predominantly unilateral pattern of ovarian involvement (except for dysgerminoma). GCT is much more common in young women but occasionally occurs in infants and older women.

Many GCTs produce tumor markers that can be measured in the blood and then used to monitor response to treatment and for follow-up care. Endodermal sinus tumors secrete alpha-fetoprotein and choriocarcinoma, and dysgerminomas occasionally secrete beta human chorionic gonadotropin (bHCG). Dysgerminoma may secrete lactate dehydrogenase and placental alkaline phosphatase.

No factors have been established related to etiology, apart from an increased incidence associated with dysgenetic gonads.

Presentation

While these tumors may be asymptomatic and present as a palpable mass, many patients present with abdominal pain. The mass may lead to acute pain due to torsion, rupture, or hemorrhage, or, patients may have abdominal distension, vaginal bleeding, or fever.

The majority are stage I and confined to the ovary at the time of diagnosis.

Diagnosis

If tumor is suspected at presentation, blood should be examined for tumor markers, including bHCG, alpha-fetoprotein, and lactate dehydrogenase. In premenarchal girls found to have an adnexal mass, perform karyotyping to determine the status of the sex chromosomes.

Other investigations include chest x-ray for lung metastases and ultrasound to help define the morphology of the pelvic tumor, to help evaluate the kidneys for evidence of ureteric obstruction, and to help detect ascites and the presence of metastases in the liver and retroperitoneum. Preoperative CT scan or MRI may document intra-abdominal disease, including liver or lymph node metastases that are deemed undetectable on ultrasound imaging.

Treatment

Surgery is the initial treatment for GCT, and, in young patients, this can be conservative, with preservation of the uterus and contralateral ovary, because chemotherapy is very effective. Second-look surgery generally is not indicated following initial treatment.

Dysgerminoma

This is the most common malignant GCT and represents 3-5% of all ovarian malignancies. Ninety percent occur in people younger than 30 years, and 75% occur in the second and third decades, with a median age of 22 years.

Dysgerminomas are bilateral in 10-35% of cases. Five percent occur in phenotypic females with abnormal gonads. They may have a 46XY karyotype with pure gonadal dysgenesis or androgen insensitivity syndrome, or, they may have a 45X, 46XY karyotype with mixed gonadal dysgenesis. Dysgerminomas may be large and usually are solid with a smooth external surface and a fleshy pink-tan color inside. The majority are confined to the ovary at diagnosis, but approximately 25% of otherwise stage I dysgerminomas have lymph node metastasis.

Surgery

Surgery is the initial management of a tumor that possibly is a dysgerminoma. Assessment of the abdominal and pelvic contents is made as for EOC (see Surgery for ovarian cancer).

Where no macroscopic disease exists outside the ovary, unilateral oophorectomy should be performed, excising the tumor intact and without rupture. Staging procedures include washings, omental biopsy, and sampling of paraaortic and pelvic lymph nodes. The opposite ovary should be carefully inspected, and a biopsy should be performed if necessary. However, in young patients, the uterus and opposite ovary should be left in situ.

If disease is present outside the ovary, an effort should be made to remove all visible tumor while maintaining fertility for the patient. In a young patient, debulking disease from the contralateral ovary, without performing oophorectomy, should be acceptable.

Many patients present having already undergone a unilateral oophorectomy that diagnosed the dysgerminoma. Consideration should be given to staging these patients, laparoscopically if possible, if a negative result will spare the patient from receiving chemotherapy. If chemotherapy will be given regardless, initial staging surgery is not warranted.

Postsurgical treatment

Adequately staged patients with stage IA disease can be monitored without further therapy, whatever the size of the primary tumor. However, 15-20% of tumors recur, mostly in the first 2 years after treatment.

All patients at a stage greater than IA require combination chemotherapy, with the most accepted regimen in the United States being bleomycin, etoposide, and cisplatin (BEP). In patients with advanced disease, the combination of vincristine, actinomycin D, and cyclophosphamide (VAC) has been used following BEP as consolidation therapy. Dysgerminoma is very radiosensitive, but radiation rarely is used, especially in young patients, because of its effect on future fertility.

Prognosis

Stage IA disease is associated with a 5-year survival rate of higher than 95%, but even with advanced disease, the 5-year survival rate is good following surgery and chemotherapy.

Immature teratoma

This is the second most common GCT. It occurs mostly in people aged 10-20 years but may occur after menopause. Tumor markers are not elevated unless the tumor contains elements of other GCTs. The cardinal histologic feature is immature elements, mostly of neural tissue. The tumor spreads most commonly to peritoneal surfaces.

In the patient who is premenopausal, treatment should include unilateral oophorectomy and surgical staging (see Surgery for ovarian cancer). The contralateral ovary rarely is involved, and biopsy of the other ovary is not necessary. If a patient no longer desires to remain fertile or is postmenopausal, hysterectomy with removal of both ovaries is sensible.

Patients with stage IA grade 1 disease do not need adjuvant therapy postoperatively. The standard of care for high-grade stage I disease postoperatively has been chemotherapy with BEP. Evidence is accumulating that such patients can be treated more conservatively following surgery, provided good follow-up care is maintained. Patients with stage IA grade 2 disease can be monitored only.

The conservative management of stage IA grade 3 is more controversial.

Follow-up

No tumor markers exist for immature teratoma, and follow-up care should include clinical examination together with ultrasound at regular intervals.

Second-look laparoscopy or laparotomy may be considered, particularly in patients who had macroscopic residual disease at the end of surgery. Immature teratoma may be associated with the development of benign teratomatous masses and peritoneal glial implants that may remain for a long time. All masses at second surgery should be removed to be sure that no immature (malignant) elements are present. If such elements are present, the patient should have further chemotherapy with VAC.

The prognosis depends on the extent of the tumor and the grade. Stage I grades 1 and 2 have almost 100% survival. Patients with incompletely resected tumor have a 50% chance of survival.

Other germ cell tumors

Endodermal sinus tumor occurs at a mean age of 18 years, and one third occur before puberty. The tumors secrete alpha-fetoprotein. Following standard surgery, all patients should be treated with BEP. Other chemotherapy regimens may be necessary. Embryonal carcinoma and choriocarcinoma are extremely rare.

Sex-Cord Stromal Tumors

These include tumors arising from the sex cords; granulosa cells; Sertoli cells; and the specialized stroma of the genital ridge, theca, and Leydig cells. They comprise fewer than 5% of all ovarian tumors.

Although granulosa cell tumors are malignant and Sertoli-Leydig cell tumors less so, they behave in a much less malignant fashion than EOC. Benign tumors in the group include thecoma and fibroma. Granulosa cell tumors and pure Sertoli cell tumors commonly secrete estrogen, while Leydig cell tumors and combined Sertoli-Leydig tumors often secrete androgens.

Granulosa cell tumor

This is the most common malignant sex-cord stromal tumor. It can occur at any age, with a mean age of the early fifties. Because of the secretion of estrogen, the presenting features depend on the patient's age. Prepubertal girls typically present with precocious sexual development, women of reproductive age have heavy or irregular periods, and postmenopausal women may have postmenopausal bleeding. At all ages, the tumor may present with acute abdominal pain due to rupture or hemorrhage.

The tumors vary in size and may be solid or partially cystic (see Media file 6). The cut surface may be grey-white or yellow, depending on lipid content. Necrosis and hemorrhage often are present, with cystic compartments filled with fluid or clotted blood (see Media file 7). The microscopic features are granulosa cells in a wide variety of patterns, and characteristic Call-Exner bodies may be present.

Ultrasound is the most useful preoperative investigation in a patient found to have a pelvic mass. Ultrasound studies may show the presence of ascites and may help define the morphology of the pelvic tumor. In addition, it can determine whether large masses are present in other parts of the abdomen, including the liver, and it can help evaluate the kidneys for evidence of ureteric obstruction. CT scan can detect enlarged pelvic masses and other evidence of intra-abdominal metastasis and disease within the chest.

Ninety percent of granulosa cell tumors are stage I at the time of diagnosis. Surgery is performed (see Epithelial Ovarian Cancer - Treatment). Because bilateral involvement of the ovaries is observed in only 2% of cases, the opposite ovary can be conserved in younger women. If the uterus is to be left behind, endometrium biopsy should be performed because of the synchronous occurrence of endometrial adenocarcinoma associated with estrogen secretion.

No adjuvant therapy is available for early-stage disease that is completely excised. Patients with recurrent disease or residual disease after surgery should be treated with BEP. No evidence demonstrates that treatment with progesterone is beneficial. Radiation has a definite role, especially for palliation in recurrent disease in the pelvis.

Granulosa cell tumors typically recur a long time after primary treatment. Factors reported to be associated with outcome include stage at presentation, age older than 40 years, tumor size, tumor rupture, histologic pattern, high mitotic count, and nuclear atypicality.

The 5-year survival rate for stage I is 86-96%, and for all other stages, it is 26-46%.

Inhibin

Inhibin is a glycoprotein produced by granulosa cells that can be used as a tumor marker. It is undetectable in the serum of postmenopausal women without ovaries and returns to normal 1 week after removal of a granulosa cell tumor. The best discrimination is made with assays detecting the alpha subunit of inhibin. Inhibin also may be elevated in postmenopausal women with mucinous carcinomas.

Recurrence

Granulosa cell tumors can recur a long time after initial treatment, with an average time interval of 5-10 years. The longest reported interval is 37 years, and lifelong follow-up care, therefore, is necessary. Recurrences can be treated with surgery and/or chemotherapy and radiation. The combination of bleomycin, etoposide, cisplatin (BEP) has historically been considered the most active chemotherapy regimen, but some have shown interest in carboplatin/paclitaxel and also anastrozole.

Sertoli-Leydig cell tumors

These tumors are rare. They are a form of low-grade malignancy that typically produces androgens and rarely estrogens.

The surgery is unilateral oophorectomy, and, if patients' childbearing has been completed, total hysterectomy and bilateral oophorectomy is performed. The overall 5-year survival rate is 70-90%.

Other rare tumors

Small-cell carcinoma: This is a rare type of carcinoma that occurs in females aged 2-46 years. It often is associated with hypercalcemia. Treatment is with surgery and chemotherapy, but the prognosis is poor.

Sarcoma: The most common form of this rare tumor in the ovary is the mixed mesodermal sarcoma or carcinosarcoma. Patients should be treated with surgery (see Epithelial Ovarian Cancer - Treatment), followed by platinum-containing chemotherapy. Prognosis is poor.

Metastatic: Metastatic tumors of the ovary arise from direct extension and spread within the bloodstream or lymphatic system or within the peritoneal cavity. Sites of origin include the endometrium; cervix; and nongynecologic sites such as breast, colon, and stomach. The classic Krukenberg tumor refers to bilateral enlargement of the ovaries from metastases from a signet-ring carcinoma of the stomach. Treatment of metastatic disease relates to the primary site.

Effects of chemotherapy on ovarian function, fertility, and the fetus

Many women experience symptoms of ovarian dysfunction, ie, amenorrhea and hot flashes, during treatment with chemotherapy. The younger the woman at the time of treatment, the more likely the return of normal ovarian function and the more tolerant the ovaries are to higher doses of alkylating agents.

An increase in congenital anomalies in babies conceived following treatment with chemotherapy does not seem to occur. The necessity for chemotherapy during a preexisting pregnancy fortunately is rare, but antifolate drugs such as methotrexate probably should be avoided during the first trimester.

Multimedia

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Media file 1: An enlarged ovary with a papillary serous carcinoma on the surface.

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Media file 2: Laparotomy on a patient with intermittent small bowel obstruction. A loop of small bowel (bottom of frame) is adherent to a poorly differentiated primary epithelial ovarian carcinoma (left of frame) that has spread to involve the pelvic sidewall, the bladder peritoneum, the serosa of the uterus, and the fallopian tube.

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Media file 3: Metastases from epithelial ovarian carcinoma involving the omentum.

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Media file 4: This photo shows a large, smooth-surfaced tumor replacing the ovary. This tumor appeared complex upon preoperative ultrasonography. Final histologic studies indicated the tumor was a mucinous carcinoma of low malignant potential.

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Media file 5: Inside of the tumor shown in Image 4. Note the multiple cysts with thick septa between. This tumor was extensively sectioned and was a mucinous carcinoma of low malignant potential.

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Media file 6: Granulosa cell tumor excised from a woman aged 44 years. Note the yellowish tumor that has eroded through, onto the surface of the ovary.

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Media file 7: This photo shows a granulosa cell tumor, with the cut surface showing classic features of a hemorrhagic cyst and yellowish solid component.

Keywords

carcinoma of the ovary, ovarian carcinoma, ovary cancer, ovary carcinoma, cancer of the ovary, ovarian cancer, ovarian malignancy, epithelial ovarian cancer, EOC, gynecological cancer, gynecological carcinoma, gynecologic cancer, gynecologic carcinoma, female genital tract malignancy, gynecological tumor, gynecologic tumor, low malignant potential tumor, LMP tumor, malignant germ cell tumor, malignant GCT, dysgerminoma, immature teratoma, teratoma, granulosa cell tumor, sex-cord stromal tumor, Sertoli-Leydig cell tumor

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