NEOPLASIA and FERTILITY

About 40% of the diagnoses of cervical cancer occur during the reproductive age. With the increasing age of first pregnancy, both cervical cancer diagnosis during conception attempt and pregnancy are more common events. Although the oncologic outcome is the primary objective of these treatments, in selected women wishing to preserve fertility, a fertility-sparing surgery (FSS) should be considered. Many factors must be evaluated including stage, histological subtype, lymph node status, lymphovascular space invasion, size of the disease, and, nonetheless, the experience of the health care team. We review the indications, techniques, fertility and obstetric outcomes of FSS. Increasing evidence has shown that cervical cancer during pregnancy is a condition that can be treated. However, many issues remain to be discussed: i) how to make a correct diagnosis and staging of the disease; ii) what is the most appropriate treatment; iii) when to start treatment and what is the risk of delaying the treatment to allow for better fetal maturity; iv) what is the preferred mode of delivery; v) how pregnancy affects the progression and prognosis of neoplasia. We have reviewed the tumor factors, gestational age, obstetrical conditions and complications related to cervical cancer during pregnancy. The chapter reviews the evidence for the best possible treatment of this challenging medical condition, including the psychological aspects related to such diagnosis, helping the clinician and the patient clarify their concerns and wishes regarding the continuation of the pregnancy and the cancer treatment.

Endometrial carcinoma is the most common gynecological malignancy in the western countries. Although majority of patients are postmenopausal, 2.5–14.4% of the cases are detected in women aged <40 years. The tumors diagnosed in young women are usually early-stage, low-grade endometrioid endometrial carcinoma [EEC]s with favorable clinical outcomes. The standard primary therapy consists of extra-fascial hysterectomy and bilateral salpingo-oophorectomy with or without node dissection. However, a fertility-sparing treatment is feasible in accurately selected young women with complex atypical hyperplasia or with EEC with G1 tumor limited to the endometrium. According to some authors, the conservative approach can be taken into consideration also in patients with stage IA, G2-3 EEC without myometrial invasion and in those with stage IA, G1 EEC with superficial myometrial invasion. After hysteroscopic resection of the lesion and the underlying myometrium, the woman istreated with anoral progestin at adequate doses or a progestin-releasing –IUD with or without Gn-RH agonists, and she undergoes the first biopsy after 3 months. In the case of a positive biopsy, the patient continues progestin therapy for additional 3 months, but if the 6-months biopsy is still positive, hysterectomy is recommended. Several women become pregnant with the aid of assisted reproductive technologies. An accurate follow-up is also needed after a successful pregnancy, whereas the debate that the opportunity of performing hysterectomy after childbearing potential is no longer required.

Fertility-sparing surgery in early-stage epithelial ovarian cancer is a feasible option for patients of childbearing age wishing for a future pregnancy. The therapeutic option needs to be managed by an expert Gynecologic Oncologist within a multispeciality oncologic team. This chapter reviews the clinical condition which may influence the final decision, in particular: stage of disease, grade of differentiation, and histologic subtype. Oncological outcomes and fertility outcomes are reported on the basis of the currently available literature.

 The association between breast cancer and pregnancy is defined as detecting breast cancer during pregnancy or within one year after delivery. The diagnosis is often difficult and delayed. It is based on clinical examination, radiological exams (ultrasound and/or RM) and biopsy of the suspected lesion. The staging examinations should be performed only if any change in therapeutic decisions or clinical practice could be made or in the presence of a high risk of distant metastases. The treatment includes surgery, radiotherapy, chemotherapy, hormonal therapy and molecular targeted therapy, and it should be as close as possible with the standard protocols of non-pregnant patients and should be discussed with a multidisciplinary team. It is important to start the treatment as soon as possible, with the exception of term pregnant patients, for whom it can be postponed after delivery. The major fetal complications seem to be related to prematurity, and the type of delivery depends on obstetrics indication. The delivery should be planned at least three weeks after the infusion of chemotherapy, and the treatment generally could be restarted one week after the cesarean section and immediately after a vaginal delivery. The apparent poor outcome in pregnant women can be explained by the delayed diagnosis and/or treatment and the biological characteristics of the tumor (often of high grade and triple negative). Finally, when the treatment is planned, reproductive counseling should always be proposed to young patients immediately after diagnosis in order to plan the best fertility preservation strategies

Melanoma is diagnosed within a wide range of ages, beginning in the third decade of life: it occurs slightly more commonly in women younger than 40, and represents the second most frequently diagnosed malignant tumor in patients 15 to 29 years of age. The overall incidence of melanoma in pregnancy is about 0.14 to 0.28 cases per 1000 births, accounting for 8% of malignancies diagnosed during pregnancy; although occurring extremely rarely; melanoma is one of the most common tumors known to metastasize to the placenta and the fetus. From the recent literature, we can conclude that chest radiography with radiation protection and abdominal ultrasounds are safe; Computed Tomography (CT) with intravenous contrast and positron emission tomography are generally contraindicating because of emission of high dose of radiation; Magnetic Resonance (MR) is safer than CT, but it is contraindicated during 1st trimester of pregnancy because it employs heart tissues and exposes the fetus to excessive noise than can cause high-frequency hearing loss in neonates. There is no conclusive evidence that pregnancy significantly affects melanoma aggressiveness in terms of increasing metastases incidence or lowering overall survival. Two recent investigations have reported increased mortality in women with pregnancyassociated malignant melanoma. Some data suggest that increased mortality of the melanoma patients with recent childbirth is mainly due to a stage-independent causal pathway: the pregnancy-associated immune suppression may permit some melanomas with high malignant potential to progress and come to clinical diagnosis in the short term following childbirth. However, some other data analysis shows no difference in tumour location and stage at diagnosis between women with PAMM and non-PAMM; furthermore, no evidence of a worse prognosis was found in women given the diagnosis of PAMM. Given these results, the authors conclude that counselling and monitoring women with PAMM do not need to be different from those provided for women with non-PPAMM. The main goals of melanoma treatment during pregnancy are to cure the neoplasia and avoid complications for the fetus; irrespective of pregnancy status, wide local excision around the melanoma site with margins proportional to the microstage of the primary lesion, is the treatment oflocalized melanomas. In more advanced cases (>4mm depth), adjuvant therapy with high dose interferon must be considered; although interferon is safely administered in pregnant patients with haematological malignancies, adjuvant therapy with high dose interferon has not been studied in pregnancy associated melanoma and therefore is not routinely recommended.

Thyroid disease is common and affects 1% to 2% of pregnant women. Pregnancy outcomes can depend on optimal management of thyroid disease, and the course of thyroid disease may be modified by pregnancy. During pregnancy, the evaluation of a thyroid nodule includes a serum TSH and a US assessment of the neck and thyroid gland. Fine needle aspiration (FNA) cytology should be performed for predominantly solid thyroid nodules >1cm discovered in pregnancy. The incidence of thyroid carcinoma is about threefold higher in women than in men, particularly during women’s reproductive years; however, results from case-control and prospective studies showed weak and inconsistent results on the associations between pregnancy, parity, menstrual cycle regularity, exogenous hormone use and menopausal status and thyroid carcinoma risk. Two guidelines on thyroid and pregnancy were developed in October 2011 and August 2012 by American Thyroid Association and Endocrine Society, respectively. A recent case report underlines the importance of the trimester of pregnancy: if well-differentiated thyroid cancer is diagnosed prior to the mid-trimester, it is possible to carry out the surgical intervention in the mid-trimester. During late pregnancy, resection after delivery is the option of choice. There is no indication for termination of pregnancy. Radioiodine or 131I (RAI) is an effective treatment of differentiated thyroid carcinoma (DTC) in both preventing relapses and treating metastases. The possibility of genetic or physical damage to the offspring in terms of congenital malformation and childhood malignancies is a real concern, but several studies did not find a statistically significant association between previous RAI exposure and unfavourable pregnancy outcome. There is a general agreement to defer the thyroid surgery to the second trimester and avoid conception within one year after RAI, allowing RAI clearance and hormonal stabilization.

Cancer is a leading cause of death in the female population, accounting for 6.7 million of new diagnoses worldwide. Cancer and its treatment can often impair the chances of having children, and the fertility sparing issueis an emerging need. In fact, more often, women are delaying conception and therefore, an increasing number of women are diagnosed with malignancy before the desired completion of childbearing. The care of these patients is challenging, and complex, and there is a total lack of validated guidelines. The problem of fertility in a cancer patient encounters not only clinical and technical problems, but it raises many other queries about ethical and psychological perspectives. Since an international consensus statement should be produced, the need for a dedicated multidisciplinary approach is mandatory to offer a clinical range of treatment options. Cancer survivors and the medical community have acknowledged the importance of patient counseling and the pursuit of options for fertility preservation. In 2006, the American Society of Clinical Oncology published the first recommendations on fertility preservation; however, despite the increasing awareness regarding these recommendations, fertility preservation services are still underutilized. ASCO guidelines advised oncologists to discuss fertility risks and preservation strategies and make referrals to fertility specialists for interested patients as early as possible. There are some programmatic requirements to set up a fertility preservation service, the most significant of which is the availability of a multidisciplinary medical team. A treatment planning approach in which medical figures are experts in different specialties aims to deliver a global treatment tailored to the patient and its disease. A multidisciplinary approach to debating with fertility-sparing issue in oncological patients has mainly two objectives: firstly, to ensure the oncological safety and, in second place, the verification of the fertility preservation desire, that should be not only the intention of the patient but also compliant to “minimum requirements” and therefore a step-wise and careful selection of the women candidate to conservative treatment is necessary. Counseling of patients pursuing fertility preservation should include a discussion of all methods of fertility preservation as well as the alternatives. Because of the sensitive and urgent nature of fertility preservation, a team approach to patient counseling is recommended. Effective provision of fertility preservation options requires an ongoing collaborative relationship among medical and surgical oncologists, reproductive endocrinologists and other medical figures. Oncologists have the initial responsibility to discuss the reproductive risks of intended therapies with the patient and subsequently make referrals to experienced specialists to discuss available reproductive options, which have to be discussed both for surgical decisions and chemotherapy and/or radiotherapy administration. Multidisciplinary teams should include: oncologists, gynecologic oncologists, radiation therapy specialists, reproductive endocrinology and infertility specialists, andrologists, fertilitydedicated biologists, and nurses in the specialties of oncology and infertility, oncopsychologists and social workers. All of these are required to work together in order to achieve a successful collaborative approach

Cryopreservation is a technique in which cells and tissues can be preserved at low temperature (-196 °C in liquid nitrogen). The advantage of this procedure is possibly the structural and functional preservation of gametes, embryos and male and female tissue, through the use of specific reagents, also known as cryoprotectors. In addition, cryopreservation is strongly recommended in the case of severe pathologies; for instance, oncologic patients who undergo chemo or radiotherapy treatments could be predisposed to infertility. In the past, cryopreservation was obtained using slow-freezing processes, but nowadays, thanks to several studies in this field, other approaches are taken into account, such as vitrification. Vitrification is used for gametes, avoiding several technical problems, but it’s not used for embryos and ovarian tissues, yet. As for the concerns regarding ovarian tissue, there is already evidence of successful implementation after thawing previous frozen ovarian tissue. However, this technique needs to be more deeply investigated to understand whether vitrification or slow freezing is the best approach. The advantage of freezing ovarian tissue in an oncologic patient, for example, is that no ovarian hyperstimulation is required before the tissue is harvested. Differently, for male oncologic patients, it’s enough to obtain the seminal liquid, except for pediatric patients in whom the cryopreservation of testicular tissue is recommended. 

Improvement in oncologic treatment has made the preservation of fertility of young women surviving cancer a demanding issue. International guidelines recommend reproductive counseling before surgery, chemotherapy or radiotherapy. Information should deal with the different ways to preserve fertility, such as embryos, oocytes or ovarian tissue cryopreservation, suppression of ovarian activity during chemotherapy, or ovarian transposition/shielding during radiotherapy. Preservation of fertility during chemotherapy depends on several factors such as ovarian reserve at the moment of treatment, age, type of treatment, type of dose and posology of the drug used. Data from the literature show that certain preservation of ovarian function can be achieved by suppressing ovarian function with a GnRH analog (GnRHa) during chemotherapy for breast cancer. However, there is no evidence that ovarian preservation can be achieved by ovarian suppression during chemotherapy for hematological neoplasms. In these cases, oocyte cryopreservation represents the only available option. Ovarian damage after pelvic radiotherapy is related to age and the dose of radiation delivered. Ovarian preservation can be achieved via the transposition of the ovaries from the radiation field by a minimally-invasive surgical approach. Three surgical techniques for ovarian transposition by laparoscopy were described with either a lateral, a medial, or an anterior approach. In conclusion, nowadays it is possible to allow reproduction in most young women surviving cancer by an individualized approach that takes into consideration the type of malignancy, the type of treatment, and the preventive measures that can be used in every single case.

Post-menopausal hormonal therapy (HT) may help to improve quality of life and prevent long-term consequences of estrogen deficiency. The use of HT in postmenopausal cancer survivors is controversial, particularly for those women having survived hormone-dependent tumors, like breast or gynecological cancers. Endometrial cancer is the most frequent gynecological cancer. The limited data of the literature on women having suffered from endometrial cancer do not show an increased recurrence or death with HT use, but guidelines do not yet indicate the generalized use of HT in these women. HT should be avoided in uterine sarcomas. Breast cancer survivors suffer from climacteric symptoms after menopause or as a consequence of adjuvant hormonal anti-estrogen treatment. The risk of cancer recurrence with HT is uncertain: the two randomized prospective controlled trials were prematurely stopped. Actually, clinical guidelines contraindicate HT use in breast cancer survivors. New therapeutic approach for selected symptoms such as ospemifene (a SERM molecule) can be promising. There is no strong evidence for denying HT to patients treated for ovarian cancer, independently of disease stage. Even for women with an endometrioid carcinoma of the ovary, an estrogen-sensitive tumor, evidence indicates no harm from HT. More controversial is the use of HT after granulosa cell tumors. HT can be administered in women treated for squamous cancers of the cervix and the vulva or vaginal neoplasm. The approach to cervical adenocarcinoma should follow that of endometrial cancer. In conclusion, HT is not contraindicated in all women with a history of gynecological cancer, but its use is dependent on the type of cancer the woman has suffered from. 

BRCA1 or two mutation carriers have an increased risk of developing breast and ovarian cancer. Moreover, they may also have reduced oocyte reserve, occult primary ovarian insufficiency, decreased fertility, poorer response to ovarian stimulation and earlier age at menopause. Even if these associations are still controversial, carriers should be properly informed in order to program motherhood and fertility preservation when appropriate. Women with Lynch syndrome (LS) have an increased risk of developing endometrial cancer at an early age and a slightly increased risk of ovarian cancer. Thus, the promotion of early parity with subsequent hormonal contraception or prophylactic hysterectomy after completing childbearing should be discussed during counseling.