Endometrial carcinoma is the most common gynecologic malignancy in the United States. It is primarily a disease of postmenopausal women. Tumors are grouped into type I and II categories based on their underlying etiology. The more common type I tumors arise due to prolonged estrogen stimulation of the endometrium. The estrogen is most commonly endogenously produced estrone arising by aromatase conversion of androstenedione in peripheral adipocytes. Obese women produce much more estrogen and are at much higher risk for developing this cancer. Exogenous estrogens prescribed without accompanying progestin in postmenopausal women greatly increases the risk of endometrial cancer as does treatment with other estrogen receptor agonists such as tamoxifen when prescribed for treatment or prevention of breast cancer. Other risk factors for development of endometrial cancer include diabetes, early menarche, late menopause, and low parity. Oral contraceptives are protective against this cancer. Also at risk are premenopausal women with chronic anovulation such as with polycystic ovary syndrome.
Complex hyperplasia with atypia is a precursor lesion for type I endometrial cancer. These tumors usually express estrogen and progesterone receptors. Type II endometrial cancer consists of anaplastic or high-grade, papillary serous, clear cell, and squamous carcinomas. These tumors rarely express estrogen or progesterone receptors and are not thought to arise as a result of estrogen stimulation. Adverse prognostic factors include grade, histology, depth of myometrial invasion, cervical extension, tumor size, and extension beyond the uterus.
Endometrial cancer is staged surgically as shown in Table 39–5.
Table 39–5.FIGO staging for endometrial cancer. ||Download (.pdf) Table 39–5. FIGO staging for endometrial cancer.
|FIGO Stage ||Revised 2009 |
|Stage I ||Tumor confined to corpus uteri |
|IA ||No or less than 50% myometrial invasion |
|IB ||Invasion equal or greater than 50% of myometrium |
|Stage II ||Tumor invades cervical stroma but does not extend beyond uterus |
|Stage III ||Local and/or regional spread. Positive cytology has to be reported separately without changing the stage |
|IIIA ||Tumor invades serosa and/or adnexae |
|IIIB ||Vaginal and/or parametrial involvement (direct or metastases) |
|IIIC ||Metastases to pelvic and/or para-aortic lymph nodes |
|IIIC-1 ||Positive pelvic nodes |
|IIIC-2 ||Positive para-aortic nodes with or without positive pelvic nodes |
|Stage IVA ||Tumor invades bladder or bowel mucosa |
|Stage IVB ||Distant metastases, including intra-abdominal and/or inguinal lymph nodes |
Postmenopausal bleeding is the presenting symptom in about 90% of cases and should be considered to be cancer until proven otherwise. Common etiologies of postmenopausal bleeding include physiologic bleeding from hormone replacement therapy (27%), benign polyps (7%-23%), cervicitis (6%-14%), endometrial carcinoma (13%-16%), atrophy (10%), cervical carcinoma (1%-4%). Despite workup, up to 20%-23% of cases will have no identified etiology. Cervical stenosis with pyometrium or hematometrium is highly suggestive of endometrial carcinoma. Pain is not a common symptom. Vaginal cytology is positive in 40%-80% of cases but is entirely unreliable as a diagnostic tool for endometrial cancer. Endometrial biopsy performed in the office using a disposable biopsy instrument is highly sensitive. If endometrial biopsy fails to provide a definitive diagnosis, dilatation and curettage of endocervix and endometrium, is definitive.
Type II endometrial carcinoma comprised of poorly differentiated, or adverse histological types, may disseminate relatively early in the course of the disease. Metastatic spread may occur to the vagina, regional pelvic and para-aortic lymph nodes, ovaries, lungs, brain, and bone. The most frequent site of recurrence following treatment for endometrial carcinoma is the vaginal vault.
Oral contraceptives have been shown to reduce the risk of endometrial cancer by up to 50% depending on duration of treatment. Progestin therapy will reduce the possibility of endometrial carcinoma in the anovulatory patient as well as in postmenopausal women receiving estrogen replacement therapy. Progestins in both OCP and hormone replacement regimens cause downregulation of estrogen receptors and atrophy of endometrium.
Endometrial cancer is staged surgically. The route of surgical approach for the staging procedure can be either via laparotomy or laparoscopy. Definitive therapy includes total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy and pelvic washings for type I cancers. For type II lesions, omentectomy is usually added. Lymphadenectomy is sometimes omitted for patients with type I lesions with low-risk such as small, grade-1 cancers without myometrial invasion.
If the cervix is grossly involved, patients may receive preoperative radiation followed by total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy and pelvic washings. Alternatively, a radical hysterectomy bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy may be performed without preoperative radiation. The radical hysterectomy includes removal of the upper third of the vagina, cardinal, and uterosacral ligaments.
Adjuvant pelvic radiation therapy is administered to patients with cervical extension (stage II); deep myometrial invasion with a grade 3, type I lesion; or vaginal extension (stage IIIB). A randomized clinical trial comparing radiation to chemotherapy with cisplatin and doxorubicin showed a survival benefit for patients with positive nodes (stage IIIC) treated with chemotherapy. Metastatic and type II lesions such as papillary serous carcinomas are very likely to recur after surgery regardless of stage. These tumors are usually treated with multimodal therapy using a combination of radiation and chemotherapy.
Metastatic or recurrent disease is usually treated with multimodal therapy using surgery, radiation and/or chemotherapy based on the location, size, and histology of lesions. Chemotherapy combinations usually include either a doublet of cisplatin with paclitaxel or doxorubicin or a triplet regimen combining all three drugs. Metastatic cancer of type I may be treated with progestin therapy.
Survival at 5 years is about 70%-90% for stage I disease, depending on grade and myometrial invasion. Survival declines to about 60% in stage II. Anaplastic tumors, deep myometrial penetration, and absence of estrogen and progesterone receptors all worsen the prognosis.
Uterine sarcomas fall into three histological groups including leiomyosarcoma, endometrial stromal sarcoma, and carcinosarcoma. These tumors are rare, accounting for about 3% of uterine neoplasms. Sarcomas of the uterus spread via hematogenous and lymphatic pathways in addition to direct extension. Lung and liver are frequent sites of metastases and recurrence.
In patients in whom the tumor is confined to the pelvic organs, treatment consists of total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, omentectomy and pelvic washings. There are no randomized trials documenting survival benefit for adjuvant therapy with either chemotherapy or radiation. However, individualized postoperative radiation and/or chemotherapy may be offered based on the poor prognosis of these tumors. Radiation reduces pelvic recurrences, but does not appear to improve overall survival.
The outlook for patients with uterine sarcoma is dependent on grade and stage of the tumor. Leiomyosarcomas with more than ten mitoses per ten high-power fields carry a poor prognosis, with recurrence within 5 years in about two-thirds of patients. About 40% of patients with carcinosarcoma survive. Isolated, late recurrence of leiomyosarcoma in the lung is treated by resection of the affected lobe with generally good salvage rates of about 50% at 2 years.
Gemcitabine and Taxotere is the combination with the highest likelihood of response for metastatic or recurrent leiomyosarcoma. High-dose progestin therapy is very effective for treatment of metastatic low-grade endometrial sarcoma. Carcinosarcoma is most effectively treated with combination of either cisplatin and ifosfamide or ifosfamide and paclitaxel.
Gestational Trophoblastic Disease
Gestational trophoblastic disease refers to tumors arising from placental tissue. They are unique among all neoplasms in that their genetic complement is provided by the father, thereby resulting in a tumor with genetic material and markers foreign to the patient. Gestational trophoblastic diseases may be divided into preinvasive and invasive types. The preinvasive types include complete and partial hydatidiform moles.
The frequency of hydatidiform mole is about 1:700 to 1:2000 pregnancies in the United States, Canada, and Western Europe and about 1:85 to 1:520 pregnancies in Asia. Hydatidiform mole is more common in women over 40. A prior history of gestational trophoblastic disease significantly increases the risk of recurrence with a future gestation.
The gross appearance of a hydatidiform mole is related to the hydropic villi in the absence of a fetal circulation. The histological appearance reveals varying degrees of trophoblastic proliferation. Hydatidiform moles can be classified as either complete or partial, based on cytogenetics and histopathology. These features are compared in Table 39–6. The majority of complete moles carry a 46XX karyotype, with chromosomes exclusively of paternal origin. Partial moles are typically triploid with 69XXX or 69XXY, where two or three sets of chromosomes are paternal in origin. Complete moles are not associated with a developing fetus, and partial moles may include a fetus that is typically small and with multiple anomalies.
Table 39–6.Features of hydatidiform moles. ||Download (.pdf) Table 39–6. Features of hydatidiform moles.
|Characteristic ||Complete Mole ||Partial Mole |
|Karyotype || |
All paternal chromosomes
69XXX or 69XXY
46 paternal chromosomes
|Fetus ||Absent ||Often present |
|Villous edema ||Prominent and diffuse ||Focal if at all |
|Fetal RBC ||None ||Usually present |
|Proliferation of trophoblast ||Prominent ||Mild to moderate |
|Likelihood of local invasion ||15% ||3.5% |
|Likelihood of metastasis ||4% ||0.6% |
Invasive gestational trophoblastic disease is categorized as invasive mole, choriocarcinoma, or placental site trophoblastic tumor. Invasive mole is diagnosed after 15% of complete moles and 3.5% of partial moles. Metastases occur following 4% of complete moles and 0.6% of partial moles. Choriocarcinoma occurs following 3%-7% of hydatidiform moles and 1:40,000 term pregnancies. Out of all choriocarcinoma cases, 50% are preceded by a mole, 25% by spontaneous abortion, and 25% by term pregnancy. Placental site trophoblast tumor (PSTT) is a very rare variant with only 55 cases reported in the literature by 1991.
Invasive mole is comprised of hyperplastic trophoblasts with villi invading myometrium. Choriocarcinoma involves sheets of syncytiotrophoblasts with no villi and demonstrates invasion into myometrium or other tissues. Necrosis and hemorrhage are common. PSTT is comprised of intermediate cytotrophoblasts.
Human chorionic gonadotropin (β-hCG) is a clinically useful tumor marker for all types of preinvasive and invasive gestational trophoblastic disease except PSTT, where human placental lactogen (hPL) may be elevated.
The most common presenting symptom with hydatidiform mole is vaginal bleeding, occurring in 97% of complete moles and 73% of partial moles. On pelvic exam, about 50% of complete moles and 8% of partial moles will reveal uterine size greater than expected for a given estimated gestational age. Theca lutein cysts are physiologic ovarian cysts as a result of hyperstimulation by very high levels of β-hCG produced by 50% of complete moles. These cysts typically resolve once the β-hCG level regresses following appropriate treatment. Preeclampsia may develop in 27% of women with complete moles and virtually never with partial moles. Clinical hyperthyroidism can develop in about 7% of women with complete moles with very high β-hCG levels due to cross reactivity of this hormone with thyroid stimulating hormone. A rare but potentially fatal complication is trophoblastic embolization to the lung during or after evacuation of large complete moles.
Diagnosis is usually confirmed with either ultrasound or β-hCG values. Serum β-hCG levels are above 100,000 mIU/mL in 46% of women with complete moles and these values persist beyond the twelfth week gestation, neither of which should be observed in a normal pregnancy. Ultrasound will usually demonstrate multiple small sonolucencies due to the hydropic villi. In a partial mole, the fetus, if present, will usually be small and afflicted with multiple anomalies.
Threatened abortion or missed abortion will often present with similar symptoms of bleeding and both are more likely than gestational trophoblastic disease. A multiple gestation must be considered because it may produce unusually high levels of β-hCG in addition to uterine size greater than the gestational date.
Metastasis is most common with choriocarcinoma, but may occur with any of the invasive types of gestational trophoblastic disease. The most common sites of spread include lung (80%), vagina (30%), pelvis (20%), brain or liver (10%), bowel or kidney or spleen (<5%). Unlike virtually any other tumor, metastatic disease is still potentially curable in many patients.
Once the diagnosis of a molar pregnancy has been established, the uterus should be evacuated by suction curettage. All specimens are submitted for histology and cytogenetics. Theca lutein cysts of the ovaries regress following treatment of the mole and should not be surgically excised.
Following evacuation of the uterus, weekly serum β-hCG levels should be monitored until normalized for 3 weeks; followed by monthly testing for 6-12 months depending on assessment of pretreatment risk factors. If the β-hCG value plateaus for 3 weeks or rises for 2 weeks, invasive gestational trophoblastic disease including either invasive mole or choriocarcinoma should be suspected. Effective contraception during the surveillance phase is important in order not to complicate interpretation of the β-hCG.
Patients with invasive or persistent gestational trophoblastic disease should be evaluated with a metastatic workup including pelvic examination, CT scan of the head, chest, abdomen, and pelvis, a complete blood count, and renal and liver function tests. Lumber puncture to detect occult central nervous system metastases is sometimes necessary.
Staging of gestational trophoblastic tumors is outlined in Table 39–7. Unlike most neoplasms, gestational trophoblastic disease is staged using a nonanatomic staging system based on prognostic factors. Current FIGO staging combines anatomic staging with the modified WHO prognostic scoring system. For anatomic stage I disease, risk is usually low and for anatomic stage IV disease, risk is usually high. Stage II and III disease is best stratified with the modified WHO prognostic scoring system. Stage is recorded as anatomic stage and FIGO modified WHO score, separated by colon.
Table 39–7.FIGO anatomic staging for gestational trophoblastic disease. ||Download (.pdf) Table 39–7. FIGO anatomic staging for gestational trophoblastic disease.
|FIGO Staging ||Description |
|Stage I ||Disease confined to the uterus |
|Stage II ||GTN extends outside of uterus, but is limited to genital structures including adnexa, vagina, broad ligament |
|Stage III ||GTN extends to lungs with or without genital tract involvement |
|Stage IV ||All other metastatic sites |
|Modified WHO Prognostic Scoring System as adapted by FIGO |
|Description ||Score |
|Factor ||0 ||1 ||2 ||4 |
|Age (years) ||< 40 ||≥40 || || |
|Antecedent pregnancy type ||Mole ||Abortion ||Term || |
|Pregnancy to treatment interval (months) ||< 4 ||4 - < 7 ||7 - 13 ||≥ 13 |
|Pretreatment β-hCG (mIU/L) ||< 103 ||103 - 104 ||104 - 105 ||≥ 105 |
|Tumor size including uterus (cm) ||– ||3 - 5 ||≥ 5 ||– |
|Site of metastases ||Lung || |
|GI || |
|Number of metastases ||0 ||1 - 4 ||5 - 8 ||> 8 |
|Previous failed chemo regimens || || ||Single ||≥ 2 |
Single-agent chemotherapy is the preferred treatment for patients with stage I or low-risk disease who wish to maintain reproductive options. If future childbearing is not an issue, patients with invasive mole may be treated with a hysterectomy and possible adjuvant chemotherapy. Preferred regimens for single-agent therapy include methotrexate or dactinomycin. Both of these regimens can be toxic and should be administered under the guidance of a gynecologic oncologist or medical oncologist. Intermediate and high-risk gestational trophoblastic disease should receive aggressive combination chemotherapy. The most effective regimen reported includes etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMACO). There is occasionally a role for surgery or radiation for selected metastatic disease sites and intrathecal methotrexate is sometimes needed for treatment of central nervous system disease.
The prognosis for cure of gestational trophoblastic tumors is excellent, including cases with pulmonary metastases, which are still considered low risk. Five-year survival of up to 85% is reported in cases with high-risk metastatic disease. The risk of recurrence of gestational trophoblastic disease in a future pregnancy has a relative risk of 20-40, but in absolute terms, this translates to a recurrence risk of less than 5%. During any subsequent pregnancy, ultrasound is recommended. The placenta should be examined after delivery, and β-hCG should be monitored until normalization.
SURGERY FOR BENIGN FALLOPIAN TUBE DISEASE
Infertility Attributed to Fallopian Tube Disease
Infertility is defined as failure to conceive after 1 year of normal coital activity without use of contraceptives. About 15% of couples are infertile within this definition. When the etiology of infertility is evaluated, approximately 40% will be attributable to male factor infertility including low sperm count, impaired motility, or abnormal morphology of sperm. Anatomic abnormality of the pelvic organs is the single most common cause of infertility in women, and tubal factor infertility is the most common cause of infertility.
Common causes for tubal factor infertility include acute and chronic salpingitis, endometriosis, and adhesions from previous appendicitis with rupture or surgery. Chlamydia and gonorrhea infections are the most common causes of tubal damage causing infertility. Desire to reverse previous tubal sterilization may also be a reason for tubal surgery. One-third of infertile couples have more than one problem.
It is important to elicit any history of sexually transmitted disease, pelvic inflammatory disease, pelvic surgery, cyclic pain, or dyspareunia.
The size and mobility of the uterus should be assessed. Adnexae should be palpated for masses consistent with endometrioma or hydrosalpinx, in particular. Cul de sac or uterosacral ligament nodularity and tenderness suggest endometriosis. Ultrasound may reveal the presence of isoechoic masses suggesting endometriosis or a tubular mass consistent with hydrosalpinx. Hysterosalpingogram, a test that involves fluoroscopic assessment of tubal patency by transcervical injection of the uterus with radiocontrast, may reveal an obstruction including its location. Use of a water-based dye is indicated for the first attempt, and if occlusion is noted, an oil contrast medium may be used subsequently. The oil based hysterosalpingogram is reported to have therapeutic benefit.
Laparoscopy is warranted if the evaluation for anatomic abnormalities is inconclusive. Therapeutic interventions including lysis of adhesions or ablation of endometrial implants may be efficacious. If laparoscopy is performed following a normal hysterosalpingogram 24% will have mild endometriosis and 6% of patients will have adhesions.
Tuboplasty procedures may be performed to restore tubal patency. However, in vitro fertilization has become a much more popular intervention in recent years for treatment of infertility attributed to tubal occlusion or when multiple infertility factors affect the couple. Hydrosalpinx is usually treated by salpingectomy in order to optimize subsequent in vitro fertilization. Other factors of prognostic significance include age of the couple, and presence of other causes of infertility including ovulatory dysfunction or male factor infertility.
Heterotopic pregnancies and multiple gestation pregnancies are much more likely than the general population for patients undergoing in vitro fertilization.
Age and severity of tubal disease are predictors of success. Women with mild adhesive disease and age less than 35 have the highest success rates, approaching 70%. For severe tubal disease, success is less than 15%. Ectopic pregnancy is twenty times more likely with a history of Fallopian tube surgery or preexisting scar resulting in a 10% incidence. IVF success rates vary by program and have generally been improving steadily in recent years. Decisions regarding planned tubal surgery versus IVF should take into account the relative costs and success rates.
Ectopic pregnancy is implantation of a viable pregnancy in a location other than within the endometrium lining the uterus. Risk factors for ectopic pregnancy include prior tubal surgery, previous ectopic pregnancy, history of pelvic inflammatory disease or Chlamydia infection, and pregnancy arising from assisted reproduction techniques. Smoking and history of infertility are also associated with increased risk of ectopic pregnancy. Over 95% of ectopic pregnancies occur in the Fallopian tube, generally within the ampullary portion. A less common location includes interstitial pregnancy within the tubal lumen where it passes through the myometrium. Rare sites include cervix, ovary, omentum, pelvis, and abdomen. Heterotopic pregnancy refers to the rare occurrence of an intrauterine pregnancy with a synchronous ectopic pregnancy. The incidence of heterotopic pregnancy has increased from a spontaneous rate of 1:30,000 pregnancies to 0.1%-1% for pregnancies arising from assisted reproductive technology.
The incidence of ectopic pregnancy has been reported to occur in approximately 2% of pregnancies, although the true incidence is difficult to ascertain due to the potential for spontaneous resolution of some ectopic pregnancies resulting in unrecognized disease in addition to under reporting of early ectopic pregnancies treated medically rather than surgically. Pregnant women with pain or bleeding have a fourfold higher incidence of ectopic pregnancy. The primary potential morbidity of ectopic pregnancy is the potential rupture of the Fallopian tube or other implantation site resulting in hemorrhage. Failure to make a timely diagnosis can result in hemorrhagic shock and death.
Patients will usually present with amenorrhea and a diagnosis of pregnancy. Subsequent irregular bleeding occurs in many but not all cases. In the early evolution of the ectopic pregnancy, patients may be asymptomatic. Presence of pain is also variable. Classic symptoms of a ruptured ectopic include severe abdominal pain, referred pain to the shoulder and hemodynamic instability. Upon pelvic examination an adnexal mass may or may not be present. The uterus is usually slightly enlarged and softened secondary to hormonal influence of the ectopic pregnancy.
Trophoblastic cells of the blastocyst produce β-hCG that may be detected shortly after implantation. The rise of β-hCG is logarithmic, with a doubling time of about 48 hours. The β-hCG should rise at least 66% every 48 hours in 85% of normal pregnancies and will plateau in normal pregnancy late in the first trimester. Ectopic pregnancies show a slower rise of β-hCG in all but 15% of cases. An absolute β-hCG does not permit distinction between an ectopic and a nonviable intrauterine pregnancy.
Transvaginal ultrasound has almost 100% sensitivity for detection of intrauterine pregnancy as long as care is taken to discriminate between an actual pregnancy and the pseudo sac, defined as intrauterine fluid that can be mistaken for an intrauterine pregnancy. A true gestational sac is located eccentrically in the uterus and should demonstrate a fetal pole. The absence of an intrauterine pregnancy in the setting of a positive β-hCG is strongly suggestive of an ectopic pregnancy if the β-hCG value is above the discriminatory threshold of transvaginal ultrasound to detect a gestational sac. The discriminatory threshold has been reported to occur with β-hCG values above 1500-3000 mIU/mL, although variables such as body mass index, quality of ultrasound equipment, and experience of the sonographer all impact on the threshold value. Diagnosis of the ectopic pregnancy by direct ultrasound localization of the pregnancy is much less accurate than detection of intrauterine implantation.
Other tests that are of value include obtaining a blood count to assess for anemia in addition to serum progesterone levels. Variability of progesterone values in normal pregnancy limits the utility of this test for diagnosis of ectopic pregnancy.
If the β-hCG shows an abnormal rate of rise, including plateau, slow rise, or declining values, then ultrasound is warranted. However, if the β-hCG value is below the discriminatory threshold, suction curettage is useful to distinguish between a nonviable intrauterine pregnancy and an ectopic gestation. The absence of chorionic villi in the curettage specimen in the presence of an elevated hCG is predictive of an ectopic pregnancy, though in early gestation the curettage may be falsely negative for villi.
Treatment of ectopic pregnancy is either surgical or medical depending on several variables. The surgical approach is definitive, but invasive and more costly than medical management. Medical management results in successful treatment for 90% of appropriately selected patients. Methotrexate is utilized for medical management. Appropriate indications for medical management require a hemodynamically stable patient who is compliant and has no medical contraindication to methotrexate. Relative contraindications include a gestational sac > 3.5 cm, presence of fetal cardiac motion, or a β-hCG value of > 15,000 mIU/mL. Administration of a single dose of methotrexate has reported efficacy of 84%. Use of multidose regimens increases the rate of success. Failure of the β-hCG value to fall by at least 15% within 4-7 days after treatment indicates that additional methotrexate or surgery is indicated. Patients who are Rh negative are given RHo(D) immune globulin whether treated medically or surgically. Other developments in medical management include the use of other agents such as potassium chloride, prostaglandins, and mifepristone, but these have not been studied as well as methotrexate.
Surgical options for treatment of ectopic pregnancy are intended to remove the ectopic gestation and preserve functional Fallopian tube, if possible. If the patient is hemodynamically stable, the laparoscopic approach is usually preferred. If she is in shock or if the abdomen is distended with blood, emergent laparotomy is necessary. If the Fallopian tube is generally healthy, a salpingostomy is possible whereby the involved section of the Fallopian tube is removed through an incision in the antimesenteric portion of the tube, while leaving the remainder of the tube intact. If the tube is more extensively damaged, complete or partial salpingectomy is recommended. If conservative approaches to preserve the Fallopian tube are utilized, the β-hCG value should be monitored postoperatively until normalization occurs.
Expectant management of a documented ectopic pregnancy may be an option in stable patients if the β-hCG value is less than 200 mIU/mL and declining. Patients must be counseled regarding the risks of rupture and hemorrhage, and emergency management must be readily available.
Contraception to prevent unwanted pregnancy may be attained using either reversible or permanent methods. Reversible methods include hormonal contraceptives via oral, transcutaneous or subcutaneous routes; injectable long acting progestins; IUD; and condoms, to name a few. Modern IUD contraceptives contain progestational hormones or copper, delivered in low doses to the uterine cavity where they inhibit sperm motility and block fertilization. They are inserted as an office procedure without requiring local anesthetic or cervical dilation in most cases. Both copper and progestin devices are highly effective and long lasting. Contemporary IUD contraceptives do not increase the risk of pelvic infection. Progestin-releasing IUD devices menstrual flow by about 50% and have been shown to be as effective for control of abnormal uterine bleeding, prevention of hyperplasia during estrogen replacement therapy, and treatment of hyperplasia.
Subdermal implant contraception uses low serum concentrations of contraceptive progestins found in birth control pills to thicken cervical mucus and inhibit ovulation. These actions result in failure rates comparable to those reported following sterilization and intrauterine contraception. Their duration of action is FDA approved for 3 years. As with intrauterine contraceptives, the principal side effect is change in menstrual bleeding; the majority of users experience a diminution in blood loss but an increase in number of days of bleeding, sometimes at unpredictable intervals.
Contraceptive implants require subdermal insertion with a disposable trocar with local anesthetic and are removed under local anesthetic through a small incision. These procedures take only a few minutes, and pain and infections are rare. Contemporary systems utilize a single-rod and are easier to use, have a shorter life, and are associated with somewhat more acceptable bleeding patterns than the now-discontinued multirod implants.
Unintended pregnancies result in about one million abortions per year in the United States. Uterine aspiration using either manual or electric vacuum pumps allows safe elective abortion in the first trimester, with a mortality rate of less than 1:200,000 procedures. Morbidity and mortality of abortion rises substantially as the length of gestation increases.
Permanent sterilization options are available for both men and women. Prior to performing any permanent sterilization procedure, the physician must carefully counsel and determine whether a permanent method of contraception is appropriate for the patient. Reversal of permanent sterilization is costly and often ineffective. Permanent male sterilization via vasectomy is safe, effective with reported failure rates of 1.5 per 1000, and minimally invasive. For women, there are several permanent sterilization options. Most of the procedures for women are designed to occlude or remove the Fallopian tube via laparotomy or laparoscopy. These include Pomeroy, Irving, Uchida, and Madelener laparotomy operations in addition to laparoscopic procedures using unipolar or bipolar electrosurgical coagulation of the Fallopian tubes, application of Silastic bands or proprietary clips (Filshie clips, Hulka clips). Mini laparotomy for Pomeroy-type tubal occlusion is often utilized for postpartum sterilization. There are now a limited number of proprietary methods of transcervical tubal occlusion based on intrauterine access to the tubal ostia using a hysteroscope.
The observed failure rate for tubal ligation procedures ranges from 0.7% to 3.6%, which is comparable to the failure rate of IUD and subdermal implants.
SURGERY FOR MALIGNANT FALLOPIAN TUBE DISEASE
Benign and malignant tumors of the Fallopian tubes are very rare. Adenocarcinoma of the Fallopian tube accounts for less than 1% of female reproductive tract cancers. Women with BRCA1 and 2 mutations are at increased risk for Fallopian tube cancer concordant with their increased risk for ovarian cancer.
The most common presenting symptoms for cancer of the Fallopian tubes are postmenopausal vaginal bleeding or history of intermittent and profuse, watery vaginal discharge. The latter symptom is referred to as hydrops tubae perfluens. An adnexal mass is sometimes, but not always palpable. Tumor markers such as CA-125 are usually elevated, although early stage disease may result in elevation of the CA-125 in less than half of patients with Fallopian tube or ovarian cancers. The diagnosis of the Fallopian tube carcinoma is usually not made preoperatively.
The differential diagnosis for Fallopian tube cancer includes disorders that may result in enlargement or obstruction of the distal Fallopian tube. The most common example would be hydrosalpinx whereby obstruction of the Fallopian tube results in accumulation of fluid within the lumen and causes distension of the tube. Common causes of hydrosalpinx include prior infection or endometriosis. Another potential confounding diagnosis is the presence of paratubal cysts, which are simple cysts arising in the mesosalpinx or loosely attached to the exterior of the tube. Paratubal cysts are nearly always benign and arise from Müllerian and Wolffian duct remnants.
Fallopian tube cancer is staged using the FIGO staging rules for ovarian cancer.
Treatment for Fallopian tube cancer is identical to treatment for ovarian cancer. Multimodal therapy including a primary surgery for staging and debulking of disease is followed by adjuvant chemotherapy based on the stage and grade of the disease. A more detailed discussion of the surgery and postoperative adjuvant therapy considerations is described in the ovarian cancer section of this chapter. If the disease is confined to the tube, the prognosis is good. Like ovarian cancer, most Fallopian tube cancers are of advanced stage at the time of diagnosis, and the subsequent survival is much lower.
SURGERY FOR BENIGN OVARIAN DISEASE
Adnexal masses are abnormal structures arising in the ovary, Fallopian tube, or broad ligament. Preoperative assessment can narrow the differential diagnosis, but definitive diagnosis usually requires surgical resection or biopsy.
The differential diagnosis of adnexal masses is complex (Table 39–8). Every structure native to the pelvis can potentially present as a detectable adnexal mass. The majority is benign, but the probability of malignancy increases with age. About 10% of persistent adnexal masses attributable to the ovary are malignant in premenopausal women rising to nearly 50% in postmenopausal women.
Table 39–8.Differential diagnosis of adnexal masses. ||Download (.pdf) Table 39–8. Differential diagnosis of adnexal masses.
Fallopian Tube Etiology
Functional ovarian cyst
Corpus luteum cyst
Theca lutein cyst
Benign ovarian neoplasm
Mature cystic teratoma
Malignant ovarian neoplasm
Endodermal sinus (yolk sac)
Low malignant potential
Granulosa cell, adult
Granulosa cell, juvenile
Non-neoplastic Fallopian tube conditions
Paraovarian or paratubal cyst
Malignant Fallopian tube neoplasms
Diseases of appendix or colon
Diseases of bladder
Functional cysts are relatively common in reproductive age women, but are also reported in postmenopausal women. These cysts are usually larger than 3 cm in order to be diagnosed and may attain diameters of up to 10 cm. Histological examination reveals no pathologic features such as atypia, necrosis, or invasion. Follicular cysts produce estrogen until resolution of the cyst and the corpus luteum cyst produces progesterone until resolution. Because of the hormone production by these types of cysts, menses may be delayed or irregular, often leading to an incorrect clinical diagnosis of ectopic pregnancy. The least common type of functional cyst is the theca lutein cyst, which arises as a physiologic response to hyperstimulation by elevated β-hCG values produced by complete hydatidiform moles. Functional cysts usually regress spontaneously within 1-3 months, or in the case of theca lutein cysts, when the β-hCG value normalizes following treatment.
Correct identification of functional cysts prevents many unnecessary surgical procedures. The functional cyst is typically a smooth, unilateral cyst on pelvic examination. Transvaginal ultrasound will show a simple, sonolucent morphology and β-hCG is not elevated. Follow-up examination with ultrasound after 4-6 weeks will generally demonstrate resolution without treatment. About 85% of functional cysts smaller than 6 cm regress, but larger masses may be more likely to persist. Feedback inhibition on pituitary gonadotropin production by hormonal suppression with oral contraceptives may prevent development of additional functional cysts and are advocated by some clinicians to assist in the regression of existing cysts. Hormonal suppression is by no means required, however, since the majority of functional cysts will regress without intervention.
The majority of functional cysts remain asymptomatic, but they will occasionally rupture or undergo torsion resulting in acute colicky abdominal or flank pain. Torsion requires prompt surgical intervention, usually with laparoscopy, in order to restore the vascular supply to the ovary by untwisting the pedicle before significant ischemia or necrosis of the ovary can occur. If the functional cyst ruptures pain of varying levels may occur. In rare cases, bleeding from the ovary leads to hemodynamic instability requiring surgery. Hospitalization for observation for 24 hours, allowing serial examinations and blood counts is appropriate for patients with symptomatic cyst rupture.
Persistent Adnexal Masses
Adnexal masses that persist are likely to be neoplasms. Benign masses can generally be removed effectively by the general gynecologic surgeon, while malignancies are more effectively treated by gynecologic oncologists with expertise for surgical staging, debulking, and administration of adjuvant therapies to optimize outcome. Triage of adnexal masses provides the best opportunity to serve the patient’s interest by having the correct surgical team involved in care of the patient.
The most useful test for assessment of the newly diagnosed adnexal mass is transvaginal ultrasound. Ultrasound is particularly well suited for delineation of the morphologic features of adnexal masses. Medical literature abounds with description of morphology that correlates with benign and malignant neoplasms of the ovary. Figure 39–7 illustrates the morphologic features used to distinguish possible cancers from likely benign lesions. The reported sensitivity for identifying a malignant ovarian neoplasm is 90%-94%, but specificity is only about 60%. Specificity can be improved to about 85% without reducing sensitivity by evaluating Doppler waveforms in the tumor vessels. Vessels arising in malignant lesions have lower resistance to flow than in normal tissues: the ratio of diastolic to systolic flow is therefore higher than in normal tissue (Figure 39–8) and this can be quantitated by reporting the pulsatility index. This test is more specialized, costly and time consuming, limiting its effective use to selected lesions. MRI appears to have a promising role in the characterization of adnexal masses, but is much more costly than ultrasonography.
Differential diagnosis of adnexal masses by ultrasound morphology. (From Kawai M et al: Transvaginal Doppler ultrasound with color flow imaging in the diagnosis of ovarian cancer. Obstet Gynecol 1992;79:163.)
Doppler waveform and pulsatility index (PI) indicating the objective differences between perfusion in normal versus malignant tissue. If the ratio of 1/PI is greater 0.8, the likelihood of cancer is 96% (p < 0.01). The waveform on the right has high diastolic flow, and the pulsatility index is low, consistent with a cancer diagnosis. PI = (peak systolic flow – peak diastolic flow)/mean flow. (From Kawai M et al: Transvaginal Doppler ultrasound with color flow imaging in the diagnosis of ovarian cancer. Obstet Gynecol 1992;79:163.)
In addition to ultrasound, tumor markers can be very useful for triage of the palpable adnexal mass. The ideal tumor marker is elevated only in the presence of cancer and should correlate with the burden of disease. In reality, no marker is perfect. There are identified markers for ovarian malignancies arising from germ cell, epithelial and stromal origin. Optimal use of tumor markers involves ordering markers most likely to be clinically useful based on clinical presentation rather than to order all of them. Commonly used tumor markers are listed in Table 39–9. Many new markers will likely be validated in the next few years, including panels of multiple markers using gene chip technology. For example, malignant germ cell neoplasms usually arise in women younger than 35, are almost always unilateral, and typically demonstrate solid morphology on ultrasound evaluation. In this setting, it would be appropriate to order tumor markers including alpha fetoprotein (AFP), β-hCG, and lactate dehydrogenase (LDH). Epithelial tumors are more often complex cystic and solid, bilateral lesions. In this circumstance CA-125, CA-19-9 and CEA are better markers. Interpretation of CA-125 is difficult in premenopausal women because benign diseases such as endometriosis, which is much more common than ovarian cancer, will cause false positive test results. In addition, many tumor markers are normally elevated in pregnancy, thereby complicating evaluation of masses diagnosed during pregnancy.
Table 39–9.Tumor markers for ovarian cancer. ||Download (.pdf) Table 39–9. Tumor markers for ovarian cancer.
|Tumor Histology ||Commonly Used Serum Markers |
|Epithelial Tumors ||CA-125, CA-19-9, CEA, HE-4, OVA1 |
| Papillary serous || CA-125 |
| Endometrioid || CA-125, HE-4 |
| Mucinous || CA-19-9, CEA |
|Germ Cell Tumors ||AFP, β-hCG, lactate dehydrogenase (LDH) |
| Dysgerminoma || LDH |
| Endodermal sinus || AFP |
| Immature teratoma || None |
| Mixed type || AFP, β-hCG, lactate dehydrogenase (LDH) |
| Choriocarcinoma || β-HCG |
|Sex-Cord Stromal Tumors ||Testosterone, estradiol, inhibin A and B |
| Sertoli-Leydig || Testosterone |
| Granulosa cell || Estradiol, inhibin A and B |
The American College of Obstetricians and Gynecologists has issued a committee opinion regarding triage of adnexal masses that recommends referral of individuals with high-risk characteristics to gynecologic oncology subspecialists. For postmenopausal women, referral is warranted for patients with a pelvic mass and at least one of the following: CA-125 above 35 U/mL, ascites, nodular or fixed mass, evidence of abdominal or distant metastasis, or family history of one or more first-degree relatives with ovarian or breast cancer. In premenopausal women, the recommendations are identical except the threshold for CA-125 is raised to > 200 U/mL, to account for diseases such as endometriosis in this age group. Motivation for referral is based upon data showing higher staging accuracy and improved outcome when subspecialists treat ovarian cancer patients.
Low-risk masses thought to be functional cysts are managed expectantly. A mass that persists, or demonstrates worrisome features on exam, imaging studies or tumor marker measurement should be resected. A basic principle of surgical resection for ovarian neoplasms is not to allow spill or rupture of cyst contents into the abdomen. It is never appropriate to needle aspirate an ovarian mass that may harbor malignancy because of the potential to spread disease intra-abdominally. The surgical procedure to be performed is either oophorectomy or ovarian cystectomy for high-risk and low-risk lesions, respectively. The route of surgical approach may be either with laparoscopy or laparotomy. The laparoscopic approach is better suited for cystic masses that are small enough to be placed in a specimen retrieval bag without spill or rupture. Large or solid masses or evidence of metastatic disease such as ascites or omental caking require laparotomy for removal. Ovarian conservation is chosen after a balanced assessment of relative risk for cardiac disease versus ovarian cancer. In women with benign appearing masses under 60, they can expect some cardioprotective benefit even after menopause.
A simple cystic mass of less than 5 cm with normal CA-125 is considered low risk, even in the postmenopausal woman. Conservative management is reasonable.
SURGERY FOR MALIGNANT OVARIAN DISEASE
Ovarian cancer is stratified into three histological groups based on the cellular origin of the tumor. Epithelial tumors, germ cell tumors, and sex cord-stromal tumors comprise the primary lesions, and the fourth category is from disease arising elsewhere that metastasizes to ovary. Epithelial carcinoma accounts for about 85% of ovarian cancers, and about 5% arise from each of the remaining categories of germ cell, sex-cord stromal and metastatic disease from other sites. The peak incidence of epithelial ovarian cancer is in the fifth and sixth decades of life, while malignant germ cell tumors are more likely to occur under the age of 30. Stromal tumors have a bimodal distribution with peaks around ages 25 and 55 years of age. Malignant ovarian disease spreads by primary extension in the peritoneal cavity, in addition to lymphatic and hematogenous spread.
Epithelial ovarian cancer etiology can be either sporadic or hereditary. The sporadic cases appear to be strongly related to number of lifetime ovulations or chronicity of gonadotropin stimulation. There are also data to suggest environmental impact with the observation that tubal ligation results in reduction of risk, and diets with high lipids relative to omega-3 fatty acids increase risk. About 10% of ovarian cancers are hereditary. Three pedigrees account for most hereditary cases, including ovary-site specific, breast-ovary, and hereditary nonpolyposis colorectal cancer (HNPCC). Genetic inheritance of a mutation in the BRCA1 or BRCA2 gene imparts up to a 40% or a 25% lifetime risk of developing ovarian cancer, respectively. Ethnic groups including Ashkenazi Jews and Icelandic peoples have increased incidence of founder mutations that increase risk. Other reproductive factors associated with an increased risk include infertility, including use of ovulation induction agents. A recent discovery is that many if not the majority of epithelial cancers may arise in the fallopian tubes and subsequently spread to the ovaries.
Epithelial tumors are divided into invasive and low malignant potential (borderline) types. The invasive type accounts for 80% of epithelial cancer and is usually detected in advanced stages. The low malignant tumors occur in women with an average age 10-15 years younger than for invasive disease and up to 80% are stage I at diagnosis. Destructive stromal invasion is absent in low malignant potential tumors, but they are considered to be malignant and have the potential to metastasize. Epithelial tumors are subcategorized by histology as serous, mucinous, endometrioid, clear cell, transitional cell, or undifferentiated types. Serous tumors are the most common, comprising about 50% of epithelial carcinomas. Endometrioid carcinomas are the second most frequent variety, accounting for 24% of ovarian cancers, and are sometimes associated with endometriosis. Clear cell tumors, accounting for less than 5% of epithelial tumors, are also associated with endometriosis and have a more virulent natural history. Mucinous tumors account for 15% of epithelial cancers, and may become very large. Epithelial ovarian cancer is commonly involves both ovaries.
Germ cell cancer types include dysgerminomas, immature teratoma, endodermal sinus tumor, mixed types, and rare nongestational choriocarcinoma. Germ cell cancers are almost always unilateral and are commonly detected while stage I. Germ cell cancers are three time more common in women of Asian or African descent. A separate entity is adult-type cancer arising in an otherwise benign mature cystic teratoma. This can occur in up to 1% of mature cystic teratomas and is most commonly a squamous carcinoma.
The most common sex-cord stromal tumors include Sertoli-Leydig, adult granulosa, and juvenile granulosa cell tumors. These are frequently hormonally active tumors. Sertoli-Leydig cell tumors occur most often in the third decade, and arise from Wolffian duct remnants. They are rare and usually produce testosterone, resulting in manifest defeminization (amenorrhea, atrophy of the breast) and virilization (deepening of the voice, hirsutism, clitoral hypertrophy). Adult granulosa cell tumors arise in the sixth decade and are estrogen-producing tumors in most instances. Because of the estrogen production, postmenopausal bleeding is common, and endometrial cancer may arise in up to 15%. Juvenile granulosa cell tumors are similar, but arise in younger patients. Like germ cell tumors, the sex-cord stromal tumors are unilateral in most cases and detection is typically at early stages.
Metastatic carcinoma from other primary sites occurs not infrequently. Common sites include the gastrointestinal tract (Krukenberg tumor), breast, pancreas, lymphoma, and kidney. These tumors are classically solid, and bilateral. Prognosis for these tumors is especially poor.
Almost 90% of stage I patients have symptoms and only 5% are asymptomatic. The symptoms usually include gastrointestinal complaints that persist for an average of 12 days per month for 3 months. Less often, pelvic pain or metrorrhagia may be present. On examination, any mass should prompt further evaluation. An ovarian mass should be regarded as potentially malignant until proven otherwise. Smooth, mobile masses on exam indicate low risk and solid, irregular, or fixed pelvic masses are suggestive malignancy. Triage of the pelvic mass should include transvaginal pelvic ultrasound and selective tumor markers as described previously in the adnexal mass section of this chapter. It should be noted that CA-125 may be negative in half of early-stage ovarian cancers. If an ovarian malignancy is suspected preoperatively, referral to a gynecologic oncologist is recommended.
Occasionally, ovarian cancer is discovered during an operation for different indication or when triage has not been properly performed. If ascites, carcinomatosis, or papillary excrescences are noted, the tumor should be removed intact and submitted for frozen section. If cancer is diagnosed, a gynecologic or surgical oncologist should be consulted for surgical staging and debulking.
Ovarian cancer is staged surgically (Table 39–10). When a complex adnexal mass is to be removed the procedure should begin with obtaining washings for cytology, and the mass should subsequently be removed intact. Upon removal of the mass, a frozen section should be obtained for definitive diagnosis. If an ovarian malignancy is confirmed, complete staging requires assessment and biopsy of the pelvic and para-aortic nodes, omentum, and peritoneum. All peritoneal surfaces are inspected and any suspicious lesions are biopsied. If no suspicious lesions are noted, a predetermined pattern of biopsies is taken from the pelvic sidewalls, cul de sac, bladder peritoneum, pericolic gutters and both hemidiaphragms. A decision must be made about possible resection of the uterus and contralateral ovary. If the patient is young and desires to retain her fertility, criteria to identify candidates for conservation of fertility should be applied. Factors that favor preservation of fertility include germ cell and sex-cord stromal tumors because they are usually unilateral, and subsequent chemotherapy, if needed, has curative potential. Low malignant potential tumors affecting one ovary or in select cases where extra-ovarian disease can be completely resected are also candidates. Patients with invasive epithelial tumors are poor candidates for conservative surgery because of the high likelihood of bilateral involvement and the primarily palliative role of chemotherapy for all but early stages of disease. If preservation of fertility is not appropriate, then hysterectomy and removal of the contralateral tube and ovary is completed.
Table 39–10.FIGO staging for ovarian cancer. ||Download (.pdf) Table 39–10. FIGO staging for ovarian cancer.
|FIGO Staging ||Description ||TNM Class |
|Stage I ||Tumor limited to the ovaries ||T1 |
|IA ||Limited to one ovary, no tumor on external surface, capsule intact; negative peritoneal cytology ||T1a |
|IB ||Limited to both ovaries, no tumor on external surface, capsule intact; negative peritoneal cytology ||T1b |
|IC ||IA or IB tumor, but with surface tumor, ruptured capsule, or positive ascites or peritoneal cytology ||T1c |
|Stage II ||Tumor extending to the pelvis ||T2 |
|IIA ||Metastasis to the uterus or tubes ||T2 |
|IIB ||Metastasis to other pelvic tissues ||T2b |
|IIC ||IIA or IIB tumor, both with surface tumor, ruptured capsule, or positive ascites or peritoneal cytology ||T2c |
|Stage III ||Tumor extending outside the pelvis and/or retroperitoneal or inguinal nodes. Extension to small bowel, omentum, or superficial liver ||T3 and/or N1 |
|IIIA ||Histologically confirmed microscopic disease of abdominal peritoneal surfaces; lymph nodes negative ||T3a |
|IIIB ||Implants of abdominal or peritoneal surfaces not exceeding 2 cm in diameter; lymph nodes negative ||T3b |
|IIIC ||Implants of abdominal or peritoneal surfaces > 2 cm in diameter, or positive retroperitoneal or inguinal lymph nodes ||T3c and/or N1 |
|Stage IV ||Distant metastasis beyond the peritoneal cavity ||M1 |
When the disease spread into the pelvis or abdomen is documented, debulking of all resectable macroscopic disease is critically important. Numerous randomized clinical trials have demonstrated the concept of debulking and consistently show survival advantage for patients with maximal cytoreduction. Intraoperative decision making for debulking focuses effort on the biggest tumor, wherever it may be. If the largest lesion can be resected, attention is directed to the next largest lesion. This process continues until either all measurable disease is removed or a lesion that is unresectable is encountered. In order to resect the disease at each decision point of this algorithm, the surgeon may need to perform intestinal resection, splenectomy, modified posterior exenteration, culdotomy, diaphragm resection, and other upper abdominal procedures. In two prospective Gynecologic Oncology Group clinical trials survival for microscopically debulked ovarian cancer was 65% at 4 years, and fell to about 35% if less than 1 cm of macroscopic residual disease remained after surgery. If greater than 2 cm of residual disease remained, the 4-year survival was only 20%. Optimal debulking can be attained in up to 70% of patients who are operated on by subspecialists trained in ovarian cancer surgery.
Patients with stage IA grade 1 or grade 2 epithelial tumors have a very good prognosis and usually are not treated with additional chemotherapy. For more advanced stages of epithelial cancer, chemotherapy is very effective for inducing clinical remission but relapses are very common with an average progression interval between 2 and 3 years. The best chemotherapy combination for treating advanced stage epithelial cancer includes both taxane and platinum agents, administered either intravenously or intraperitoneally for at least six cycles. Intraperitoneal chemotherapy has been demonstrated to induce longer progression free intervals, but acute toxicity is much higher and only 40% of patients are able to complete planned therapy on this regimen. The CA-125 tumor marker is useful as a marker for assessing the effectiveness of therapy.
The best current regimen for malignant germ cell tumors is cisplatin, etoposide, and bleomycin, administered as a 3- or a 5-day treatment that is continued until at least one cycle after normalization of elevated tumor markers. Sex-cord stromal tumors are treated similarly.
The prognosis for epithelial ovarian carcinoma is related primarily to stage and histological grade. Because most ovarian cancers are of advanced stage at the time of initial diagnosis, the long-term survival rate for ovarian cancer is only 50%. Five-year survival rates for patients with stage III or stage IV disease are around 20%-35%. Prolonged disease-free intervals can be achieved by combining comprehensive surgical staging aggressive debulking and adjuvant chemotherapy.
Oral contraceptives reduce the risk of ovarian epithelial carcinoma. The magnitude of risk reduction is based on dose and duration of therapy. The protective effects are durable, lasting for a decade or more after discontinuation of the medication.
Any woman with a strong family history should be considered for genetic counseling and testing. For patients with a confirmed hereditary risk of ovarian cancer based on careful pedigree analysis or genetic testing will benefit from prophylactic removal of ovaries and Fallopian tubes. The current recommendation is for removal after completion of childbearing at age 35 or 10 years younger than the earliest incidence of disease in the family. Prophylactic removal of ovaries and tubes reduces the risk of ovarian cancer at least 95%, but a small number of individuals may still develop primary peritoneal carcinoma.
To date, no screening test for ovarian cancer has proven to be sufficiently sensitive or specific enough to have earned the recommendation of the US Preventive Services Task Force, ACOG, or the American Cancer Society. Prospective ultrasound screening studies and combined CA-125/ultrasound studies show a trend toward earlier stage at time of diagnosis on screened patients, resulting in prolongation of progression-free intervals, but not survival.
l-M: The origin and pathogenesis of ovarian cancer- a proposed unifying theory. Am J Surg Pathol 2010;34(3):433–443.
et al.: Rethinking ovarian cancer: Recommendations for improving outcomes. Nat Rev Cancer 2012;11(10):719–725.
SURGERY FOR MULTIORGAN DISEASE
Chronic pelvic pain is generally defined as 6-12 months of pain below the umbilicus producing a significant impact on quality of life. Evaluation and treatment of chronic pelvic pain accounts for up to 40% of all referrals to gynecologists, leading to up to 40% of all laparoscopies, and 12% of all hysterectomies.
The differential diagnosis chronic pelvic pain is complex. While many patients attribute their pain to a gynecologic cause, the physician must consider nongynecologic diagnoses of the gastrointestinal, urinary, and musculoskeletal systems in addition to psychological and psychosomatic problems. The most common nongynecologic diagnoses include irritable bowel syndrome, inflammatory bowel disease, nephrolithiasis, interstitial cystitis, ventral or inguinal hernia, muscle strain, nerve injury, depression, and somatization. Of note, patients are more likely to have suffered sexual assault as an adult or child.
The gynecologic causes of chronic pelvic pain are classified as cyclic or continuous in nature. Sources of cyclic pain include primary dysmenorrhea, defined as painful menses without identifiable pelvic pathology; and secondary dysmenorrhea attributable to pathologic conditions such as endometriosis or adenomyosis. Mid-cycle ovulatory pain may occur that produces unilateral pain at mid-cycle that resolves after a day or two. Continuous pain sources include endometriosis and adenomyosis, and pelvic organ prolapse, both discussed earlier in this chapter, in addition to chronic salpingitis, and pelvic adhesions. Another cause of continuous pain is ovarian remnant syndrome, which occurs when residual ovarian tissue after oophorectomy becomes retroperitoneal location. Pain may occasionally be caused by degenerating fibroids or by mass effect from large fibroids.
The pelvic examination requires careful communication with the patient to understand where and when her pain occurs. Identification of palpable abnormalities and localization of focal tenderness is important. If a pelvic mass is detected, it should be triaged as discussed previously in the adnexal mass section of this chapter. An abnormal pelvic examination has about an 80% predictive value for pelvic abnormalities noted at laparoscopy.
Nongynecologic causes of pain are treated according to the diagnosis. Gynecologic pain etiology is also treated according to the diagnosis. Reproductive-age women with cyclic pain are offered treatment consisting of nonsteroidal anti-inflammatory drugs and ovulation suppression, usually with oral contraceptives if appropriate for the age and medical risk factors of the patient. Continuous pain attributable to endometriosis or adenomyosis is treated similarly. Other causes of continuous pain include spasm or tension in pelvic floor musculature. Physical therapy and “reverse Kegel” exercises to relax the muscles often result in improvement. An antibiotic may be prescribed if a chronic infection is suspected, but care should be taken to treat documented infection and not to over prescribe antibiotics. Concurrent depression is common, usually arising as a secondary effect of the pain rather than as the primary etiology. Treatment with antidepressant medication is often beneficial. The tricyclic antidepressant class is often more effective that serotonin reuptake inhibitors for this indication. Severe and refractory pain may require prescribing of narcotics to attain control. The physician must use careful judgment regarding initiation of narcotics in a chronic setting due to the potential for dependence and addiction. It is often useful to manage these patients with a narcotic contract between the patient and her physician to regulate drug use. Referral to a multidisciplinary pain service is often useful for difficult or refractory cases.
If the pain is refractory to medical management or if the physical examination is abnormal, then diagnostic laparoscopy is indicated. During the laparoscopic procedure, upper abdominal structures, pelvic organs and peritoneum, appendix, rectum, and sigmoid colon are carefully inspected. The most commonly identified pathology is endometriosis occurring in one-third of patients and adhesions in one third of cases. Most of the remaining cases will have no identified pathology. The presence of abnormalities may not explain the pain, and treatment of disease such as endometriosis may not resolve the pain.
The evidence for therapeutic benefit of laparoscopy for treatment of pelvic pain is tenuous, at best. Procedures that remove or ablate adhesions, endometriosis may or may not relieve pain. If pain is attributed to the uterus or cervix and cannot be controlled with lesser procedures or medical management, options include hysterectomy, or if fertility preservation is desired, interruption of the autonomic nerve tracts with a presacral neurectomy. Pain attributed to degenerating or large fibroids may be relieved either with uterine artery embolization procedures or surgical removal of the leiomyomata with either hysterectomy or myomectomy. Severe dysmenorrhea that is refractory to medical management may be significantly improved with endometrial ablation.
Published data indicate that laparoscopic treatment will produce a short-term reduction of pain in about 60%-80% of patients, but long-term benefits are not well documented. In patients who have completed their childbearing or who wish definitive treatment, hysterectomy has reported success rates of up to 95% if uterine pathology such as degenerating fibroids is present. If no pelvic pathology is noted, 50%-91% experience improvement. The success rate is poor if the patient has symptoms of depression. Patients with endometriosis should also be offered bilateral salpingo-oophorectomy to minimize pain from residual implants.
Endometriosis is defined as extrauterine, functional endometrial tissue. The most common sites include ovaries, uterosacral ligaments, and the cul-de-sac. Less commonly, Fallopian tubes, uterine serosa, sigmoid colon and rectum, peritoneum, and small intestine or mesentery are involved. Ectopic endometrium is occasionally detected at distant sites including lung, lymph nodes, surgical incision sites, umbilicus, perineum, and breasts.
The etiology of endometriosis is thought to occur any of three potential mechanisms: (1) retrograde menstruation with implantation; (2) metaplasia of Müllerian duct remnants or coelomic epithelium; and (3) lymphatic or venous dissemination. Retrograde menstruation through the uterine tubes is common and yet rarely causes endometriosis. It is not known what factors contribute to implantation and growth of endometriosis. Uterine outflow obstruction from cervical stenosis or congenital anomalies such as imperforate hymen increases the likelihood of developing endometriosis.
Endometriosis may develop at any time after onset of menarche and will virtually regress after menopause. Prevalence of endometriosis is difficult to determine because many women with the disease are asymptomatic. The estimated prevalence of endometriosis is about 15%-20%. Endometriosis may cause scarring that impairs fertility. As a consequence, diagnosis of endometriosis during a workup for infertility is higher, with up to 20%-47% of patients affected. Conversely, in women with proven fertility who elect tubal sterilization are found to have endometriosis on only 1%-5% of cases. The incidence of endometriosis is higher in women who choose to delay childbearing, or in women with a family history of the disease. There may be environmental toxins that predispose to endometriosis, such as dioxin. Pregnancy and hormonal contraceptive hormones are protective.
Carcinoma may arise in endometriosis at any site and is most commonly of endometrioid histology. Clear cell carcinoma is rare and more aggressive.
An anatomic staging system for endometriosis has been developed by the American Society of Reproductive Medicine (Figure 39–9.) The Revised AFS classification system is accepted worldwide. The staging system is broadly predictive of outcome with treatment. The stage of endometriosis does not correlate well with pain symptoms. Alternate systems that recognize the varied presentation of endometriosis in addition to development of serum markers have been proposed.
Staging of endometriosis. (American Society for Reproductive Medicine: Revised American Society for Reproductive Medicine classification of endometriosis. Fertil Steril 1997;67:817.)
Endometriosis frequently causes pain. The pain often begins shortly before menses and continues during menstruation. The presence of pain and its severity is highly variable. Some patients with extensive disease are asymptomatic, while others with small peritoneal implants may be incapacitated. Unexplained infertility may be present in asymptomatic endometriosis. Symptoms may occur at any time during reproductive years, but are most common in the third and fourth decades of life. Symptoms usually resolve with menopause unless the patient is prescribed a hormone replacement regimen. Patients may also complain of dyspareunia, tenesmus, back pain, or sciatica. Rare manifestations may include ureteral obstruction or bowel obstruction.
Bimanual pelvic examination including the rectovaginal examination should be performed. Common findings include pelvic tenderness, adnexal masses, and soft nodularity in the cul de sac or along the uterosacral ligaments. Adnexal masses attributable to endometriosis are often bilateral and are frequently immobile due to adhesions along the posterior broad ligament.
Ultrasound description of isoechoic masses within the ovaries is highly suggestive of endometrioma. Serum concentrations of CA-125 are elevated above 35 U/mL in about one-third of patients with advanced disease, which complicates triage of adnexal masses that may be either benign (endometriosis) or malignant. Following surgical and medical treatment, measurement of the CA-125 trend is a useful marker of treatment efficacy and disease recurrence similar to how the marker is used for monitoring treatment of ovarian cancer.
Definitive diagnosis requires biopsy, usually obtained with a laparoscopic procedure. The biopsy diagnosis requires the presence of both glands and stroma. Location and extent of disease is noted at the time of surgery to complete disease staging. Characteristic peritoneal implants include the so called “powder-burn” marks of darkly colored endometrium, in addition to red, blue, and white lesions. Peritoneal disease may be flat or raised, including nodular or vesicular appearance. Laparotomy is occasionally necessary for large ovarian masses, or bowel and ureteral obstructions that may be present.
Treatment should be tailored to severity of symptoms, age of the patient, desire for fertility, and the stage of disease. The range of therapeutic options includes observation, medical management with hormones and analgesics, up to hysterectomy with bilateral salpingo-oophorectomy. A conservative approach is preferred for patients with minimal symptoms or minimal measurable disease on pelvic exam. Surveillance examinations should be regularly performed, with the interval determined by severity of symptoms, age of the patient, desire for fertility, and the stage of disease. If symptoms or physical finding worsen, the management plan may be changed accordingly.
The goal of medical therapy is to control disease by inducing a remission. There are no known medical therapies that result in a cure. Hormonal therapy is not administered for patients actively attempting to conceive. Upon treatment discontinuation, symptoms commonly recur. Long-term suppression with hormonal contraceptive regimens should be considered.
Norethynodrel, norethindrone acetate, and medroxyprogesterone acetate are commonly used. Continuous progestins induce amenorrhea resulting in decreased symptoms in more than three quarters of patients. Progestin therapy causes downregulation of estrogen receptors in endometrial tissue, resulting in atrophic change in both endometriosis and endometrium. Breakthrough bleeding is not unusual. Side effects include weight gain secondary to appetite stimulation, fluid retention, headaches, and mood swings.
Oral contraceptives with a low estrogen dose and a high potency progestin are preferred and may be administered either as cyclic or as continuous regimens without withdrawal intervals each month. Symptoms are relieved in up to 80% of patients. Oral contraceptive may be continued long term as a maintenance therapy in healthy women. Women over 35 who smoke or individuals with hypertension are at increased risk of thromboembolic complications. Side effects include headaches, fluid retention, breast tenderness, breakthrough bleeding, and occasional nausea.
GnRH analogs act by negative feedback inhibition on the pituitary resulting in prevention of FSH and LH secretion. The consequence of low gonadotropin levels is absence of follicle development and low estrogen production. This treatment strategy induces the medical equivalent of the postmenopausal state. Endometrial implants atrophy in the hypoestrogenic environment and about 80% of patients report clinical improvement. Side effects mimic menopause with vasomotor symptoms, vaginal dryness, and mood swings. Long-term treatment causes osteopenia and osteoporosis. To prevent bone loss, “add-back” therapy with either norethindrone acetate or combined hormone replacement therapy concurrent with GnRH analog may be prescribed and does not interfere with treatment of the endometriosis.
Indications for surgery include treatment of current infertility, treatment to preserve future fertility, or control of symptoms. Medical therapy is unlikely to result in reduction of symptoms for bulky disease, and surgery is recommended for any endometrioma larger than 4 cm. Options for preservation of fertility in symptomatic women who have failed medical therapy include laparoscopic procedures for resection or ablation of implants, lysis of adhesions, or presacral neurectomy. When definitive therapy is necessary and preservation of fertility is not an issue, total hysterectomy and bilateral salpingo-oophorectomy is indicated. Endometriosis is dependent upon estrogen. Preservation of an ovary in this setting causes symptoms sufficient to prompts additional surgery in 20% of cases. Bowel implants can be locally resected by appropriately trained surgeons.
Postoperative estrogen replacement therapy usually does not lead to exacerbation of endometriosis. The use of estrogen-progestin combinations is generally not required.
LC: Clinical practice: endometriosis. N Engl J Med 2010;362(25):2389–2398.