2005 © Oxford University Press
Fertility-Sparing Surgery for Malignancies in Women
Correspondence to: David M. Gershenson, MD, Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center–Unit 1362, P.O. Box 301439, Houston, TX 77230–1439 (e-mail: dgershen{at}mdanderson.org).
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ABSTRACT |
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 Top Abstract IntroductionGENERAL CONSIDERATIONSOVARIAN CANCERCERVICAL CANCERENDOMETRIAL HYPERPLASIA AND...References |
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Never before have women with newly diagnosed gynecologic malignancies had more options for preservation of fertility. Girls or women of childbearing age with several ovarian cancer subtypes have a high probability of unilateral ovarian involvement, and, thus, may be candidates for fertility-sparing surgery with preservation of a contralateral normal ovary and uterus. These subtypes include ovarian tumors of low malignant potential, malignant ovarian germ cell tumors, and ovarian sex cord-stromal tumors. For women with invasive epithelial ovarian cancer who have early-stage disease, fertility-sparing surgery may be an option. In some cases, fertility-sparing surgery may be followed by postoperative chemotherapy. For women with invasive cervical cancer, fertility-sparing surgery may be possible. Options include conization alone for stage IA1 or IA2 disease, radical trachelectomy with stage IA2 or IB disease, or ovarian transposition for women undergoing chemoradiation. Non-operative options, such as hormonal therapy, may be considered for women with early-stage, low-grade endometrial cancer. For all women of childbearing age with gynecologic malignancies, in vitro fertilization techniques or cryopreservation of ovarian tissue may be an option prior to definitive treatment.
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INTRODUCTION |
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TopAbstractIntroductionGENERAL CONSIDERATIONSOVARIAN CANCERCERVICAL CANCERENDOMETRIAL HYPERPLASIA AND...References |
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Although gynecologic cancers generally affect older women, a significant subset of women is of childbearing age. Never before have younger women with gynecologic malignancies had more options for preservation of fertility. This current status is based principally on our incremental understanding of the biologic behavior—histopathology, prognostic factors, epidemiology, molecular biology, and natural history—of all gynecologic cancers over the past few decades.
This enhanced understanding has been accompanied by therapeutic advances, including improvements in surgical management. Fertility-sparing surgery may be one of the options available to girls and young women with newly diagnosed gynecologic cancers. This article will discuss these fertility-sparing surgical procedures and the considerations surrounding their appropriate selection for patients.
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GENERAL CONSIDERATIONS |
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TopAbstractIntroductionGENERAL CONSIDERATIONSOVARIAN CANCERCERVICAL CANCERENDOMETRIAL HYPERPLASIA AND...References |
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There are several key factors that influence the recommendation for and performance of fertility-sparing surgery. First of all, there must be a desire on the part of the patient, or, in the case of a child, her parents, to retain fertility potential, if possible. Of course, gynecologic cancers principally affect women beyond the childbearing years. And even for women of childbearing age, it is frequently not possible to preserve fertility in providing optimal cancer care. Factors that will impact the patient's desire to preserve fertility and the physician's recommendation include her age, obstetrical history, family history, a history of infertility, and the cause of infertility, if known.
Ideally, fertility potential can be preserved, when appropriate, without compromising curability. The extent of the patient's cancer is a major determinant of whether fertility-sparing surgery should be recommended. Thus, optimal cancer therapy should always supersede fertility preservation as a primary objective.
In considering the option of fertility-sparing treatment for girls or young women with gynecologic malignancies, the physician must articulate the standard therapy for the patient's condition. Any deviation from the standard treatment with the objective of preserving fertility must be discussed in the context of associated risk.
Unfortunately, there are several instances in which fertility preservation is not discussed with the patient and her family. Particularly with regard to the clinical management of ovarian masses, initial surgical treatment may be rendered by a non-oncologist who does not possess the expertise necessary to appropriately counsel the patient. Expertise of a gynecologic oncologist and gynecologic pathologist is critical in optimizing a patient's potential for fertility preservation; however, such experts may not always be available in the community. It is therefore of utmost importance that patients wishing to preserve fertility be directed to the physician or center with the most experience and expertise.
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OVARIAN CANCER |
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TopAbstractIntroductionGENERAL CONSIDERATIONSOVARIAN CANCERCERVICAL CANCERENDOMETRIAL HYPERPLASIA AND...References |
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Ovarian cancer accounts for approximately 26 000 cases annually in the United States (1). Ovarian cancer is not one but several different malignancies. While the vast majority of ovarian cancers are of advanced stage and occur in postmenopausal women, a significant subset—approximately 15%—occur in girls or younger women; some of these patients will be candidates for fertility-sparing surgery. Subcategories of patients who might be appropriate for such management include those with malignant germ cell tumors, sex cord-stromal tumors, tumors of low malignant potential, and stage IA invasive epithelial ovarian cancer. The types of surgical procedures that would constitute fertility-sparing surgery for an ovarian malignancy include ovarian cystectomy, unilateral salpingo-oophorectomy, unilateral salpingo-oophorectomy plus hysterectomy (with preservation of the contralateral ovary), and bilateral salpingo-oophorectomy (with preservation of the uterus). Of course, after the latter two procedures, assisted reproductive technology (ART) would be necessary to achieve a pregnancy. In all cases, these procedures should be performed in conjunction with comprehensive surgical staging.
Malignant ovarian germ cell tumors comprise approximately 5% of all ovarian malignancies. They typically occur in girls and young women, with an average age during the teenage years. With the exception of dysgerminoma, which is bilateral in 15% of cases, they are almost always unilateral. Furthermore, approximately 60% are stage I (confined to the ovary). In about 10% of cases, a concomitant benign cystic teratoma is present in the ipsilateral or contralateral ovary, but this can be managed with ovarian cystectomy. Thus, the surgical management of these tumors can usually consist of unilateral salpingo-oophorectomy plus surgical staging. In the case of bilateral ovarian dysgerminomas, standard management consists of bilateral salpingo-oophorectomy, but bilateral ovarian cystectomies or unilateral salpingo-oophorectomy plus ovarian cystectomy has been performed in an attempt to preserve a portion of a normal ovary. One caveat with regard to this practice is that, in a small percentage of patients with this diagnosis, dysgenetic gonads are present; this condition is frequently associated with the presence of a Y chromosome, and bilateral adnexectomy is necessary because of the risk of future malignancies. In any case, these latter patients are infertile.
Except for stage I dysgerminoma and stage IA, grade 1 immature teratoma, the current standard practice calls for postoperative chemotherapy consisting of the combination of bleomycin, etoposide, and cisplatin (BEP). In addition, the treatment of other tumor types within this category—high-grade immature teratoma, yolk sac tumor, and embryonal carcinoma—with surgery alone is currently under investigation. If chemotherapy is administered, there is a risk of ovarian failure up to approximately 30% (2–7). Additional patients will subsequently develop premature menopause. However, most patients with malignant germ cell tumors may be treated with fertility-sparing surgery followed by chemotherapy with preservation of fertility potential. Because the cure rates approach 100% for those with early-stage disease and are 75%+ for patients with advanced-stage disease, the opportunity for future childbearing is excellent. Table 1 presents the outcomes of six large studies in terms of ovarian function and pregnancies following definitive treatment (2–7). As noted, several successful pregnancies have been reported after primary surgery plus combination chemotherapy.
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Sex cord-stromal tumors of the ovary, although most commonly observed in postmenopausal women, may occur at any age. The most common cell type is granulosa cell tumor, which generally has an indolent course even if it recurs. Approximately 95% of granulosa cell tumors are unilateral, and up to 95% are stage I. Adult granulosa cell tumor has an excellent prognosis, but relapse may occur in approximately 10%–15% of patients. Late relapse has been reported not uncommonly. Juvenile granulosa cell tumor is a neoplasm histologically distinct from the more common adult type (8,9). It is characterized by young age at diagnosis (approximately 80% are diagnosed before age 20), high frequency of hormonal manifestations, and an excellent prognosis, with approximately 90% survival. However, for patients who relapse, they generally do so within 2–3 years and have a poor prognosis.
Thus, fertility-sparing surgery is possible in a high percentage of young patients. For patients with primary advanced disease or recurrent disease, platinum-based chemotherapy is the most common treatment. However, there is no consensus about standard therapy. Because of the rarity of this tumor type, subsequent pregnancies have been documented only in case reports and small series (10,11).
Ovarian tumors of low malignant potential account for 10%–15% of all epithelial tumors. Although considered to have the potential for metastatic spread, these tumors have an excellent prognosis, with a 10-year survival of approximately 90% (12). The most common cell type is serous, with mucinous tumors being the second most common type. The median age is 15–20 years younger than that for invasive epithelial ovarian tumors. Approximately 50% of serous tumors and 80%–90% of mucinous tumors are unilateral, and 60% and 90% are stage I, respectively. Fertility-sparing surgery with unilateral salpingo-oophorectomy or ovarian cystectomy, or, in the case of bilateral tumors, some combination thereof, is possible in a high proportion of young patients. Several series have documented successful pregnancies after treatment for ovarian tumors of low malignant potential (Table 2) (13–17).
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Invasive epithelial ovarian cancer is generally a disease of postmenopausal women, and, because of the lack of effective screening methods, over 70% are diagnosed after the cancer has already spread beyond the ovary. Approximately 25% of tumors are stage I, and this early-stage disease is associated with a 5-year survival rate approaching 90%. Thus, fertility-sparing surgery in combination with comprehensive surgical staging may be performed in selected young patients with apparent disease confined to one ovary (stage IA). Even with stage IA disease, postoperative platinum-based chemotherapy is recommended for those patients with high-risk factors. Successful pregnancies have been reported in patients after treatment for early-stage invasive ovarian cancer (Table 3) (18–23). However, there is a risk of relapse. When relapse occurs in the residual ovary alone, salvage treatment may result in cure. On the other hand, if disseminated recurrence with peritoneal carcinomatosis is observed, cure is uncommon.
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Approximately 10% of women with ovarian cancer have hereditary ovarian cancer. Special consideration should be given to young women with early-stage invasive ovarian cancer who may have high-risk factors (family history of ovarian or breast cancer, personal history of breast cancer, etc.). If such a patient does undergo fertility-sparing surgery, genetic counseling and possible genetic testing should be considered. If a BRCA1 or BRCA2 mutation is detected, then the patient should be counseled regarding prophylactic mastectomy and subsequent salpingo-oophorectomy plus or minus hysterectomy once childbearing is completed or in the event of persistent infertility. If BRCA status is known prior to primary surgery for ovarian cancer—a rare phenomenon—the risks and benefits of preserving a normal contralateral ovary should be discussed preoperatively.
In addition, for women with ovarian tumors of low malignant potential or invasive ovarian cancer, if ART is recommended for infertility following primary treatment, the patient should be counseled regarding the potential associated benefits and risks. Although earlier studies suggested an increased risk for ovarian cancer associated with the use of clomiphene or gonadotropins (24,25), more recent studies have not confirmed such a link (26). However, further studies are needed to clarify this issue.
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CERVICAL CANCER |
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TopAbstractIntroductionGENERAL CONSIDERATIONSOVARIAN CANCERCERVICAL CANCERENDOMETRIAL HYPERPLASIA AND...References |
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Approximately 10 500 women are diagnosed with cervical cancer annually in the United States (1). Globally, however, cervical cancer remains a major health problem, with almost 400 000 cases annually and an annual death rate of almost 200 000. Standard treatment for cervical cancer consists of either surgery—radical hysterectomy + bilateral pelvic lymphadenectomy—or radiotherapy for early-stage disease, and chemoradiation for advanced disease. Again, however, there are several options for clinical management that involve fertility preservation. These options include cervical conization, radical trachelectomy, retention of ovaries at radical hysterectomy, or ovarian transposition—either at the time of radical surgery or prior to definitive chemoradiation. In addition, in vitro fertilization techniques may be employed prior to definitive therapy if time delays are not significant.
Cervical conization is generally reserved for young patients who wish to preserve fertility and have stage IA1 disease (stromal invasion 
3 mm and horizontal extension 7 mm) (27–29). Lymph node metastasis or recurrence risk is quite low, in the range of only 1%. Recent reports suggest that this form of fertility-sparing surgery may be equally applicable to patients with both squamous carcinoma and adenocarcinoma. In avoiding more radical treatment, it is imperative that the margins of the cone specimen be negative.
Radical trachelectomy is a relatively new surgical technique that may be recommended for young patients with stage IA1 with positive lymph-vascular space involvement, stage IA2, or stage IB1. The procedure may be performed using either a vaginal or abdominal approach and is most commonly combined with an initial laparoscopic lymph node assessment. To date, this procedure is available only in a few centers; this is related to the learning curve necessary to develop the appropriate skills. Several large series have been reported, with a number of successful pregnancies following radical trachelectomy (Table 4) (30–34). It should be noted, however, that there have been a few recurrences and deaths reported. In the 5 large studies reported to date, there were 11 relapses and 7 deaths among 277 patients who underwent radical trachelectomy (30–34). In addition, although the first trimester pregnancy loss rate of 17% following radical trachelectomy appears to be similar to the general population, the second trimester pregnancy loss rate of 12% is higher than expected (35). Typically, following resection of the cervix and paracervical tissue, a cerclage is placed in an attempt to prevent preterm labor or pregnancy loss. This cerclage is usually permanent, necessitating a cesarean delivery. Thus, it is important that potential candidates for the procedure fully understand the associated risks.
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Ovarian transposition is a procedure in which the ovaries with their attached blood supply are surgically detached from the uterus and transposed to an area outside the planned radiation field, generally in the paracolic gutters above the pelvis. The purpose of this procedure is to place the ovaries outside the radiation field to preserve normal ovarian function for potential future in vitro fertilization techniques. The two principal settings for performance of this procedure are as follows: 1) at the time of radical hysterectomy, in case postoperative chemoradiation will be recommended based on poor prognostic histopathologic factors, or 2) prior to definitive pelvic radiation or chemoradiation. Currently, the procedure is usually performed laparoscopically when it is done prior to definitive chemoradiation. Unfortunately, reported series of the technique document an approximate 25% rate of subsequent benign ovarian cysts (not infrequently necessitating further surgery), and a 50% incidence of ovarian failure, most likely related to ischemia (36–39). In addition, a small percentage of patients, most commonly those with cervical adenocarcinoma, will have occult metastatic cervical cancer in the ovaries, usually resulting in subsequent relapse and death. Thus, the problems and sequelae associated with ovarian transposition have made it less appealing in recent years.
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ENDOMETRIAL HYPERPLASIA AND ENDOMETRIAL CANCER |
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TopAbstractIntroductionGENERAL CONSIDERATIONSOVARIAN CANCERCERVICAL CANCERENDOMETRIAL HYPERPLASIA AND...References |
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Complex atypical hyperplasia of the endometrium is a precursor to endometrial cancer. This condition is generally diagnosed by office endometrial biopsy or curettage in a woman who presents with abnormal uterine bleeding. Kurman et al. reported that 29% of women with complex atypical hyperplasia progressed to endometrial cancer (40). In addition, the risk of concomitant endometrial cancer in hysterectomy specimens from women with the preoperative diagnosis of complex atypical hyperplasia is up to 25% (41–43). Although the standard treatment for women with complex atypical hyperplasia is hysterectomy, non-surgical treatment in the form of hormonal therapy may be recommended for young women who have not completed childbearing. The most popular regimens include medroxyprogesterone acetate 20–40 mg/day for 14 days monthly, megestrol acetate 40–160 mg daily, or a gonadotropin-releasing hormone agonist such as leuprolide acetate. Initially, endometrial sampling should be performed after 3 months to assess the effects of hormonal therapy.
Approximately 40 000 women are diagnosed with endometrial cancer annually in the United States (1). Although the median age of patients with this neoplasm is in the early 60s, approximately 5% of patients are younger than age 40 when diagnosed. Standard treatment consists of hysterectomy and bilateral salpingo-oophorectomy plus surgical staging. Although there is no known fertility-sparing surgical option for women with endometrial cancer, selected young patients who wish to preserve fertility may consider treatment with progestin therapy (as described above) rather than surgery. The optimal candidate for medical treatment is a woman of childbearing age who has an apparent early lesion—stage IA, grade 1 adenocarcinoma. If such treatment is contemplated, it is recommended that a thorough hysteroscopy and curettage be performed to rule out a worse lesion prior to initiation. A review of the literature indicates 101 patients with a median age of 29 years who were treated with progestin therapy rather than definitive surgery subsequently had 56 children (44).
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