Ovarian Cancer - technical article 2

Ovarian cancer - technical article 2

Ovarian cancer accounts for 3% of cancers in women and is the fifth leading cause of cancer-related death in American women, after lung, breast, colorectal, and pancreatic cancers. Ovarian cancer is the second most common gynecologic cancer, following cancer of the uterine corpus.

Epidemiology of ovarian cancer

For women in the United States, lifetime risk of developing the disease is estimated to be 1 in 70 (1.4%). This likelihood increases with age, with a median age at diagnosis of 63 years.

The risk of malignancy in an adnexal mass is 7% in a premenopausal woman and rises to 30% in a postmenopausal woman. Each year an estimated 21,650 women will be diagnosed, and 15,520 will die from their ovarian cancer. Ovarian cancer has the highest mortality of all female reproductive system malignancies.

Ovarian neoplasms, 80% of which are benign, are divided into three major groups: epithelial, germ cell, and sex cord-stromal tumors (Table 1). The ovary can also be a site of metastatic cancer, particularly from the breast or the gastrointestinal tract (e.g., Krukenberg's tumors).

Epithelial ovarian tumours

Tumors derived from the coelomic epithelium are the most common ovarian neoplasms, accounting for 65% of ovarian neoplasms and 90% of ovarian cancers. Types include serous, mucinous, endometrioid, clear cell, and transitional (Brenner's).

Risk Factors

Age over 40 years, white race, nulliparity, infertility, history of endometrial or breast cancer, and family history of ovarian cancer consistently have been found to increase the risk of invasive epithelial cancer. Higher parity, use of oral contraceptive pills (OCPs), history of breast-feeding, tubal ligation, and hysterectomy have been associated with a decreased risk of ovarian cancer.
Patients with a family history of ovarian, breast, endometrial, or colon cancer are at increased risk of developing ovarian carcinoma.
- Hereditary familial ovarian cancer accounts for approximately 10% of all newly diagnosed cases. Women with one first-degree relative with ovarian cancer have a 5% lifetime risk of developing the disease and those with two first-degree relatives with ovarian cancer have a 7% risk.
- There are three distinct autosomal dominant syndromes that have been termed familial ovarian cancer: site-specific ovary, breast-ovary, and hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome).
HNPCC is an autosomal dominant cancer susceptibility syndrome. Lynch syndrome II describes a familial predisposition to other cancers (endometrial, ovarian, genitourinary tract) in addition to HNPCC.
- Women with HNPCC have a 40% to 60% lifetime risk for endometrial cancer and 12% lifetime risk for ovarian cancer. Mutations in three DNA mismatch repair genes, MLH1, MSH2, and MSH6, account for over 95% of mutations found with Lynch syndrome.
BRCA. Two breast and ovarian cancer susceptibility genes (BRCA1, located on chromosome 17q, and BRCA2, located on chromosome 13q) have been identified. These genes, involved in DNA repair, have been linked to familial breast cancer, breast-ovary, and site-specific ovarian cancer syndromes.
- Women with BRCA gene mutations have a lifetime risk of breast cancer of 82% and lifetime risk of ovarian cancer of 25% to 60% for BRCA1 carriers and 15% to 25% for BRCA2 carriers. These women also develop the disease at an earlier age than women without the mutations. Screening tests for these genes are available.
Environmental factors may play a role in ovarian cancer. A recent meta-analysis does not support a causal relationship between talc exposure and ovarian cancer.
Reproductive factors play an important role in ovarian cancer risk. Increasing parity is associated with decreased relative risk of developing ovarian cancer, whereas nulliparity is associated with increased risk.
The use of OCPs also has been associated with a decreased relative risk.
Women with a history of breast-feeding have a lower risk of ovarian cancer than nulliparous women and parous women who have not breast-fed.
Women with infertility have an elevated risk of ovarian cancer, independent of nulliparity. Although fertility drugs have been implicated in the development of ovarian cancer, their association has not been clearly separated from the risk that nulliparity and infertility confer.
Tubal ligation and hysterectomy with ovarian preservation both appear to lower the risk of ovarian cancer, although the mechanisms are unclear.

Classification of Ovarian Neoplasms

1. Epithelial Tumors

Serous (histology resembles the lining of the fallopian tube)
Mucinous (histology resembles endocervical epithelium)
Endometrioid (histology resembles endometrial lining)
Clear cell (histology resembles vaginal mucosa)
Transitional cell (Brenner's; histology resembles bladder)

2. Germ Cell Tumors

Dysgerminoma
Endodermal sinus tumor
Embryonal carcinoma
Polyembryoma
Choriocarcinoma
Teratoma:
- Immature
- Mature

3. Sex Cord-Stromal Tumors

Granulosa-stromal cell
Granulosa cell
Thecoma-fibromas
Sertoli-Leydig cell
Sex cord tumor
Sex cord tumor with annular tubules
Gynandroblastoma

4. Unclassified and Metastatic

Screening and Prevention

Early ovarian cancer is often asymptomatic. No available screening test has sufficient positive predictive value for early-stage ovarian cancer.
Routine yearly pelvic examination is currently recommended for the general population as a screening tool, but it has poor sensitivity for detecting early disease.
Cancer antigen 125 (CA-125), first described in the 1980s, is a biomarker for ovarian cancer. A level >35 U/mL is usually considered abnormal. Approximately 50% of ovarian cancer cases confined to the ovary and >85% of advanced ovarian cancer cases have elevated CA-125 levels. However, this biomarker alone is neither sufficiently sensitive nor specific enough to be diagnostic for ovarian cancer.
- CA-125 levels may be elevated in several benign conditions, including pelvic inflammatory disease, endometriosis, fibroids, pregnancy, hemorrhagic ovarian cysts, liver disease, and any other lesion that can promote peritoneal irritation, as well as other malignant conditions, including breast, lung, pancreatic, gastric, and colon cancer. In addition, CA-125 is normal in approximately half of women with stage I ovarian cancer. The most important use is following serial CA-125 levels in monitoring response to treatment and detecting recurrence in women with known ovarian cancer.
Other biomarkers. CA 19-9, CA 15-3, CA 72-4, lipid-associated sialic acid, lysophosphatidic acid, OVX1, and osteopontin are being investigated.
Transvaginal ultrasonography also has been considered as a screening tool. Characteristics suggestive of malignancy include complex ovarian cysts with solid components, the presence of septations, papillary projections into the cyst, thick cyst walls, surface excrescences, ascites, and neovascularization. However, transvaginal ultrasonography has a poor positive predictive value when used to screen the general population. When limited to postmenopausal women with pelvic masses, a sensitivity of 84% and a specificity of 78% have been reported.
Multimodal screening using CA-125 measurement with transvaginal sonography yields a higher specificity and positive predictive value than either modality alone. In postmenopausal women, the combination of transvaginal ultrasound and a CA-125 >65 U/mL increased sensitivity to 92% and specificity to 96%. Prospective trials are underway to determine the appropriateness of multimodal screening for ovarian cancer.
Current recommendations for screening According to the US Preventive Services Task Force, no existing evidence suggests that any screening test, including CA-125, ultrasound, or pelvic examination, reduces mortality from ovarian cancer; therefore, routine screening is not recommended. The American College of Obstetricians and Gynecologists (ACOG) agrees that routine screening tests are not beneficial for lowrisk, asymptomatic women. ACOG advises the obstetrician-gynecologist to remain vigilant for the early signs and symptoms of ovarian cancer and then evaluate with a pelvic examination. The American Cancer Society does not recommend routine screening but states that women at high risk of ovarian cancer should be offered a combination of a thorough pelvic exam, transvaginal ultrasound, and CA-125.
Prophylactic bilateral salpingo-oophorectomy. Women over age 45 who are undergoing any pelvic surgery may consider prophylactic removal of the ovaries. A bilateral salpingo-oophorectomy will essentially eliminate her risk for developing ovarian cancer. The potential for surgical menopause must be weighed against the potential benefit of averting ovarian malignancy. Women at high risk of ovarian cancer (e.g., Lynch syndrome, BRCA mutations) should consider prophylactic bilateral salpingo-oophorectomy when childbearing is complete.
OCP prophylaxis. The overall estimate of protection with OCPs is approximately 40%. Increased duration of OCP use appears to be associated with decreased risk, and the protective effect persists for ten or more years after discontinuation. The OCP is the only documented method of chemoprevention for ovarian cancer, and the effect is substantial.

Presentation and Diagnosis

Presentation. Only 19% of ovarian cancer cases are diagnosed while the cancer is localized (stage I), and approximately 68% of patients with epithelial ovarian cancer have advanced (stage III or greater) disease at time of diagnosis. Although some women with early disease experience symptoms, the majority are asymptomatic.
- When symptoms develop, they are nonspecific and can include abdominal bloating, early satiety, weight loss, constipation, anorexia, urinary frequency, dyspareunia, fatigue, and irregular menstrual bleeding.
- On physical examination, a pelvic mass is an important sign of disease. In more advanced stages of disease, abdominal distention may develop, and chest examination may reveal evidence of pleural effusion.
Workup. Evaluation of a pelvic mass varies depending on the patient's age, significant medical and family history, and the sonographic characteristics of the mass. Women with pelvic masses that are suspicious for malignancy should be referred to a gynecologic oncologist (Table 1). In premenopausal women, an adnexal mass <8 to 10 cm with no other concerning features is typically monitored with serial sonograms. After the decision is made to proceed to surgical evaluation, the preoperative evaluation should include a full history and physical examination, including a pelvic examination and a pap smear.
- Additional tests should be performed on the basis of a patient's risk factors and underlying medical status. Consideration should be given to performing a CT scan of the chest, abdomen, and pelvis to evaluate for metastatic disease. All patients who undergo surgery must have available a surgeon capable of performing an adequate staging procedure, preferably a gynecologic oncologist, to optimize outcome.

Table 1 Pelvic Mass Evaluation: Criteria for Gynecologic Oncology Referral
Premenopausal Women	Postmenopausal Women
Very elevated CA-125 (>200 U/mL)	Elevated CA-125
Ascites	Ascites
Evidence of abdominal or distant metastasis	Evidence of abdominal or distant metastasis
Family history of one or more first-degree relatives with ovarian or breast cancer	Family history of one or more first-degree relatives with ovarian or breast cancer
	Nodular or fixed pelvic mass

From American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 280. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol 2002;100:1413-1416.

Staging and Prognosis

Ovarian cancer is surgically staged (Table 2).

Table 2 FIGO Staging System for Carcinoma of the Ovary (1988)
Stage	Tumor characteristics
I	Growth limited to the ovaries
IA	Growth limited to one ovary; no ascites; no tumor on the external surface; capsule intact
IB	Growth limited to both ovaries; no ascites; no tumor on the external surfaces; capsule intact
IC	Tumor either stage IA or IB but with tumor on surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells; or with positive peritoneal washings
II	Growth involving one or both ovaries with pelvic extension
IIA	Extension or metastases to the uterus or tubes
IIB	Extension to other pelvic tissues
IIC	Tumor either stage IIA or IIB but with tumor on surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells; or with positive peritoneal washings
III	Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum
IIIA	Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces
IIIB	Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative
IIIC	Abdominal implants >2 cm in diameter or positive retroperitoneal or inguinal nodes
IV	Growth involving one or both ovaries, with distant metastases. If pleural effusion is present, cytologic findings must be positive to allot a case to stage IV. Parenchymal liver metastasis equals stage IV

From Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. FIGO Committee on Gynecologic Oncology. Int J Gynecol Obstet 2009;105:3-4.

The importance of complete surgical staging in developing a proper treatment plan and prognosis cannot be overemphasized. The standard surgical approach involves a vertical midline incision to allow for adequate exposure, although more recent advances in laparoscopic surgery have made minimally invasive options available (Table 3).
Epithelial ovarian tumors are classified by cell type and behavior as benign, atypically proliferating, or malignant. Atypically proliferating tumors are also referred to as tumors of low malignant potentials (LMPs) or “borderline” tumors.
Ovarian cancer can spread by direct extension, by exfoliation of cells into the peritoneal cavity (transcoelomic spread), via the bloodstream, or via the lymphatic system. The most common pathway of spread is transcoelomic. Cells from the tumor are shed into the peritoneal cavity and circulate, following the clockwise path of the peritoneal fluid. All peritoneal surfaces are at risk. Lymphatic spread to the pelvic and para-aortic lymph nodes can occur. Hematogenous spread to the liver or lungs can occur in advanced disease.

Table 3 Surgical Staging Procedures for Ovarian Cancer

Obtain ascites for cytologic evaluation
Washings from the pelvis, gutters, and diaphragm
Systematic exploration of all organs and surfaces
Hysterectomy*
Bilateral salpingo-oophorectomy*
Infracolic omentectomy
Sampling pelvic and para-aortic lymph nodes
Multiple biopsy specimens from peritoneal sites
- Pelvic side walls
- Surfaces of the rectum and bladder
- Cul-de-sac
- Lateral abdominal gutters
- Diaphragm

*May be preserved in select patients, particularly if future fertility is desired. From Young RC, Decker DG, Wharton JT, et al. Staging laparotomy in early ovarian cancer. JAMA 1983;250(22):3072-3076; and Trimbos JB, Schueler JA, van Lent M, et al. Reasons for incomplete surgical staging in early ovarian carcinoma. Gynecol Oncol 1990;37:374-377.

Prognostic Factors

Most important are stage, grade, histology of the tumor, the amount of residual disease remaining after initial debulking surgery, and the age of the patient.
The 5-year survival rate of patients with epithelial ovarian cancer correlates directly with tumor stage (Table 4). Within each histologic category, a spectrum of subgroups is present, including benign, LMP, and malignant.
- Serous. The serous histologic subtype resembles cells of the fallopian tube and is the most common, accounting for over 50% of all malignant ovarian tumors. Approximately one third are malignant, one sixth are LMP, and half are benign. The mean age of patients at diagnosis is 57 years. Psammoma bodies are present in 25%.
- Mucinous tumors are lined by cells that resemble the cells of the endocervical glands. Primary ovarian mucinous tumors account for 3% to 4% of epithelial tumors. Sixty percent of mucinous tumors are stage I, and most are unilateral. They are typically large, often filling the abdominal cavity, cystic, and multiloculated. The mean age of patients diagnosed with malignant mucinous tumors is 54 years. CA-125 levels may not be markedly elevated.
  - Pseudomyxoma peritonei is a condition associated with mucinous neoplasms, usually of gastrointestinal origin, and is characterized by gelatinous mucus or ascites in the abdomen.
- Endometrioid tumors resemble the histology of the endometrium and account for 6% of epithelial tumors. Most are malignant; 20% may be LMP. The mean age of patients diagnosed with malignant tumors is 56 years. About 14% of women will also have endometrial cancer, and 15% to 20% or more will also have endometriosis. Endometrioid tumors appear to have a better prognosis than serous tumors, most likely because of their early stage at diagnosis.
- Clear cell carcinomas account for 3% of epithelial ovarian cancers. These tumors are the most chemoresistant type of ovarian cancer and are most commonly associated with paraneoplastic syndromes. Endometriotic implants are commonly present (30% to 35% cases). About 50% of patients present in stage I. Tumors are large, with a mean diameter of 15 cm. Histologically, hobnail-shaped cells are characteristic of the clear cell carcinomas. The mean age at diagnosis is 57 years.
- Transitional cell tumors histologically resemble the bladder. The two types of malignant transitional cell tumors are Brenner's tumors and transitional cell carcinomas. Approximately 10% to 20% of advanced stage ovarian carcinomas contain a transitional cell carcinoma component. The mean age for malignant Brenner's tumors is 63 years.
Grade is an important independent prognostic factor, particularly in patients with early-stage disease.
- Grade 1 is well differentiated, grade 2 is moderately differentiated, and grade 3 is poorly differentiated.
Debulking, also called cytoreduction, is defined as removal of as much tumor as possible during surgical exploration. Optimal cytoreduction implies that tumor nodules no larger than 1 cm in diameter are left behind and survival improves as the amount of residual disease decreases.
Tumor ploidy has been demonstrated to be an independent prognostic variable. Diploid tumors are often stage IA, whereas aneuploid tumors are often seen in more advanced cancer.

Table 4 Five-Year Survival for Epithelial Ovarian Cancer, by Stage (2010)
Stage	5 Year Survival (%)	Stage	5 Year Survival (%)
IA	94	IIC	57
IB	91	IIIA	45
IC	80	IIIB	39
IIA	76	IIIC	35
IIB	67	D	18

From American Cancer Society SEER data, last updated July 07, 2010.

Management of Epithelial Ovarian Cancer

Treatment of epithelial ovarian cancer depends on the stage and grade of the disease, type of disease (i.e., primary or recurrent), previous treatment, and the patient's performance status.

Tumors of Low Malignant Potential (LMP)

These tumors show a different pattern of behavior than malignant ovarian disease. Approximately 15% of all epithelial ovarian malignancies are low malignant potential tumors (LMPs) and are often found in younger patients. These tumors are most commonly of serous histology (85%), followed by mucinous.
Serous LMPs with invasive implants tend to behave as low-grade carcinomas with a mortality rate of 34%.
Mucinous LMPs confined to the ovary have a survival rate approaching 100%, whereas those with advanced-stage disease have a survival rate of 40% to 50%. Mucinous LMPs may be associated with a concurrent appendiceal primary tumor, and affected patients should also undergo appendectomy. Mucinous LMPs that display aggressive behavior are associated with pseudomyxoma peritonei, which is of appendiceal origin.
Surgical staging of LMPs is advocated because of the possibility of identifying an invasive cancer on final pathology. Because of the indolent growth of LMPs, adjuvant therapy is not recommended even in patients with advanced disease. If disease recurs, it recurs an average of ten years after initial diagnosis, and resection can be performed again at the time of recurrence. Most patients die with the disease rather than from the disease.
In addition, early-stage disease in women who want to maintain fertility may be treated with unilateral salpingo-oophorectomy, or even with unilateral cystectomy, with good results.

Early Invasive Disease (Stage I or II)

Initial surgical resection is necessary for establishing a histologic diagnosis and appropriate staging. Options exist for young patients who wish to preserve fertility. If intraoperative findings are consistent with stage I disease and the contralateral ovary is normal in appearance, unilateral salpingo-oophorectomy with thorough surgical staging may be performed. The uterus and normal-appearing contralateral ovary may remain in situ. The patient needs to understand the potential for a second primary in the preserved ovary, and a total abdominal hysterectomy and removal of the remaining tube and ovary should be considered after childbearing is completed.
Chemotherapy. For patients with stage IA, grade 1 or 2 disease, chemotherapy is not required. For patients with early-stage disease with prognostic factors placing them at higher risk for recurrence, postoperative chemotherapy is recommended. The appropriate chemotherapy regimen for patients with early-stage disease is still being evaluated in clinical trials.
Radiation. Radiation therapy is very infrequently used today as effective chemotherapy is available.

Advanced Invasive Disease

Advanced disease requires surgical staging, debulking, and a course of platinumbased chemotherapy.
Primary cytoreductive surgery, or debulking, is central in the treatment of advanced disease because maximal cytoreduction is one of the most powerful predictors of survival in patients with advanced cancer. The determination of residual disease upon closure of the procedure does not include the total volume of tumor cells left behind but rather the diameter of the largest single residual nodule. For example, a patient with one unresected nodule measuring 2.5 cm has not undergone optimal debulking, whereas debulking is considered to be optimal in a patient with residual miliary studding of the entire peritoneal cavity.
Neoadjuvant therapy has been associated with a lower overall survival compared to initial surgery. However, it may be an appropriate alternative for patients whose performance status prohibits initial surgery. In addition, for patients in whom suboptimal debulking is likely, neoadjuvant chemotherapy has been used as an alternate strategy before surgery in an attempt to increase the likelihood of optimal tumor debulking.
Combination chemotherapy is most often used as postoperative (adjuvant) treatment for advanced epithelial ovarian cancer. Combination chemotherapy with six cycles of carboplatin plus paclitaxel is the treatment of choice for patients with advanced disease. A cycle is given every 3 weeks, with monitoring of tumor status by physical examination, CA-125 levels, and CT imaging.
Intraperitoneal chemotherapy. Recent data have shown a substantial improvement in overall survival and progression-free survival in patients with newly diagnosed, optimally debulked stage III ovarian cancer by the administration of cisplatin and paclitaxel via an intraperitoneal (IP) port rather than the conventional intravenous (IV) administration. The median survival was 65.6 months in the IP group compared to 49.7 months in the IV group. However, an increase in toxic events and catheter-related complications is a disadvantage of this therapeutic approach and can prevent completion of all six cycles.
Alternative therapies, including biologic therapy using autologous tumor-infiltrating lymphocytes and monoclonal antibodies, are under investigation.
Consolidation treatment. Eighty percent of patients who complete optimal tumor debulking followed by six cycles of carboplatin and paclitaxel will achieve a clinical remission. Consolidation treatment strategies to lengthen time to recurrence are currently being investigated. Administration of tamoxifen or aromatase inhibitors to patients with estrogen positive primary tumors can be considered.

Post-treatment surveillance

Asymptomatic Patients

Appropriate follow-up for asymptomatic patients after primary surgery and chemotherapy should include a physical examination with rectovaginal examination, CA-125 testing, and CT scan. Patients should be seen every 3 months for the first 2 years.
- In patients whose CA-125 level was elevated preoperatively, CA-125 is a reliable marker of disease recurrence. The combination of thorough physical examination and CA-125 testing has been shown to detect recurrent disease in 90% of patients. Combined positron emission tomography imaging and CT may have clinical use in detecting disease recurrence in select patients.
Second-look surgery by laparotomy or laparoscopy can be performed on patients with advanced epithelial ovarian cancer who have undergone primary debulking followed by chemotherapy and who have no clinical evidence of disease. The use of second-look surgery remains controversial and should be performed only in the P.580 setting of a clinical trial or on an individualized basis, as no data exist to prove that it prolongs survival. Patients need to be counseled that the procedure is not therapeutic but may provide prognostic information.

Recurrent or Persistent Disease

Secondary debulking. Patients with recurrent or persistent disease may be candidates for further surgical therapy, or secondary cytoreduction. Surgery should be reserved for patients in whom therapy has a good chance of prolonging life or palliating symptoms. Those with longer disease-free intervals (at least 6 to 12 months) and fewer sites of recurrence are the best candidates for secondary cytoreduction.
Second-line chemotherapy. Response rates for second-line chemotherapy are in the range of 20% to 40%. A host of chemotherapy options are available for recurrent ovarian cancer.
Hormone therapy has been used as salvage treatment. Both megestrol acetate (Megace) and tamoxifen have been used to treat recurrent disease. Response rates are low.
Experimental studies. Many investigators are currently studying the underlying molecular biology of epithelial ovarian cancer. Microarray analysis and proteomics provide insight into the differential expression of mRNA and proteins, respectively. Translational studies to further characterize these molecular changes, as they relate to the clinical disease state, provide an opportunity to develop novel therapeutic agents. Clinical trials are also currently investigating antiangiogenic drugs.

Complications of Advanced Ovarian Cancer

Intestinal obstruction. Many women with ovarian cancer develop intestinal obstruction, either at initial diagnosis or with recurrent disease. Obstruction may be related to mechanical blockage or carcinomatous ileus. Correction of intestinal obstruction at initial treatment is usually possible; obstruction associated with recurrent disease, however, is a more complex problem. Some of these obstructions may be treated conservatively with IV hydration, total parenteral nutrition, and gastric decompression. The decision to proceed with palliative surgery must be based on the physical condition of the patient and her expected survival. If patients are unable to undergo surgery or are judged to be poor operative candidates, placement of a percutaneous gastric tube may offer some relief.
Ascites. Initial ascites on presentation with ovarian cancer is almost always improved by debulking surgery and several courses of chemotherapy. Persistent ascites is difficult to manage and is a very poor prognostic sign. Ascites is best managed by repeated paracenteses and chemotherapy.

Survival

Age. Overall survival rate 5 years after diagnosis in women younger than age 65 is nearly twice that of women over age 65 (57% and 28%, respectively).
Stage. Patients with stage I disease have up to a 94% 5-year survival rate. In contrast, overall survival for women with distant disease on presentation is 29% (Table 45-5).
Performance status. The Karnofsky Performance Scale Index (Table 5) classifies patients according to their functional impairment and can be used to assess prognosis in individual patients. Lower scores are associated with worse survival for most serious illnesses.

Peritoneal Carcinoma

The primary malignant transformation of the peritoneum is termed primary peritoneal carcinoma, which clinically and pathologically resembles serous epithelial ovarian cancer. Primary peritoneal carcinoma can therefore appear with a clinical P.581 presentation similar to ovarian cancer in patients with a history of oophorectomy or with pathologically normal-appearing or minimally involved ovaries. Extensive upper abdominal disease is common, and clinical course, management, and prognosis are similar to those for epithelial ovarian cancer.

Table 5 The Karnofsky Performance Scale
Description	Percentage (%)
Normal; no complaints; no evidence of disease	100
Able to carry on normal activity; minor signs, and symptoms of disease	90
Normal activity with effort; some signs and symptoms of disease	80
Cares for self; unable to carry on normal activity or do work	70
Requires occasional assistance but is able to care for most personal needs	60
Requires considerable assistance and frequent medical care	50
Disabled; requires special care and assistance	40
Severely disabled; hospitalization indicated although death not imminent	30
Very sick; hospitalization necessary; requires active support treatment	20
Moribund; fatal processes progressing rapidly	10
Dead	0

Originally published by Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer, in Macleod CM, ed. Evaluation of Chemotherapeutic Agents. New York: Columbia University, 1949:199-205.

Fallopian tube cancer

Epidemiology. Carcinoma of the fallopian tube is very rare, accounting for <1% of cases of gynecologic cancer in women. Carcinoma of the fallopian tube is seen most often in the fifth and sixth decades of life.

Histology. To confirm a histologic diagnosis of fallopian tube cancer, most of the tumor must be present in the fallopian tube, the mucosa of the tube must be involved, and a demonstrable transition from benign to malignant tubal epithelium must exist. Over 90% of tumors are papillary serous adenocarcinoma, resembling ovarian serous carcinoma.

Clinical presentation and diagnosis. The triad of symptoms of fallopian tube carcinoma is watery vaginal discharge (hydrops tubae profluens), a pelvic mass, and pelvic pain. However, only 15% of patients present with this triad. Vaginal discharge or bleeding is the most common presenting symptom (50% to 60%), followed by abdominal pain and an abdominal mass. As in ovarian cancer, presentation may be nonspecific. Ascites may be present if the disease is advanced. Unlike ovarian cancer, fallopian tube carcinoma more often presents at an early stage. A preoperative diagnosis of fallopian tube cancer is made in only a minority of patients; the usual clinical diagnosis is ovarian tumor or pelvic inflammatory disease. The majority of patients will have elevated CA-125 levels.

Natural history and patterns of spread. Tubal cancers spread in a similar fashion to ovarian cancers.

Staging. The ovarian cancer staging system has been adapted for the fallopian tube.

Treatment is similar to that of ovarian cancer, with surgical debulking as the mainstay of treatment, followed by combination platinum-based chemotherapy. Chemotherapy for early-stage disease is the subject of controversy.

Prognosis and survival are related to the stage of disease. Data on 5-year survival rates are as follows from stage I to IV: 95%, 75%, 69%, and 45%.

Germ cell ovarian tumors

Epidemiology

Approximately 20% of all ovarian tumors are of germ cell origin, with only 2% to 3% of these being malignant. Types include the following: dysgerminoma, endodermal sinus tumor, embryonal, polyembryoma, choriocarcinoma, and teratoma.
Roughly 70% to 80% of all germ cell tumors occur before age 20, and approximately one third of these are malignant. The median age of women diagnosed with a malignant germ cell tumor is 16 to 20 years. About 50% to 75% of patients with malignant germ cell tumors present with stage I disease. Overall survival rates, including those with advanced disease, are 60% to 80%.
The most common germ cell tumor is the dermoid (benign cystic teratoma), and the most common malignant tumor is the dysgerminoma.

Pathology

Germ cell tumors are derived from the primordial germ cells of the ovary; however, they are a heterogeneous group of tumors. They gradually differentiate to mimic tissues of embryonic origin (ectoderm, mesoderm, endoderm) and extraembryonic origin (trophoblast, yolk sac). They are aggressive tumors, frequently unilateral, and usually curable if treated early.

Diagnosis

Clinically, germ cell malignancies grow quickly and are often characterized by acute pelvic pain. The pain can be caused by distention of the ovarian capsule, hemorrhage, necrosis, or torsion. A palpable pelvic mass is a common finding on presentation. Abdominal distention and abnormal vaginal bleeding may also be the presenting complaint. The tumors are often large at presentation, with a median diameter of 16 cm.
Ovarian masses that are 2 cm or larger in premenarchal girls or 8 to 10 cm or larger in premenopausal patients are concerning and generally require exploratory surgery.
Preoperative workup. Measurement of serum tumor markers may assist in the diagnosis of germ cell malignancies. Workup should include measurement of serum hCG, alpha-fetoprotein (AFP) titers, lactate dehydrogenase (LDH) levels, a CBC, and liver function tests. A chest radiographic study is important to rule out pulmonary metastases. A preoperative CT scan should be considered to assess for the presence or absence of liver metastases and retroperitoneal lymphadenopathy.

Germ Cell Tumor Types

Dysgerminomas are the most common malignant germ cell tumor, comprising up to 50%. All dysgerminomas are malignant; however, not all are aggressive. Seventy-five percent of dysgerminomas occur in the second and third decades of life. They are the only germ cell tumor that tends to be bilateral (10% to 15% of cases). The 5-year survival rate for stage IA disease is 95% and for all stages is 85%.
Endodermal sinus tumors (yolk sac tumors) are derived from cells of the primitive yolk sac and are the second most common malignant germ cell tumor, accounting for 20%. Pathologically, they are characterized by Schiller-Duval bodies. These tumors tend to grow rapidly and aggressively. They secrete AFP. The disease-free survival rate for all stages is >80%.
Embryonal carcinoma. These tumors are extremely rare and occur in children and young adults. They may secrete both hCG and AFP. Patients may present with sexual precocity and vaginal bleeding.
Polyembryoma. These tumors are exceedingly rare and highly malignant. They resemble early embryos and may secrete AFP or hCG.
Choriocarcinoma. Pure, nongestational choriocarcinoma is very rare and is histologically similar to gestational choriocarcinoma. Almost all patients are premenarchal. The tumor often produces high levels of hCG. Precocious puberty is seen occasionally, and patients may present with vaginal bleeding. This tumor has historically had a poor prognosis but does respond to combination chemotherapy.
Immature malignant teratomas contain tissues resembling those in an embryo. They account for 20% of malignant germ cell tumors and 1% of ovarian malignancies. Half of immature teratomas occur in patients between ages 10 and 20. These tumors may secrete AFP. The most important prognostic factor is the grade of the tumor. The 5-year survival rate is 95% for stage I disease and 75% for advanced disease.
Mixed germ cell tumors account for 10% of malignant germ cell tumors and contain elements of two or more of the germ cell tumors discussed previously.

Management of Germ Cell Tumors

Surgical. Primary treatment for all germ cell tumors is surgical and should include proper surgical staging to rule out the presence of extraovarian microscopic disease. Because most of the patients are of reproductive age, preservation of fertility is important.
- Unilateral oophorectomy is performed along with unilateral pelvic and para-aortic lymphadenectomy. A frozen section should be performed. Bilateral involvement is rare in germ cell tumors, with the exception of dysgerminomas (10% to 15% bilaterality). The contralateral ovary should be inspected, and a biopsy may be performed if there is suspicion of involvement, but the ovary should be removed in a young patient only if disease is present. The remaining pelvic organs may be left in situ to preserve fertility.
- For patients who have completed childbearing, a total abdominal hysterectomy with bilateral salpingo-oophorectomy is reasonable. When the disease is metastatic on initial surgery, cytoreductive surgery is recommended, although data are limited.
- Surgical therapy alone is recommended for stage IA dysgerminomas and stage IA, grade I immature teratomas. These patients have a 5-year survival of >90%. Approximately 15% to 25% will recur but can be treated successfully at the time of presentation. For endodermal sinus tumors, staging is not always recommended because chemotherapy should be given regardless.
Adjuvant therapy. The decision to administer adjuvant therapy depends on the histologic type of germ cell tumor. All patients, except those with stage IA, grade I immature teratoma and stage IA dysgerminoma, require postoperative chemotherapy. Dysgerminomas are very sensitive to radiation therapy; however, fertility is lost as a consequence of irradiation. Therefore, chemotherapy is the first-line treatment. Combination therapy with three agents (bleomycin, etoposide, and cisplatin, or BEP) is recommended. Prognosis has significantly improved with platinum-based chemotherapy.
Ninety percent of patients with germ cell tumors who experience a recurrence will do so in the first 2 years after therapy. If initially treated with surgery alone, BEP chemotherapy can be used. Patients who initially received chemotherapy can be treated with a platinum-based agent.

Sex cord-stromal ovarian tumors

Sex cord-stromal tumors are derived from the sex cords and mesenchyme of the embryonic gonad and account for 5% to 8% of all ovarian neoplasms. Most of these tumors are hormonally active (Table 45-7). Types include the following: granulosa-stromal cell, Sertoli-Leydig, sex cord tumor, and gynandroblastoma.

Granulosa Cell Tumor

Incidence. The granulosa cell tumor is the most common malignant sex cordstromal tumor, accounting for 70%. Adult granulosa cell tumors occur primarily in the perimenopausal years, with a mean age of 52 at presentation. Two forms exist: an adult form (95%) and a much rarer juvenile form (5%). The tumor is bilateral in <10% of cases.
Diagnosis and presentation. In the majority of cases, the tumor secretes estrogen and inhibin. Histologically, Call-Exner bodies are seen. Patients may present with abnormal vaginal bleeding, abdominal distention, pain, or a mass, most >10 cm in diameter. Granulosa cell tumors are characteristically hemorrhagic and can present with a hemoperitoneum.
- The incidence of concurrent endometrial hyperplasia is over 50%, and the incidence of concurrent endometrial adenocarcinoma ranges from 3% to 27%. The majority (90%) of affected patients present with stage I disease, mainly because the hormonal effects of the tumor cause symptoms early in the disease. In juvenile type, patients present with pseudo precocious puberty and have elevated serum estradiol.
Treatment. Surgery alone is usually sufficient treatment only for disease of stage IA or IB. For all other stages, chemotherapy is recommended. Similar regimens utilized for germ cell tumors such as BEP are often employed. Radiation, chemotherapy, or both are used for recurrent disease. If the patient desires to maintain fertility, a unilateral salpingo-oophorectomy is adequate for treating stage IA tumors, and a staging operation should also be performed. If the patient has completed her childbearing, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed. If the uterus is left in situ, dilation and curettage should be performed to rule out endometrial hyperplasia or adenocarcinoma. Chemotherapy after surgery does not prevent recurrence of the disease.
Prognosis and survival. Granulosa cell tumors have a propensity for late recurrence, with recurrence reported as many as 30 years after treatment for primary tumor. The 10-year and 20-year survival rates are 90% and 75%, respectively.

Sertoli-Leydig Cell Tumor

Incidence. Sertoli-Leydig cell tumors account for only 0.2% of cases of ovarian neoplasms. The average age at diagnosis is 25. The tumors are most frequently lowgrade malignancies, and nearly all patients (97%) present at stage I.
Diagnosis and presentation. Sertoli-Leydig cell tumors often produce androgens. Patients present with virilization (30% to 50%), menstrual disorders, and other symptoms related to an abdominal mass. Average size of mass is about 16 cm. These tumors may produce testosterone, androstenedione, or AFP.
Treatment. In young patients, unilateral salpingo-oophorectomy with staging may be performed to preserve fertility. In older patients, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed as well. Treatment in those with higher stage and/or grade typically includes chemotherapy.
Prognosis and survival. Prognosis is related to stage and histologic grade. The 5-year survival rate is 70% to 90%.

Special considerations in ovarian cancer

Metastatic tumors account for 5% to 20% of ovarian malignancies and are often, but not always, bilateral.
Gastrointestinal tract tumors are the most likely to metastasize to the ovary. Krukenberg tumors are usually bilateral and account for 30% to 40% of metastatic tumors to the ovary. The tumor is characterized histologically by signet-ring cells, in which the nucleus is flattened against the cell wall by the accumulation of cytoplasmic mucin. In postmenopausal women who undergo evaluation for an adnexal mass, metastatic colon cancer should be ruled out, if possible, using colonoscopy.
Breast cancer is the second most likely cancer to metastasize to the ovary.
Lymphomas can also metastasize to the ovary. Burkitt's lymphoma may affect children or young adults. Rarely, ovarian lesions are the primary manifestation of disease in lymphoma patients.
Metastatic gynecologic tumors may involve the ovaries. Fallopian tube cancer is the most common malignancy to metastasize to the ovaries and occurs by direct extension. Cervical cancer very rarely spreads to the ovaries. Endometrial cancer may metastasize to the ovaries; however, synchronous endometrioid adenocarcinoma, primary to both the ovary and the endometrium, can also occur.
Malignant mixed-mesodermal tumors of the ovary are extremely rare. These lesions are very aggressive, and treatment consists of surgical resection followed by combination chemotherapy.
Ovarian tumors during pregnancy are very rare. The incidence of an adnexal mass during pregnancy is approximately 1 in 800. The majority of adnexal masses discovered during the first trimester resolve by the second trimester. However, approximately 1% to 6% of these masses are malignant.
- Germ cell tumors (primarily dysgerminoma) account for approximately 45% of ovarian malignancies diagnosed in pregnancy.
- The masses are usually diagnosed during routine ultrasonography or at the time of cesarean section. The majority of patients (74%) are diagnosed with stage I disease.
- Early-stage disease can be treated with conservative surgery in the second trimester of pregnancy, usually with good maternal and fetal results. Late-stage and highgrade disease should be treated aggressively after appropriate counseling of the patient.