Neoplasia and Fertility

By Bentham Science Publishers

Research on young individuals and childbearingadults being treated for neoplasia has revealed a rising number of requests for treatmentsaimed to maintain the possibility to conceive. To answer such requests, it isimportant for medical professionals to consider the necessity to cure thewoman, to preserve her fertility, to give information both on the effect ofneoplasia and treatments on pregnancy. Patients have to be informedon the possible treatment alternatives that are less aggressive towards thereproductive function, but at the same time, give desirable results in terms ofsurvival. Neoplasiaand Fertility describes the state-of-the-arton fertility preservation in women affected by neoplasia. The 11 book chapters informthe reader with the goal of equipping them with the required information needed to present the condition and to discuss the possibility of conceiving, andhow to manage patients after oncologic treatments at different stages of pregnancy. KeyFeatures- Informs the reader about therelationship between gynecological cancer and fertility in women through 11chapters- Describes a broad range of cancers andrelevant treatment options for maintaining fertility- Explains the role of a ‘FertilitySparing Team’ in clinics- Familiarizes the reader with theethics behind oncology treatments with reference to female fertility- Describes fertility issues related to hereditarycancers in women- Includes references for furtherreading The book serves as an informativereference on the subject to medical doctors in the gynecology, obstetrics and midwifespecialties, and nurses training the gynecological oncology. It will also be ofinterest to healthcare administrators involved in fertility and oncologyclinics, as well as general practitioners in family medicine.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Jan 5, 2003
• ISBN: 9789815050141

Book preview

Fertility Preservation and Cervical Cancer: Fertility-Sparing Surgery and Cervical Cancer in Pregnancy

Lorenzo Ceppi¹, ², Tommaso Grassi¹, ², Robert Fruscio¹, ², Eleonora Preti³, Fabio Landoni¹, ², *

¹ Department of Medicine and Surgery, University of Milan-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milan, Italy

² Clinic of Obstetrics and Gynecology, San Gerardo Hospital, Via Pergolesi 33, 20900 Monza, Italy

³ Division of Gynecologic Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy

Abstract

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.

Keywords: Cancer in pregnancy, Cervical cancer, Chemotherapy in pregnancy, Conization, Fertility, Fertility-sparing surgery, HPV, Radiation therapy in pregnancy, Trachelectomy.

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* Corresponding author Fabio Landoni: Department of Medicine and Surgery, University of Milan-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milan, Italy; E-mail: [e-mail]

Cervical Cancer and Fertility Sparing Surgery

Introduction

The worldwide incidence of cervical cancer in 2012 was 527,600 cases, and the registered number of death was 265,700 [1]. It is the second most commonly diagnosed cancer and the third cause of cancer death among females in less developed countries. In the United States, it is the third most common gynecologic cancer and cause of death among gynecologic cancers; the estimated number of new cervical cancer cases and deaths in 2017 was 12,820 and 4,210, respectively [2]. In Europe, more than 58,000 new cases were diagnosed in 2012, and 24,000 patients died of cervical cancer [3]. Nearly 90% of cervical cancer deaths occurred in developing countries.

Cervical cancer accounted for the highest number of cancer related deaths among women in the United States in 1930. The cervical cancer screening with Papanicolaou (Pap) test reduced cancer incidence by 60-90% and death rate by 90%. A more recent screening tool is the HPV test, which has demonstrated higher sensitivity for high-grade cervical intraepithelial neoplasia [4, 5]. This tool relies on the presence of HPV deoxyribonucleic acid (DNA), which is found in almost all cervical cancers. The primary prevention of cervical cancer includes the introduction of HPV vaccination, which causes a decrease in high-grade cervical abnormalities, but the effect of vaccination on the incidence of cervical cancer has not been determined yet [4].

From the histological point of view, the World Health Organization (WHO) classifies the epithelial tumors of the cervix into three categories: squamous, glandular (adenocarcinoma) and other epithelial tumors, including adenosquamous carcinoma, neuroendocrine tumors, and undifferentiated carcinoma. 70-80% of cervical cancers are squamous cell carcinomas, while 20-25% are adenocarcinomas.

Cervical cancer is the only clinically staged gynecological cancer based on tumor size, vaginal or parametrial involvement, bladder/rectum extension and distant metastases. The staging system is the Federation International de Gynecologie et d’Obstetrique (FIGO) and the Union for International Cancer Control (UICC) TNM staging classifications (8th edition) (Table 1). At the end of 2018, the FIGO staging system was revised (Table 1B) [6]. In the current chapter, we are using the previous version of the FIGO staging system because most of the papers revised are using the old system. Therefore, if it is not specified, we refer to the 2009 FIGO staging system (Table 1A).

Table 1A The FIGO and TNM staging of cervical tumors [4,201].

a Extension to corpus uteri should be disregarded.b The depth of invasion should be taken from the base of the epithelium, either surface or glandular, from which it originates. The depth of invasion is defined as the measurement of the tumour from the epithelial–stromal junction of the adjacent most superficial papillae to the deepest point of invasion. Vascular space involvement, venous or lymphatic, does not affect classification.c All macroscopically visible lesions even with superficial invasion are T1b/IB.d Vascular space involvement, venous or lymphatic, does not affect classification.e Bullous oedema is not sufficient to classify a tumour as T4.f No FIGO equivalent. TNM, tumour, node and metastasis.

Table 1B The 2018 FIGO staging system of cervical tumors.

a Imaging and pathology can be used, when available, to supplement clinical findings with respect to tumor size and extent, in all stages. Pathological findings supercede imaging and clinical findings.b The involvement of vascular/lymphatic spaces should not change the staging. The lateral extent of the lesion is no longer considered.c Isolated tumor cells do not change the stage but their presence should be recordedd Adding notation of r (imaging) and p (pathology), to indicate the findings that are used to allocate the case to stage IIIC. For example, if imaging indicates pelvic lymph node metastasis, the stage allocation would be Stage IIIC1r; if confirmed by pathological findings, it would be Stage IIIC1p. The type of imaging modality or pathology technique used should always be documented. When in doubt, the lower staging should be assigned.

About 40% of cervical cancer diagnoses occur during the reproductive age [7]. Cancer risk in women younger than 50 years is higher (5.4%) than men (3.4%) due to the relatively high burden of breast, genital, and thyroid cancers. In 2012 cervical cancer was the second cause of cancer death among women from 20 to 39 years old in the USA, with more than 400 deaths [8]. In this group of young patients affected by cervical cancer, some women may not have completed their reproductive desire yet, particularly in the western world, where pregnancy is postponed after the third decade.

In this chapter, the relationship between fertility and cervical cancer will be discussed in two different ways:

Indications and limitations of fertility-sparing surgery (FSS) for cervical cancer and its obstetrical outcomes.

Cervical cancer in pregnancy and its therapy during different gestational ages.

Fertility-Sparing Surgery

The oncologic outcome is the main objective of the treatment. In highly motivated women, the fertility and obstetric outcomes need to be meticulously appraised, preserving the oncological one. At present, fertility-sparing surgery (FSS) is a suitable option for young patients affected by early-stage cervical cancer with negative lymph nodes. In literature, different FSSs are available for cervical cancer: conization or simple trachelectomy, vaginal radical trachelectomy (RT), abdominal RT (laparotomic or minimally invasive), and neoadjuvant chemotherapy (NACT) followed by FSS (conization/simple trachelectomy or RT). There is no evidence of the advantage of one technique over another; therefore, in the choice of the FSS technique, many different factors should be considered: the tumor prognostic factors (stage, size, histology, lymphovascular space invasion (LVSI) status, lymph node involvement, depth of cervical stromal invasion), the experience of the treating team, morbidity and fertility outcomes. The treatment options should be discussed with the patient, considering the oncologic and fertility outcomes with the aim of finding the best balance between them.

In this chapter, we are going to analyze when FSS is appropriate at different disease stages and which factors should be taken into account by a gynecologic oncologist from both an oncologic and obstetric perspective.

FIGO Stage IA

FIGO Stage IA1

For FIGO stage IA1 squamous cell cervical carcinoma, most authors agree that cervical conization is the best option, thanks to the low risk of node metastasis (< 1%) and 100% of healing rate when the resection margins are negative, similar to patients that underwent hysterectomy [9-11]. For patients with LVSI, pelvic lymph node dissection is recommended due to the increased risk of nodal involvement [12]. Sentinel node biopsy should be considered (see the section below). Moreover, for these patients, some authors suggest trachelectomy. For FIGO stage IA1 cervical adenocarcinoma, data from the literature are controversial. Some papers reported that in patients that underwent a hysterectomy after conization for adenocarcinoma in situ (AIS), the persistence of AIS was in 30-50% of patients with negative cone resection margins and the presence of invasive adenocarcinoma in non-resected tissue was in 13-20% of patients [13-18]. More recent studies advocated that conization with negative margins should be considered treatment for the absence of parametrial spread and pelvic lymph node involvement in early lesions [19-22]. For this reason, fertility-sparing procedures should be carefully weighted [23, 24].

FIGO Stage IA2

For FIGO stage IA2 squamous cell cervical carcinoma, the risk of nodal metastasis is 2 to 8% in the absence or presence of LVSI, respectively [25]. For patients wishing to preserve fertility, cone biopsy with free margins of resection or radical trachelectomy (both of them with pelvic lymphadenectomy) may be considered [26-30]. Sentinel node biopsy may also be considered (see the section below). The same FSSs may be considered in FIGO stage IA2 cervical adenocarcinoma; however, as discussed above for FIGO stage IA1, data for the adenocarcinoma subtype are arguable. In a recent retrospective study of women affected by micro-invasive adenocarcinoma of the cervix, neither the histotype (squamous versus adenocarcinoma) nor the surgical approach (local excision versus radical hysterectomy versus simple hysterectomy) influence the survival of patients [31]. In other studies, the risk of recurrence is described as similar in patients that underwent conservative therapy (conization or radical trachelectomy both with pelvic lymphadenectomy) or radical hysterectomy. However, these series reported a limited number of cases [23, 24, 32].

FIGO Stage IB

FIGO Stage IB1

The clinical and histological characteristics of patients with stage IB1 cervical cancer need to be carefully evaluated to enroll a patient in a fertility-sparing approach.

Clinical and Histological Characteristics Evaluation

The evaluation of nodal involvement is the first critical selective step for FSS since node-positive disease is a contraindication to a fertility-sparing approach, while it is an indication for adjuvant therapies (Table 2).

Additionally, the histologic subtype needs careful evaluation. As for stage IA, stage IB1 adenocarcinoma needs to be carefully managed. However, this histotype is not a contraindication to an FSS since some series of patients did not show a higher risk of recurrences compared to squamous histotype [33-36]. The reason for the cautious management is related to some cases of adenocarcinoma IB1 (also with tumor size 2 cm or smaller) treated with vaginal radical trachelectomy that developed a pelvic recurrence and sometimes had a worse prognosis [37-39]. The scarce data about rare histological subtypes and their intrinsic bad prognosis possibly constitute exclusion criteria for FSS (Table 2). The rare and aggressive neuroendocrine tumors of the cervix are considered a contraindication to FSS in the majority of centers due to the high risk of recurrence and the potential need of adjuvant therapy [34, 35, 40-43]. Also, for the adenosquamous histological subtype, the few data of the literature available are not sufficient to express a clear indication for FSS [35, 44].

Table 2 Indications and contraindications for six different FSS strategies for patients with FIGO stage IB cervical cancer [54].

The evaluation of the proximal extension of the neoplasia to the uterine corpus is necessary to obtain an acceptable free margin of resection (at least 8-10 mm) for both oncologic and obstetric outcomes [35, 45]. The superior part of the endocervical canal must not be involved in the neoplasia (colposcopy, hysteroscopy, and MRI evaluation are all indicated in the preoperative assessment). MRI is a useful tool for pre-operatory assessment of the patients because of its high sensitivity in identifying the invasion beyond the internal orifice of the cervix uterine [46], the endocervical extension and the volume of the neoplasia [45-50]. A paper suggests that for an adequate surgical plan for FSS the MRI report should provide the tridimensional diameters of the lesion, uterine and cervical lengths, the distance from the internal os, the degree of stromal invasion, and the presence of extra cervical or nodal involvement [51].

Choice of Fertility Sparing Surgery technique

The choice between the different fertility-preserving procedures at this stage mainly depends on tumor size and LVSI status, as well as the experience and surgical confidence of the team (Fig. 1). Some authors also suggest the evaluation of the depth of invasion of the cervical stroma, while few recommendations exist in the literature regarding the tumor grade as a criterion for the feasibility and safety of an FSS.

Fig. (1))

Algorithm for the management of Stage IB1 cervical cancer [54]. LVSI=lympho-vascular space invasion. RT=radical trachelectomy. NACT=neoadjuvant chemotherapy. *Some patients had stage IA disease with LVSI, although the number is not specified in all series. †Recurrence was micro-invasive with no invasive lesion. ‡Proportion of patients with positive margins based on the overall population undergoing this treatment.

The tumor size is divided into smaller or bigger than 2.0 cm (Fig. 1) (see the sections below).

LVSI is a prognostic factor in the early stages of cervical cancers [52]. LVSI should be interpreted as a sign of biological aggressiveness. This factor is unknown if the diagnosis of cervical cancer is based on a biopsy, so some authors suggest a cone resection before the proposal of an FSS, especially in those patients with a visible lesion of the cervix. This is an indication for authors that interpret the presence of LVSI as a contraindication to FSS in stage IB1 [53] (Fig. 1).

The depth of invasion of the cervical stroma was described as a prognostic factor in early-stage cervical cancers [52], so for some authors, a depth of invasion higher than 10 mm (as an estimate of the boundary between the middle and outer 1/3 of the cervical stroma) or >50% of cervical stroma at RMI had been considered as a high-risk tumor factor [54].

FIGO Stage IB1 and Tumor Size < 2.0 cm (2018 FIGO Stage IB1)

Currently, radical trachelectomy (RT) is considered by most international guidelines the standard procedure for FSS in FIGO stage IB1 cervical cancer, with tumor size smaller than 2 cm; however, at present, the oncologic value of parametrial dissection is a controversial issue. In the literature three fertility-sparing procedures are described in these cases: vaginal RT (Dargent’s procedure), conization or simple trachelectomy, and abdominal RT (laparotomic or minimally invasive).

Radical trachelectomy with pelvic lymphadenectomy was described for the first time in 1994 by Dargent and colleagues for stage FIGO IB1 cervical cancer in a selected group of patients. The first surgical approach in this procedure is laparoscopic systematic lymphatic node evaluation to evaluate the presence of node metastasis. In the case of positive pelvic nodes, radical trachelectomy is not indicated. If lymphatic nodes are negative during laparoscopy, it’s good advice to prepare the spaces for the parametrial resection to simplify the vaginal time. The beginning steps of vaginal trachelectomy mirror those for vaginal hysterectomy, so after the circumcision of the vaginal wall around the cervix, the vesicovaginal space has to be prepared to lift the bladder. With the opening of the posterior fornix and the posterior cul-de-sac of Douglas, the resection of the proximal part of the uterosacral ligaments is indicated. Then proceed with resection of the proximal parametrium at the isthmus level after identification of ureters. Only the descending arm of the uterine artery is sectioned due to its position at the isthmus level. Then proceed with resection of the cervix 1 cm down the isthmus of the uterus. An intraoperative frozen section of the cervix is strongly suggested. The minimum free section between the neoplasia and the resected tissue should be 8 mm, and if this target is not reached, completion of the resection is indicated. After closing the posterior cul-de-sac and posterior fornix, cervical cerclage is positioned with a non-absorbable suture, and the vaginal wall is closed on the new eso-cervix. At the end of the vaginal time, a laparoscopic control of hemostasis and integrity of the pelvic structures is recommended.

In a recent review of literature it is described that among 1364 eligible patients that underwent Dargent’s procedure (radical trachelectomy with pelvic lymphadenectomy as described above), 58 (4%) had recurrent disease, and 24 (2%) died [34, 42, 55]. The main factors associated with recurrent disease were tumor size and LVSI status: among those patients with stage IB1 tumors larger than 2 cm, 17% had recurrent disease, compared with 4% among 617 patients with stage IB1 tumors of 2 cm or smaller. Positive margins were reported n 3% of patients. In 473 patients in which LVSI description was present, 162 patients (34%) were LVSI positive, and 311 (66%) patients were LVSI negative, of whom respectively 7% and 5% had recurrent disease. In patients with FIGO stage IB1 with tumor size of 2 cm or smaller and LVSI negative, the recurrence rate was 6% [55].The morbidities related to Dargent’s procedure are related to the lymphadenectomy or cerclage (cervical stenosis and erosions). Cervical stenosis is the most common complication that may impact fertility.

In 1997 an alternative approach to the vaginal RT was proposed, the abdominal RT, to create an alternative to a procedure that required both vaginal and laparoscopic skills [56]. Three types of abdominal radical trachelectomy are described: laparotomic or minimally invasive procedure using a pure laparoscopic or robotic-assisted laparoscopic RT [57-68]. In a comparison of the surgical outcome between vaginal RT and abdominal RT, 43 women with FIGO stage IB1 underwent fertility-sparing RT. The median measured parametrial dissected length in the abdominal RT group was more than 50% greater than in the vaginal RT group, while the blood loss was more in the abdominal RT group, but not in a statistically significant way [58]. As a comparison, the parametrectomy of the Dargent’s operation is comparable to a modified radical hysterectomy (type B), while the abdominal RT with its large parametrectomy is similar to a type C1 radical hysterectomy [57, 62, 69]. This was the origin of the idea that for patients with less favorable prognostic factors, the abdominal radical trachelectomy can be proposed to be more radical in terms of parametrial and paracervical resection. The abdominal RT is described in the patients with stage FIGO IB1 cervical cancer with tumor size less than 2 cm as an alternative to vaginal RT. The choice between the two procedures should include the surgical experience of the treating team. A series of 15 women with stage IA2 and IB1 disease (squamous cell carcinoma or adenocarcinoma) with tumor size less than 2 cm underwent an abdominal laparotomic radical trachelectomy and pelvic lymphadenectomy. In a median follow-up time of 32 months, no recurrence was described, and three patients had three pregnancies: 1 pre-term delivery and two-term deliveries [60].

The oncologic value of parametrial dissection in patients with a tumor smaller than 2 cm, negative LVSI and node-negative is debated [70]. The idea of less radical surgery in these patients resulted from a series of studies in which women who underwent radical surgery for a cervical cancer stage FIGO IB1 could be safely cured by a simple hysterectomy or cervical conization [54, 70-74]. As described by Wright in a retrospective study of 594 cases with early-stage cervical cancer that underwent a radical hysterectomy, the incidence of parametrial involvement is less than 1% in women with tumor size smaller than 2 cm, negative pelvic lymph nodes and no LVSI [73]. In another study, any residual disease is reported in approximately 60%–65% of simple vaginal trachelectomy specimens after diagnostic cone in patients with an early stage low-risk cervical cancer, questioning the need for radical surgery in patients with low-risk tumors [35, 75, 76]. To reduce the morbidity and have a higher pregnancy rate, it is described that less radical treatment may be a valid choice for FSS in this high-selected group of patients. A series of 36 women with a stage IB1 disease smaller than 2 cm (both squamous carcinoma and adenocarcinoma) underwent cervical conization and pelvic lymphadenectomy.