help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 10, No. 8, 613-622, September 2005; doi:10.1634/theoncologist.10-8-613
© 2005 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leitao, M. M.
Right arrow Articles by Chi, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leitao, M. M., Jr
Right arrow Articles by Chi, D. S.

Fertility-Sparing Options for Patients with Gynecologic Malignancies

Mario M. Leitao, Jra, Dennis S. Chib

a Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Women’s Health, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA; b Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Correspondence: Dennis S. Chi, M.D., Memorial Sloan-Kettering Cancer Center Gynecology Service, Department of Surgery, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-5016; Fax: 212-717-3214; e-mail: chid{at}mskcc.org


   LEARNING OBJECTIVES
Top
 Learning objectives
Abstract
 Introduction
 Ovarian transposition
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
 Summary
 Disclosure of potential...
 References
 
After completing this course, the reader will be able to:

  1. Describe the options available for women with gynecologic malignancies that will allow the preservation of fertility.
  2. Identify women with gynerologic malignancies who might be eligible for fertility-sparing alternatives.
  3. Discuss the limited data supporting these novel fertility-sparing options.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning objectives
 Abstract
Introduction
 Ovarian transposition
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
 Summary
 Disclosure of potential...
 References
 
Gynecologic malignancies are most often diagnosed in postmenopausal women, but these malignancies also arise in premenopausal women, in whom issues of fertility can be a major concern. An increasing number of women are delaying childbearing. This has led to a significant increase in the number of women diagnosed with a gynecologic malignancy before desired completion of childbearing. Many of the standard treatments for these malignancies result in permanent sterility; however, there are now options for select young women who desire to preserve fertility. Patients should be told that data on fertility-sparing procedures are limited and that many of these options are of an experimental, nonstandard nature. The care of these patients is challenging and complex and requires a multidisciplinary approach, which should include gynecologic oncologists, reproductive endocrinologists, and perinatologists.

Key Words. Fertility-sparing • Ovarian cancer • Cervical cancer • Endometrial cancer • Radical vaginal trachelectomy • Ovarian transposition


   INTRODUCTION
Top
 Learning objectives
 Abstract
 Introduction
Ovarian transposition
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
 Summary
 Disclosure of potential...
 References
 
In 2005, there will be an estimated 79,480 newly diagnosed cancers of the female genital system in the U.S.; approximately 28,910 women will die of these types of disease [1]. The most common malignancies will be endometrial, ovarian, and cervical cancers, all with median ages of diagnosis in the postmenopausal years [1]. However, many premenopausal women will also be diagnosed with these malignancies. Endometrial cancers are rarely found in women younger than 25 years old, but the incidence is 1.2–24 per 100,000 in women aged 25–49 years [2]. The incidence of cervical cancer is 1.5–14.9 per 100,000 in women aged 20–49 years [2]. The incidence of ovarian cancer in adolescents less than 20 years old is 0.7–1.4 per 100,000, with the majority of these being germ cell or sex cord–stromal tumors instead of carcinomas [2, 3]; and the incidence rate of ovarian cancer in women aged 20–49 years is 1.6–16.6 per 100,000 [2] (Table 1Go). The treatment of these malignancies, including radical pelvic surgery and/or pelvic radiation therapy, often leads to permanent sterility and infertility.


View this table:
[in this window]
[in a new window]
  		Table 1. Surveillance, Epidemiology, and End Results data: age-specific incidence of gynecologic cancers, 1997–2001
 
From 1970 to 2000 the mean age of first-time mothers increased by 3.5 years (21.4–24.9 years) [4]. Among women aged 30–34, 35–39, and 40–44 years, 28.4, 10.4, and 2.0 of 1,000, respectively, will deliver their first child [5]. Many young women diagnosed with a gynecologic malignancy will be cured and survive for many years as a result of recent advances and improvements in cancer therapy. This has led to an increasingly challenging situation, with many more nulliparous women who have been diagnosed and treated for gynecologic malignancies desiring the retention of fertility.

There are now some options for young women diagnosed with gynecologic malignancies who wish to maintain their ovarian function and fertility. Patients need to understand that there are limited data regarding many of these options and that they are not considered "standard" therapeutic approaches in many cases. Patients must be extensively counseled and be aware that they are assuming a small but undefined risk. They must also be extremely compliant with the prescribed follow-up care.

Close collaboration with gynecologic oncologists, reproductive endocrinologists, and perinatologists is essential. Patients need to be assessed for the realistic probabilities of achieving conception based on their age, history, and infertility evaluation. In addition, many patients will require assisted reproductive technologies (ARTs) to help achieve a pregnancy, especially in vitro fertilization (IVF). Patients may also consider ovarian tissue, oocyte, or embryo cryopreservation prior to definitive cancer therapies. The ART aspect of fertility preservation is not discussed in this review. Patients also need to understand the risk of premature delivery and the consequences of prematurity. We focus on the options and alternatives to the traditional and standard radical surgical approaches for gynecologic malignancies.


   OVARIAN TRANSPOSITION
Top
 Learning objectives
 Abstract
 Introduction
 Ovarian transposition
Cervical cancer
 Endometrial cancer
 Ovarian cancer
 Summary
 Disclosure of potential...
 References
 
The ovaries are one of the most radiosensitive organs in the body. The degree of ovarian damage depends on radiation doses and fields, as well as patient age. In women less than 40 years old, doses greater than 20 Gy induce permanent ovarian failure, compared with only 6 Gy in older women [6]. A dose of approximately 50 Gy given externally via teletherapy is typically recommended for the treatment of the common gynecologic malignancies that require radiation therapy.

Ovarian transposition outside the pelvis was proposed more than 40 years ago as a way to preserve ovarian tissue in patients with cervical cancer treated with radical surgery and radiation therapy [7]. Some authors consider this procedure to be underused; others question its use altogether. Anderson et al. concluded that this procedure should not be considered in women undergoing radical hysterectomy for cervical cancer and who would likely require postoperative radiation therapy [8]. They reported that ovarian function was preserved in only 4 (33%) of 12 surviving patients who had ovarian transposition and went on to receive postoperative radiation therapy. In addition, ovarian function was lost in 33 (35%) of 51 surviving patients who did not receive any further therapy, and 14% of those patients developed ovarian cysts. A unilateral ovarian transposition was performed in nearly 80% of the 82 patients who underwent the procedure. The site of transposition was at the level of the inferior pole of the kidney and posterior to either the cecum or sigmoid colon. Subsequent series of mainly bilateral transposition into the paracolic gutters report much better rates of ovarian function preservation, including future pregnancy [9–16].

In the largest series of ovarian transposition at the time of radical hysterectomy for cervical cancer, ovarian function was preserved in 79 (83%) of 95 patients [10]. Preservation of function was affected by the use of postoperative radiation therapy. Ovarian function was preserved in all 11 patients who required no further therapy and in 90% (53/59) of those who received intravaginal brachytherapy alone, compared with 60% (15/25) in those who received both external-beam teletherapy and intravaginal brachytherapy. Ovarian transposition was bilateral in 97% (104/107) of the cases. The ovaries were transposed just above the pelvic brim in the paracolic gutters. Benign ovarian cysts developed in 22 (23%) of the 95 patients but led to a surgical procedure in only three cases.

Ovarian transposition has traditionally been performed via laparotomy but can be safely and effectively completed laparoscopically [9, 11–13]. Morice et al. noted preservation of ovarian function in 15 (79%) of 19 patients who underwent laparoscopic bilateral ovarian transposition and received postoperative therapy [9]. This was confirmed in a recent review of the literature; ovarian function was preserved in 89% of patients younger than 40 years old who underwent laparoscopic ovarian transposition for various pelvic malignancies requiring pelvic radiation therapy [11]. Laparoscopy offers the benefit of a quicker recovery with a lower likelihood of adhesion formation and should be offered to patients who elect to have an ovarian transposition and who do not require a laparotomy to treat their malignancy.

Successful pregnancies have been achieved in patients who have had ovarian transpositions. A total of 18 pregnancies was achieved in 12 (32%) of 37 patients who were followed for at least 2 years after ovarian transposition and had received pelvic radiation therapy with an intact uterus [16]. The majority (16/18; 89%) were spontaneously conceived, with a median time to conception of 4.3 years after completion of therapy. The ovaries were still in an abdominal position in 12 pregnancies (67%). There were 13 liveborns (72%), all of whom were full-term except for one that was delivered at 28 weeks’ gestation. Surrogate pregnancies involving patients with cervical cancer who underwent a hysterectomy and pelvic radiation therapy have also been reported [14, 15]. The ovaries were transposed prior to initiation of pelvic radiation. These patients then underwent ovarian stimulation 2–6 years after completion of therapy with oocyte retrieval. Surrogate mothers were identified by the patients and successfully carried and delivered healthy infants.

Metastases or recurrences, as well as benign cysts and further surgery, in the transposed ovaries are a concern. This is rare, however, with only 2 of 107 patients with cervical cancer reported in one series developing a recurrence in the ovaries [17]. Both those patients had both lower uterine segment (LUS) involvement and lymph-vascular space invasion (LVSI). It might be helpful to obtain a preoperative pelvic magnetic resonance image (MRI) to assess the extent and size of the tumor and rule out lower uterine extension in patients with cervical cancer who are contemplating ovarian transposition. Benign ovarian cysts may develop in up to 23% of these patients but infrequently lead to further surgeries [8, 10].

Ovarian transposition is an option for young women with gynecologic malignancies that require pelvic radiation therapy (Table 2Go). Retention of the ovaries in their normal pelvic location will almost definitely produce sterility. Transposition of the ovaries gives certain patients an opportunity to retain ovarian function as well as attempt future pregnancies. This should be done laparoscopically if a laparotomy is not essential for the treatment of the primary malignancy. The ovaries should be sutured to the peritoneum in the paracolic gutters above the pelvic brim. Patients should be counseled on the possible risks associated with ovarian transposition. Proper selection of patients will help reduce the risk of ovarian metastases and loss of ovarian function.


View this table:
[in this window]
[in a new window]
  		Table 2. Suggested eligibility criteria for ovarian transposition
 

   CERVICAL CANCER
Top
 Learning objectives
 Abstract
 Introduction
 Ovarian transposition
 Cervical cancer
Endometrial cancer
 Ovarian cancer
 Summary
 Disclosure of potential...
 References
 
The standard treatments for cervical cancer, hysterectomy (simple or radical) and/or pelvic radiation result in permanent sterility. As mentioned above, ovarian transposition may be an option for young women with cervical cancer who may not be candidates for other fertility-sparing procedures. These other procedures include excisional cone biopsy, radical abdominal trachelectomy, and radical vaginal trachelectomy (RVT). These options can only be used in a very select group of patients. However, nearly half of all patients younger than 40 years of age who might otherwise undergo a radical hysterectomy may be candidates for fertility-sparing procedures [18].

Excisional cervical cone biopsies alone without lymph node evaluation may be considered in patients with stage IA1 (≤3 mm stromal invasion, microinvasive) cervical cancer and no LVSI. These patients have a 0.8% risk for pelvic node metastasis, compared with nearly 8% in patients with >3 mm stromal invasion or with LVSI [19]. Residual microinvasive cancers have been reported in 5% of patients with completely excised lesions [20]. However, in the largest series reported, all 200 patients with stage IA1 cervical cancer and no LVSI who were treated with a laser cone biopsy were alive without evidence of recurrence [21]. The median follow-up in that group of 200 patients was 117 months (range, 72–420 months). It is essential that both negative endocervical margins and curettings be obtained. Patients who have both positive margins and curettings may have a 10% chance of having a lesion >3 mm (stage IA2) [20]. These patients require a more extensive procedure as well as evaluation of the pelvic lymphatics and are not candidates for cone biopsy alone.

The standard treatment of patients with more extensive disease confined to the cervix is radical hysterectomy with pelvic and para-aortic lymph node dissection or pelvic radiation with concurrent platinum therapy. This eliminates any chance of future fertility. Some of these patients may now be candidates for a radical trachelectomy, which can be accomplished either abdominally or vaginally. Lymph node assessment can be done at the same time, and the uterus is preserved as well as the ovaries.

Daniel Dargent performed the first RVT in 1987. In 1994, Dargent and colleagues published, in the French literature, the results of his first 28 cases [22]. The first report in the English literature was published in 1998 [23]. Proper selection and examination of patients is essential. A thorough gynecologic and colposcopic examination should be performed. Any available biopsy specimens need to be extensively reviewed with special attention to tumor size, depth of stromal invasion, histology, differentiation, and presence of LVSI. It might be useful to obtain a preoperative pelvic MRI. Table 3Go lists the criteria for patient selection. In general, RVT should be considered only for young patients who desire future fertility and have lesions smaller than 2 cm confined to the cervix.


View this table:
[in this window]
[in a new window]
  		Table 3. Suggested eligibility criteria for radical vaginal trachelectomy
 
RVT involves a two-step procedure and is well described in the literature [24]. A laparoscopic pelvic (with or without para-aortic) lymphadenectomy is performed first. If the nodes are negative, then the RVT is performed. A rim of 1–2 cm of vagina is delineated, and a vaginal incision is made. The cut edges of the vagina are then closed over the cervix. A posterior colpotomy is performed. The vesicouterine space is developed, but the anterior cul-de-sac is not entered. The paravesical and pararectal spaces are developed. The uterosacral ligaments are transected. The bladder pillars, which contain the knee of the ureters, are identified. These pillars are vascular and are carefully transected, mobilizing the ureters cephalad. The parametrial tissue is clamped and transected, followed by ligation of the cervical branch of the uterine artery. The cervix is amputated with care to maintain at least 1 cm of cervix attached to fundus. The cervix is sent for frozen-section analysis of the proximal margin. The procedure is completed if there is a ≥8-mm free margin. Excision of additional margin is attempted if there is a <5-mm free margin. The RVT is aborted and a radical hysterectomy is performed if the margin is positive. A permanent cerclage is placed into the remaining cervix. The vagina is sutured to the remaining cervical stroma without occluding the new external os. Finally, laparoscopic reassessment of the pelvis is performed. Figure 1Go is a representative RVT specimen.



View larger version (141K):
[in this window]
[in a new window]
  		Figure 1. Gross pathologic specimen after completion of a radical vaginal trachelectomy. Blue suture is on the endocervical margin and clamps are on the parametria.

 
Table 4Go and Table 5Go detail the reported experience with RVT in the world’s literature [25–31]. The RVT is aborted approximately 11%–12% of the time due to lymph node metastasis, more extensive disease than expected, or inability to achieve a negative cervical margin. Successfully completed RVTs have been reported in 254 cases. Recurrences developed in eight patients (3.1%), and seven (2.8%) have died of their disease. This outcome is comparable with the outcome after radical hysterectomy. The most significant predictor of recurrence in these patients is tumor size. The tumor size was >2 cm in six of the eight patients who developed recurrence. Currently, RVT is preferred only in patients with tumors <2 cm in size. Adenocarcinoma histology and LVSI are relative contraindications. There was one patient in whom a neuroendocrine tumor was diagnosed on final pathologic assessment [29]. This patient recurred quickly and died, as is usually the case with patients with these tumors. Neuroendocrine tumors of the cervix are rare and aggressive and are not amenable to RVT.


View this table:
[in this window]
[in a new window]
  		Table 4. Ability to complete intended RVT and oncologic outcomes
 

View this table:
[in this window]
[in a new window]
  		Table 5. Pregnancy-related outcomes after RVT
 
Pregnancies have been documented after RVT [25–29, 31]. One hundred thirty-seven patients have attempted to become pregnant, with 71 patients (52%) having 104 pregnancies. The outcomes in early pregnancy appear to be similar to those of the general population. However, there is a higher rate of late (>14 weeks) pregnancy losses and a higher rate of prematurity seen among the liveborn infants. Among the 68 livebirths, 20 (29%) were preterm. The etiology is unclear. Possible explanations for this rate of prematurity include loss of the natural cervical barrier to infection during pregnancy, loss of cervical substance and strength to hold a pregnancy to term, and subclinical infections due to the presence of the cerclage. Dargent and colleagues have reported two procedures that have resulted in the reduction of late losses [29]. The first is the placement of a permanent cerclage and the second is the closure of the cervical os in the third month of pregnancy. The late losses in his series were reduced from 50% to 22%, and subsequently to 10%. The closure of the vaginal mucosa during pregnancy has not been reported by other authors but does merit strong consideration. All patients need to be delivered via cesarean delivery due to the presence of the permanent cerclage.


   ENDOMETRIAL CANCER
Top
 Learning objectives
 Abstract
 Introduction
 Ovarian transposition
 Cervical cancer
 Endometrial cancer
Ovarian cancer
 Summary
 Disclosure of potential...
 References
 
In retrospective reviews, it has been reported that up to 35% of endometrial cancers are diagnosed in premenopausal women, in whom issues of fertility are important [31–37]. Women younger than 40 years of age may account for 3%–14% of all cases of endometrial cancer [32–35]. Endometrial cancer has also been diagnosed, albeit rarely, in women younger than 25 years old and even as young as 15 [38–41]. Young patients who develop endometrial cancer often have some degree of hyperestrogenism, anovulation, obesity, and lipid and carbohydrate imbalance. Nearly half are nulliparous, and the vast majority present with abnormal menstrual bleeding [33, 34, 36, 37, 42, 43].

The standard treatment of early-stage endometrial carcinoma is total abdominal hysterectomy, bilateral salpingo-oophorectomy (BSO), and lymph node sampling of the pelvic and para-aortic regions, followed by adjuvant therapy in some [44]. Hysterectomy may not be an acceptable option for premenopausal women desirous of childbearing. Conservative approaches that provide a chance at successful pregnancies and deliveries are possible in only a small, select group of young patients with endometrial carcinoma.

It is well recognized that tumor grade, depth of myometrial invasion, LVSI, and histology are strongly associated with outcome in endometrial carcinoma [44, 45]. These factors are predictive of advanced disease and risk of recurrence. Survival is highly related to stage, with nearly 100% of patients with cancer limited to the endometrium (stage IA) surviving after surgery alone [44]. It is therefore essential that these factors be closely reviewed prior to any consideration of conservative management. Patients with grade 1 endometrioid adenocarcinomas limited to the endometrium without evidence of LVSI or extrauterine disease appear to be the optimal candidates for conservative therapy. It is necessary to carefully and accurately evaluate these patients because they do not undergo the standard surgical staging.

Pretreatment evaluation of patients considering conservative therapy includes a detailed history and physical examination to look for signs and symptoms of advanced metastatic disease, dilatation and curettage (D&C), and radiologic imaging, preferably contrast-enhanced MRI. All these evaluations may underestimate the extent of disease, but in combination should provide an adequate evaluation in patients who will be followed closely.

Office endometrial sampling is probably sufficient for patients who will undergo hysterectomies [46]. However, a D&C should be performed on all patients with endometrial carcinoma prior to the institution of conservative therapy. Office sampling has been shown to confirm over 95% of endometrial carcinomas in patients known to have carcinoma [46]. Better agreement with final grade and detection of occult malignancy can be achieved on tissue obtained at a D&C. Significantly fewer cases are upgraded at the time of hysterectomy (26% for office biopsy versus 10% for D&C) [47, 48]. Also, 11% of patients will have no residual disease after D&C, compared with only 2% of those who undergo an office biopsy [47]. Hysteroscopy is extremely operator-dependent, and results have been difficult to interpret [49]. In the follow-up of patients being managed conservatively, office endometrial sampling is sufficient, with D&C reserved for cases with unclear results. Grade, histology, and lymph-vascular status may be ascertained with a D&C, but determination of depth of invasion must rely on radiologic imaging.

Transvaginal ultrasound (TVUS), computed tomography (CT), and MRI have all been used in the assessment of endometrial carcinoma [50–55]. A meta-analysis of 47 studies demonstrated no statistical differences among the three modalities in overall performance, but assessment of myometrial invasion was best achieved with the use of contrast-enhanced MRI [55]. Conventional, noncontrast MRI is 88%–92% accurate in staging endometrial carcinoma, and myometrial invasion is hardly ever found histologically when MRI shows the tumor to be limited to the endometrium [50, 52]. Actually, the majority of erroneous MRI diagnoses are overestimations of the extent of invasion because of polypoid tumors, endometrial cavity distention, atrophic myometrium, and poor tumor/myometrial contrast [50–53]. The addition of contrast to MRI has proven to be essential to distinguish among tumor, endometrium, and myometrium [54, 55]. MRI has been shown to be superior to TVUS and CT in assessing the depth of myometrial invasion in patients who all underwent TVUS, CT, and noncontrast MRI prior to surgery [54]. Studies on helical (spiral) CT scanning have not been performed. No imaging guidelines or algorithms exist for the use of imaging in the pretreatment assessment of endometrial carcinoma. Available data suggest that contrast-enhanced MRI provides the most reliable, accurate, and comprehensive assessment of patients with endometrial carcinoma.

The data on conservative management of endometrial cancer using progestational agents instead of surgery are very limited. A recent comprehensive review of the English literature identified a total of 81 patients treated conservatively from 1961 to 2003 [56]. Many different agents were used, but the most common ones were medroxyprogesterone acetate and megestrol acetate. There were 62 patients (76%) who responded to initial therapy, with a median time to response of 12 weeks (range, 4–60 weeks). Of these, 47 patients (76%) did not recur. Retreatment with progestational agents resulted in a second response in five (71%) of the seven patients retreated; all were alive without evidence of disease, with a median follow-up of 46 months. This means that 52 (64%) of the 81 patients responded to at least one course of hormonal therapy and were disease-free. There were 10 patients who recurred and underwent hysterectomy at some point. Only six (60%) had residual carcinoma, and all were grade 1.

Nineteen (24%) of the 81 patients did not respond to therapy at all. A hysterectomy was performed in 15 of those patients. Residual carcinoma was documented in 10 (67%) of the 15 patients. Nine (90%) of these 10 patients had grade 1 carcinoma. All patients were alive without evidence of disease at the time of this review.

Pregnancies were documented in 20 patients, but it is unknown how many patients actually attempted to become pregnant. ART was used by 12 patients. There were a total of 31 live births among 16 patients.

Figure 2Go demonstrates a suggested treatment algorithm for patients with endometrial cancer who desire future fertility. These patients need to understand that there are very limited data and they must be willing to accept a small but undefined risk. The timing of pregnancy in these patients is unclear. A prudent idea is to document a response prior to attempting a pregnancy. The high levels of progesterone during pregnancy may actually help in the regression of these lesions, but this is not proven.



View larger version (33K):
[in this window]
[in a new window]
  		Figure 2. Suggested algorithm for conservative treatment of well-differentiated early-stage endometrioid adenocarcinoma. Abbreviation: D&C, dilatation and curettage; MRI, magnetic resonance imaging; po, orally; qd, daily.

 

   OVARIAN CANCER
Top
 Learning objectives
 Abstract
 Introduction
 Ovarian transposition
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
Summary
 Disclosure of potential...
 References
 
Ovarian carcinoma is less common in premenopausal, as opposed to postmenopausal, women. However, ovarian cancers do develop in young women, including women younger than 20 years of age [2]. The vast majority of these are malignant germ cell tumors and sex cord–stromal tumors [3]. These tumors can be seen in very young women and have an overall excellent prognosis. These tumors are frequently limited to one ovary and almost always present at a very early stage without extraovarian spread. Surgery with staging is the mainstay of treatment but should not result in sterility. The uterus and normal contralateral ovary should be maintained, and chemotherapy should be used as indicated. Epithelial ovarian tumors in premenopausal women are often borderline tumors. Conservative surgical approaches are possible in young women who develop epithelial ovarian tumors, including carcinomas that are grossly limited to one ovary.

Zanetta and colleagues reported the largest experience of fertility-sparing procedures in young women with malignant germ cell tumors [57]. Preservation of the uterus and contralateral ovary was possible in 138 (81%) of 169 patients. The survival rate of the patients treated conservatively (90%–100%) was the same as that of the entire group (89%–100%). Nearly 88% (28 of 32) of the patients who attempted to become pregnant were able to conceive whether they received adjuvant chemotherapy or not. Fifty-five conceptions resulted in 38 (69%) full-term, normal infants.

Borderline ovarian tumors are often diagnosed incidentally after ovarian cystectomies or unilateral oophorectomies in young women. An oophorectomy after a borderline tumor is diagnosed in a cystectomy specimen is not necessary. The risks of recurrence are 6% for an ipsilateral recurrence, 3% for a contralateral recurrence, and 3% for a bilateral recurrence [58]. These patients can be salvaged with further excision and can expect to have a long survival time. Many will become pregnant and have a normal delivery [58]. A higher rate of recurrence in patients who undergo fertility-sparing procedures was seen in the two largest series, which were reported recently [59, 60]. However, survival rates were similar for patients treated conservatively and those who had a hysterectomy and BSO [59, 60].

Surgical staging after the final pathologic diagnosis of an ovarian borderline tumor is not necessary, as both staged and unstaged patients have the same outcomes [61, 62]. However, frozen-section analysis of an ovarian borderline tumor may differ from the final pathologic analysis, with the final pathologic analysis identifying an invasive tumor anywhere from 6%–53% of the time [63–66]. Staging may be considered at the time of a frozen-section diagnosis prior to the final pathologic analysis. Staging in this situation avoids a potential second surgical procedure at a later time if the final pathologic analysis reveals an invasive tumor and should not adversely affect fertility any more than the initial adnexal procedure. It is also acceptable to not perform a staging procedure and wait until the final pathologic analysis.

Ovarian carcinomas grossly confined to the ovary also can be managed conservatively with preservation of the uterus and normal contralateral ovary. Biopsy of normal ovaries should not be performed as the diagnostic accuracy is questionable. A focus of carcinoma may be entirely missed on a random biopsy of a normal-appearing ovary. In addition, isolated bilateral ovarian carcinoma is relatively rare and would not change the management of these patients. These patients should have a unilateral salpingo-oophorectomy performed as well as comprehensive staging to include bilateral pelvic and para-aortic lymph node sampling up to the level of the renal vessels.

Chemotherapy should then be administered as indicated in patients with ovarian carcinoma. The development of premature ovarian failure after chemotherapy is always a concern and has been reported to be as high as 68% [6]. The highest rates of amenorrhea are seen among older women and those who receive alkylating agents such as cyclophosphamide. The current standard agents used in ovarian carcinoma, carboplatin (Paraplatin®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and paclitaxel (Taxol®; Bristol-Myers Squibb), may also lead to permanent ovarian failure but to a much lower rate than other agents. It is always important to balance the possible risk of loss of fertility with disease recurrence and survival.

The recurrence and survival rates among the small number of patients with ovarian carcinoma who were treated conservatively reported in the literature appear to be comparable with those of patients who undergo more aggressive surgical procedures [67]. Schilder et al. described that there have been 71 pregnancies reported in the literature among 46 patients treated conservatively, with 54 term deliveries [67].


   SUMMARY
Top
 Learning objectives
 Abstract
 Introduction
 Ovarian transposition
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
 Summary
Disclosure of potential...
 References
 
The diagnosis of a gynecologic malignancy can be devastating to young patients who desire future fertility. The standard therapies for many of these malignancies often result in sterility. Options for these patients exist. Patients who require pelvic radiation may benefit from a laparoscopic ovarian transposition. An excisional cone biopsy or RVT in very select patients allows preservation of fertility in patients with cervical cancer. Hormonal therapy is an option for patients with grade 1 endometrioid adenocarcinomas of the uterus confined to the endometrium. Patients with ovarian cancers do not require hysterectomy or BSO. A multidisciplinary approach is crucial; the care of these patients needs to be coordinated among gynecologic oncologists, reproductive endocrinologists, and perinatologists. Patients need to understand the limited data in most instances and the undefined risks that they are assuming, as well as the intense follow-up that is required.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning objectives
 Abstract
 Introduction
 Ovarian transposition
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
 Summary
 Disclosure of potential...
References
 
The authors indicate no potential conflicts of interest.


   REFERENCES
Top
 Learning objectives
 Abstract
 Introduction
 Ovarian transposition
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
 Summary
 Disclosure of potential...
 References
 

  1. Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
  2. Ries LAG, Eisner MP, Kosay CL et al., eds. SEER Cancer Statistics Review, 1975–2001. Bethesda, MD: National Cancer Institute. Available at http://seer.cancer.gov/csr/1975_2001. Accessed December 23, 2004.
  3. Berek JS. Ovarian cancer. In: Berek JS, ed. Novak’s Gynecology, Thirteenth Edition. Philadelphia: Lippincott Williams & Wilkins, 2002:1246–1321.
  4. Mathews TJ, Hamilton BE. Mean age of mother, 1970–2000. Natl Vital Stat Rep 2002;51:1–13.[Medline]
  5. Hamilton BE, Martin JA, Sutton PD. Births: preliminary data for 2003. Natl Vital Stat Rep 2004;53:1–17.
  6. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001;7:535–543.[Abstract/Free Full Text]
  7. McCall ML, Keaty EC, Thompson JD. Conservation of ovarian tissue in the treatment of carcinoma of the cervix with radical surgery. Am J Obstet Gynecol 1958;75:590–600; discussion 600–605.[Medline]
  8. Anderson B, LaPolla J, Turner D et al. Ovarian transposition in cervical cancer. Gynecol Oncol 1993;49:206–214.[CrossRef][Medline]
  9. Morice P, Castaigne D, Haie-Meder C et al. Laparoscopic ovarian transposition for pelvic malignancies: indications and functional outcomes. Fertil Steril 1998;70:956–960.[CrossRef][Medline]
  10. Morice P, Juncker L, Rey A et al. Ovarian transposition for patients with cervical carcinoma treated by radiosurgical combination. Fertil Steril 2000;74:743–748.[CrossRef][Medline]
  11. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gynecol 2003;188:367–370.[CrossRef][Medline]
  12. Tulandi T, Al-Took S. Laparoscopic ovarian suspension before irradiation. Fertil Steril 1998;70:381–383.[CrossRef][Medline]
  13. Visvanathan DK, Cutner AS, Cassoni AM et al. A new technique of laparoscopic ovariopexy before irradiation. Fertil Steril 2003;79:1204–1206.[CrossRef][Medline]
  14. Azem F, Yovel I, Wagman I et al. Surrogate pregnancy in a patient who underwent radical hysterectomy and bilateral transposition of ovaries. Fertil Steril 2003;79:1229–1230.[CrossRef][Medline]
  15. Giacalone PL, Laffargue F, Benos P et al. Successful in vitro fertilization-surrogate pregnancy in a patient with ovarian transposition who had undergone chemotherapy and pelvic irradiation. Fertil Steril 2001;76:388–389.[CrossRef][Medline]
  16. Morice P, Thiam-Ba R, Castaigne D et al. Fertility results after ovarian transposition for pelvic malignancies treated by external irradiation or brachytherapy. Hum Reprod 1998;13:660–663.[Abstract/Free Full Text]
  17. Morice P, Haie-Meder C, Pautier P et al. Ovarian metastasis on transposed ovary in patients treated for squamous cell carcinoma of the uterine cervix: report of two cases and surgical implications. Gynecol Oncol 2001;83:605–607.[CrossRef][Medline]
  18. Sonoda Y, Abu-Rustum NR, Gemignani ML et al. A fertility-sparing alternative to radical hysterectomy: how many patients may be eligible? Gynecol Oncol 2004;95:534–538.[CrossRef][Medline]
  19. Benedet JL, Anderson GH. Stage IA carcinoma of the cervix revisited. Obstet Gynecol 1996;87:1052–1059.[CrossRef][Medline]
  20. Roman LD, Felix JC, Muderspach LI et al. Risk of residual invasive disease in women with microinvasive squamous cancer in a conization specimen. Obstet Gynecol 1997;90:759–764.[CrossRef][Medline]
  21. Ueda M, Ueki K, Kanemura M et al. Conservative excisional laser conization for early invasive cervical cancer. Gynecol Oncol 2004;95:231–234.[CrossRef][Medline]
  22. Dargent D, Brun JL, Roy M et al. The radical trachelectomy: An alternative to radical hysterectomy in the treatment of invasive cancers that develop on the external os of the uterine cerix. J Obstet Gynecol 1994;2:285–292. [French]
  23. Roy M, Plante M. Pregnancies after radical vaginal trachelectomy for early-stage cervical cancer. Am J Obstet Gynecol 1998;179:1491–1496.[CrossRef][Medline]
  24. Plante M, Roy M. Radical trachelectomy. In: Gershenson D, Fowler M, eds. Operative Techniques in Gynecologic Surgery. Philadelphia: WB Saunders, 1997:187–199.
  25. Covens A, Shaw P, Murphy J et al. Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix? Cancer 1999;86:2273–2279.[CrossRef][Medline]
  26. Shepherd JH, Mould T, Oram DH. Radical trachelectomy in early stage carcinoma of the cervix: outcome as judged by recurrence and fertility rates. BJOG 2001;108:882–885.[CrossRef][Medline]
  27. Burnett AF, Roman LD, O’Meara AT et al. Radical vaginal trachelectomy and pelvic lymphadenectomy for preservation of fertility in early cervical carcinoma. Gynecol Oncol 2003;88:419–423.[CrossRef][Medline]
  28. Schlaerth JB, Spirtos NM, Schlaerth AC. Radical trachelectomy and pelvic lymphadenectomy with uterine preservation in the treatment of cervical cancer. Am J Obstet Gynecol 2003;188:29–34.[CrossRef][Medline]
  29. Mathevet P, Laszlo de Kaszon E, Dargent D. [Fertility preservation in early cervical cancer.] Gynecol Obstet Fertil 2003;31:706–712. French.[CrossRef][Medline]
  30. Plante M, Renaud MC, Francois H et al. Vaginal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecol Oncol 2004;94:614–623.[CrossRef][Medline]
  31. Bernardini M, Barrett J, Seaward G et al. Pregnancy outcomes in patients after radical trachelectomy. Am J Obstet Gynecol 2003;189:1378–1382.[CrossRef][Medline]
  32. McGee WB. Carcinoma of the endometrium in women under forty years of age: report of three cases. Obstet Gynecol 1958;11:388–390.[Medline]
  33. Crissman JD, Azoury RS, Barnes AE et al. Endometrial carcinoma in women 40 years of age or younger. Obstet Gynecol 1981;6:699–704.
  34. Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984;64:417–420.[Medline]
  35. Quinn MA, Kneale BJ, Fortune DW. Endometrial carcinoma in premenopausal women: a clinicopathological study. Gynecol Oncol 1985;20:298–306.[CrossRef][Medline]
  36. Gitsch G, Hanzal E, Jensen D et al. Endometrial cancer in premenopausal women 45 years and younger. Obstet Gynecol 1995;85:504–508.[CrossRef][Medline]
  37. Evans-Metcalf ER, Brooks SE, Reale FR et al. Profile of women 45 years of age and younger with endometrial cancer. Obstet Gynecol 1998;91:349–354.[CrossRef][Medline]
  38. Ostor AG, Adam R, Gutteridge BH et al. Endometrial carcinoma in young women. Aust N Z J Obstet Gynaecol 1982;22:38–42.[Medline]
  39. Farhi DC, Nosanchuk J, Silverberg SG. Endometrial adenocarcinoma in women under 25 years of age. Obstet Gynecol 1986;68:741–745.[Medline]
  40. Moukhtar M, Aleem FA, Hung HC et al. The reversible behavior of locally invasive endometrial carcinoma in a chromosomally mosaic (45,X/46Xr(X)) young woman treated with Clomid®. Cancer 1977;40:2957–2966.[CrossRef][Medline]
  41. Kim YB, Holschneider CH, Ghosh K et al. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women. Report of seven cases and review of the literature. Cancer 1997;79:320–327.[CrossRef][Medline]
  42. Tran BN, Connell PP, Waggoner S et al. Characteristics and outcome of endometrial carcinoma patients age 45 years and younger. Am J Clin Oncol 2000;23:476–480. (CCT)[Medline]
  43. Geisler HE, Huber CP, Rogers S. Carcinoma of the endometrium in premenopausal women. Am J Obstet Gynecol 1969;104:657–663.[Medline]
  44. Barakat RR, Grigsby PW, Sabbatini P et al. Corpus: epithelial tumors. In: Hoskins WJ, Perez CA, Young RC, eds. Principles and Practice of Gynecologic Oncology, Third Edition. Philadelphia: Lippincott-Raven, 2000:919–959.
  45. Creasman WT, Morrow CP, Bundy BN et al. Surgical pathologic spread patterns of endometrial cancer: A Gynecologic Oncology Group study. Cancer 1987;60:2035–2041.[CrossRef][Medline]
  46. Stovall TG, Photopulos GJ, Poston WM et al. Pipelle endometrial sampling in patients with known endometrial carcinoma. Obstet Gynecol 1991;77:954–956.[Medline]
  47. Daniel AG, Peters WA 3rd. Accuracy of office and operating room curettage in the grading of endometrial carcinoma. Obstet Gynecol 1988;71:612–614.[Medline]
  48. Larson DM, Johnson KK, Broste SK et al. Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in endometrial cancer. Obstet Gynecol 1995;86:38–42.[CrossRef][Medline]
  49. Perez-Medina T, Bajo J, Folgueira G et al. Atypical endometrial hyperplasia treatment with progestogens and gonadotropin-releasing hormone analogues: long-term follow-up. Gynecol Oncol 1999;73:299–304.[CrossRef][Medline]
  50. Hricak H, Stern JL, Fisher MR et al. Endometrial carcinoma staging by MR imaging. Radiology 1987;162:297–305.[Abstract/Free Full Text]
  51. Lien HH, Blomlie V, Trope C et al. Cancer of the endometrium: value of MR imaging in determining depth of invasion into the myometrium. AJR Am J Roentgenol 1991;157:1221–1223.[Abstract/Free Full Text]
  52. Sironi S, Taccagni G, Garancini P et al. Myometrial invasion by endometrial carcinoma: assessment by MR imaging. AJR Am J Roentgenol 1992;158:565–569.[Abstract/Free Full Text]
  53. Yamashita Y, Mizutani H, Torashima M et al. Assessment of myometrial invasion by endometrial carcinoma: transvaginal sonography vs contrast-enhanced MR imaging. AJR Am J Roentgenol 1993;161:595–599.[Abstract/Free Full Text]
  54. Kim SH, Kim HD, Song YS et al. Detection of deep myometrial invasion in endometrial carcinoma: comparison of transvaginal ultrasound, CT, and MRI. J Comput Assist Tomogr 1995;19:766–772.[Medline]
  55. Kinkel K, Kaji Y, Yu KK et al. Radiologic staging in patients with endometrial cancer: a meta-analysis. Radiology 1999;212:711–718.[Abstract/Free Full Text]
  56. Ramirez PT, Frumovitz M, Bodurka DC et al. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 2004;95:133–138.[CrossRef][Medline]
  57. Zanetta G, Bonazzi C, Cantu M et al. Survival and reproductive function after treatment of malignant germ cell ovarian tumors. J Clin Oncol 2001;19:1015–1020.[Abstract/Free Full Text]
  58. Lim-Tan SK, Cajigas HE, Scully RE. Ovarian cystectomy for serous borderline tumors: a follow-up study of 35 cases. Obstet Gynecol 1988;72:775–781.[Medline]
  59. Morice P, Camatte S, El Hassan J et al. Clinical outcomes and fertility after conservative treatment of ovarian borderline tumors. Fertil Steril 2001;75:92–96.[CrossRef][Medline]
  60. Zanetta G, Rota S, Chiari S et al. Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study. J Clin Oncol 2001;19:2658–2664.[Abstract/Free Full Text]
  61. Winter WE 3rd, Kucera PR, Rodgers W et al. Surgical staging in patients with ovarian tumors of low malignant potential. Obstet Gynecol 2002;100:671–676.[CrossRef][Medline]
  62. Rao GG, Skinner E, Gehrig PA et al. Surgical staging of ovarian low malignant potential tumors. Obstet Gynecol 2004;104:261–266.[Medline]
  63. Menzin AW, Rubin SC, Noumoff JS et al. The accuracy of a frozen section diagnosis of borderline ovarian malignancy. Gynecol Oncol 1995;59:183–185.[CrossRef][Medline]
  64. Houck K, Nikrui N, Duska L et al. Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis. Obstet Gynecol 2000;95:839–843.[CrossRef][Medline]
  65. Pinto PB, Andrade LA, Derchain SF. Accuracy of intraoperative frozen section diagnosis of ovarian tumors. Gynecol Oncol 2001;81:230–232.[CrossRef][Medline]
  66. Tangjitgamol S, Jesadapatrakul S, Manusirivithaya S et al. Accuracy of frozen section in diagnosis of ovarian mass. Int J Gynecol Cancer 2004;14:212–219.[CrossRef][Medline]
  67. Schilder JM, Thompson AM, DePriest PD et al. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy. Gynecol Oncol 2002;87:1–7.[CrossRef][Medline]
Received March 1, 2005; accepted for publication July 14, 2005.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leitao, M. M.
Right arrow Articles by Chi, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leitao, M. M., Jr
Right arrow Articles by Chi, D. S.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS