Detection of invasive cervical cancer during pregnancy is rare, with reported incidence rates ranging from 0.05% to 0.1%. However, cervical cancer is one of the most common malignancies diagnosed during pregnancy.
The management of invasive cervical cancer in pregnancy is extremely challenging and requires a multidisciplinary team approach to optimise the treatment for the patient by simultaneously providing the best chance of survival for the foetus. The approach is based mainly on the following factors: gestational age at the time of the diagnosis, stage, histological subtype, desire regarding fertility and quality of life.
The gold standard treatment for this condition in pregnancy is not yet established. This is due to the absence of prospective studies and clinical trials. Therefore, its management presents a dilemma that requires individualisation of care. The various factors that need to be considered for obtaining a good outcome for both mother and child are described in this study.
Highlights
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A multidisciplinary care team should be involved in the management.
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The management is mainly based on stage, foetal viability and fertility desire.
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Magnetic resonance imaging (MRI) is safe to evaluate cervical cancer in pregnancy.
Diagnosis
Signs and symptoms
The symptoms of invasive cervical cancer depend mainly on the clinical stage and size of the tumour. With the advent of screening, most cancers are diagnosed at an early stage with a small disease volume. Two-thirds of cancers diagnosed during the first two trimesters are stage 1B tumours . However, pregnancy can either simulate or mask the diagnosis of most of them, hence complicating the process . In the early stages of the disease, women are generally asymptomatic; therefore, the diagnosis becomes an incidental finding during routine pelvic examination or cytological investigations. Early stages of cervical cancer can sometimes present with abnormal bleeding, unusual or unpleasant vaginal discharge, post-coital bleeding and dyspareunia, whereas in advanced stages, urinary dysfunction, pelvic pain, changes in bowel habit, back pain and swelling of legs are also reported .
Pelvic examination
When a cervical abnormality is suspected, an accurate pelvic examination (speculum and bimanual examination) needs to be performed, regardless of gestational age. In speculum examination, the clinician assesses bleeding, abnormal discharge and vault/cervical lesions. Size, shape and consistency of the cervix and/or cervical lesions are assessed during the bimanual examination.
However, because of physiological cervical ectopy, cervical assessment can be more challenging in pregnant women than their non-pregnant counterparts. Exophytic, friable, necrotic and cervical lesions that bleed easily are to be considered suspicious and require further investigation.
Obstetricians should be involved in the gynaecological oncology team when relevant lesions are detected during the examination. Careful biopsy should be considered if any doubt arises about the nature of a cervical lesion.
Cytology
A woman’s cervical cytology history should be investigated when a cancer is suspected. A smear test needs to be performed when she could not provide clear data. For this reason, clinics in some developed countries perform cervical cytology as a routine assessment during the first antenatal visit, which could provide a gynaecological assessment for irregularly followed up women.
However, it is more difficult to interpret cervical cytology during pregnancy , as the Arias-Stella phenomenon and the hyperplastic epithelium, which are common features of pregnancy, can simulate malignant changes. An abnormal smear test should alert the obstetrician, and a gynaecological oncology referral and/or colposcopy follow-up should be organised .
Colposcopy
The colposcopic assessment includes a full lower genital tract examination of women. However, it differs between pregnant and non-pregnant women for several reasons.
The hormonal changes, on the one hand, make the cervix hypertrophic and hyperplastic, which results in eversion of the columnar epithelium. Hence, the transformation zone is clearly visible in 90–100% of the patients .
On the other hand, these changes lead to decidualisation of the cervical stroma, which becomes prominent and causes densely opaque aceto-white lesions. The physiological ectropion and the consequent exposure to the vaginal pH can cause squamous metaplasia. All these physiological changes could be misinterpreted as dysplasia.
Colposcopic features of invasive cancer are similar for both pregnant and non-pregnant women. These include abnormal vessels, irregular surface and complex patterns, such as mosaicism or punctation. Biopsies performed during colposcopic examination are considered safe for the foetus in all the trimesters and reliable for diagnosis. However, it is recommended that any type of invasive procedure be performed after the first trimester to reduce the risk of spontaneous miscarriage . After a cervical biopsy, the vaginal pack may be considered to have an increased risk of bleeding because of the increased vascularisation of the cervix in pregnancy. Endocervical curettage is contraindicated in any trimester because of an increased risk of miscarriage .
Staging
International Federation of Gynaecology and Obstetrics stages
The International Federation of Gynaecology and Obstetrics (FIGO) proposed a common staging classification for both pregnant and non-pregnant women based on clinical findings .
Examination under anaesthesia
Because the FIGO staging classification is based on clinical findings, a full assessment must be performed to determine an appropriate therapeutic approach . In non-pregnant women, if the cervical lesion is clearly visible, examination under anaesthesia (EUA) is usually performed to assess whether parametrium, rectum and bladder are involved. It is usually considered safe to perform surgical procedures under general anaesthesia after the first trimester; however, it is highly recommended to avoid an EUA during pregnancy and therefore assess the patient gently when she is awake .
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is important for assessing the local extension of the disease and the involvement of lymph node. As no radiation is used, MRI scans are safe; in addition, they have acceptable sensitivity and specificity . Balleyguier et al. reported the role of MRI in the management of 12 women for the diagnosis of cervical cancer during pregnancy. In all patients, MRI was performed without contrast. The regional extension of the disease, the image impairment due to foetal movement and the pitfalls in lesion visibility were evaluated. MRI did not show any involvement of lymph node in all patients with cervical cancer. In the early stages, MRI provided a safe method of follow up until the time of delivery. In women with locally advanced tumour, radiologists were able to detect the involvement of parametrium, bladder and vagina. T2-weighted sequences were used; however, the signal intensity did not correlate with the tumour grade. In patients who had received neoadjuvant chemotherapy (NACT), MRI follow-up was performed every 4 weeks until the 30th week of gestation to monitor treatment response.
The use of iodinated or gadolinium-based media in pregnancy has been discussed widely. The former is considered safe for both the mother and foetus . Regardless of pregnancy, diffusion-weighted imaging (DWI) is the most valuable sequence to assess the primary cervical tumour. DWI helps calculate the apparent diffusion coefficient (ADC), which improves the characteristics of primary lesion . However, DWI is not consistent and has a low rate of reproducibility.
Positron emission tomography–computed tomography
Positron emission tomography–computed tomography (PET–CT) scans can be used to further evaluate the involvement of lymph node. Zanotti-Fregonara et al. recently reported that pregnancy is not an absolute contraindication in performing PET scans. This study described the largest series (six) of women investigated with FDG PET. Recently, MRI/PET has appeared as a good alternative for assessment during pregnancy as it allows accurate dosimetric calculation of the tracer. However, currently it is not widely available.
Chest radiograph study
Chest X-ray study can be conducted safely after the first trimester to eliminate distant disease. However, a proper shielding of abdomen is recommended. It is also recommended that this study be performed only in cases of locally advanced disease (>FIGO IB2).
Staging
International Federation of Gynaecology and Obstetrics stages
The International Federation of Gynaecology and Obstetrics (FIGO) proposed a common staging classification for both pregnant and non-pregnant women based on clinical findings .
Examination under anaesthesia
Because the FIGO staging classification is based on clinical findings, a full assessment must be performed to determine an appropriate therapeutic approach . In non-pregnant women, if the cervical lesion is clearly visible, examination under anaesthesia (EUA) is usually performed to assess whether parametrium, rectum and bladder are involved. It is usually considered safe to perform surgical procedures under general anaesthesia after the first trimester; however, it is highly recommended to avoid an EUA during pregnancy and therefore assess the patient gently when she is awake .
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is important for assessing the local extension of the disease and the involvement of lymph node. As no radiation is used, MRI scans are safe; in addition, they have acceptable sensitivity and specificity . Balleyguier et al. reported the role of MRI in the management of 12 women for the diagnosis of cervical cancer during pregnancy. In all patients, MRI was performed without contrast. The regional extension of the disease, the image impairment due to foetal movement and the pitfalls in lesion visibility were evaluated. MRI did not show any involvement of lymph node in all patients with cervical cancer. In the early stages, MRI provided a safe method of follow up until the time of delivery. In women with locally advanced tumour, radiologists were able to detect the involvement of parametrium, bladder and vagina. T2-weighted sequences were used; however, the signal intensity did not correlate with the tumour grade. In patients who had received neoadjuvant chemotherapy (NACT), MRI follow-up was performed every 4 weeks until the 30th week of gestation to monitor treatment response.
The use of iodinated or gadolinium-based media in pregnancy has been discussed widely. The former is considered safe for both the mother and foetus . Regardless of pregnancy, diffusion-weighted imaging (DWI) is the most valuable sequence to assess the primary cervical tumour. DWI helps calculate the apparent diffusion coefficient (ADC), which improves the characteristics of primary lesion . However, DWI is not consistent and has a low rate of reproducibility.
Positron emission tomography–computed tomography
Positron emission tomography–computed tomography (PET–CT) scans can be used to further evaluate the involvement of lymph node. Zanotti-Fregonara et al. recently reported that pregnancy is not an absolute contraindication in performing PET scans. This study described the largest series (six) of women investigated with FDG PET. Recently, MRI/PET has appeared as a good alternative for assessment during pregnancy as it allows accurate dosimetric calculation of the tracer. However, currently it is not widely available.
Chest radiograph study
Chest X-ray study can be conducted safely after the first trimester to eliminate distant disease. However, a proper shielding of abdomen is recommended. It is also recommended that this study be performed only in cases of locally advanced disease (>FIGO IB2).
Management
The main factors to be considered in the initial management of cervical cancer in pregnancy are illustrated in Fig. 1 .
It is important to discuss the advantages and disadvantages of pregnancy preserving treatment with the woman and her partner during the initial management. Psychological support is fundamental in this phase, and we strongly recommend providing adequate care for the couple. The diagnosis of cancer in pregnancy is a traumatic event for any couple. Otherwise, they will have to face a potentially life-threatening disease post delivery . Hence, it is necessary to have a clinical nurse specialist (CNS) support at the time of diagnosis and during the overall management of the disease .
The first discussion should be focussed on the possibility/choice to interrupt the pregnancy.
In the UK, termination of pregnancy (TOP) is legal until 24 weeks of gestation if medically indicated. Standard treatment for cervical cancer, in accordance with the desire regarding fertility, can then be initiated in patients who decide to terminate the existing pregnancy.
Management of women wishing to terminate the existing pregnancy
Low-stage tumours (stage 1A1–1B1) that are managed surgically
Medical TOP should be offered in the first trimester to avoid dissemination of the disease during surgical evacuation.
If the diagnosis is made after 12–14 weeks of gestation, hysterotomy should be performed to avoid cervical dilatation during the termination.
In stage 1A1 tumour, a cone biopsy is the curative treatment of choice. Conisation in stage 1A1 tumour can be performed in all patients, regardless of their desire regarding fertility. It must be noted that conisation is performed during pregnancy only when an invasive disease is strongly suspected. Clearly, the risk of bleeding and miscarriage is significant, which should be delayed before the early second trimester if possible. Thus, in the context of a smear suggestive of invasion combined with concerning colposcopic findings with or without a biopsy showing microinvasion, in an unwanted pregnancy, termination should be carried out medically. Cone biopsy may then be performed safely.
Radical hysterectomy is recommended in women having stage 1A2 and 1B1 tumours, who have already completed their childbearing, when the diagnosis is made before the 24th week of gestation. The surgical procedure is similar to that used in non-pregnant women; however, the increased vascularity in pregnancy leads to a higher risk of bleeding. Whether radical hysterectomy is more favourable when performed during pregnancy or after delivery is a matter of debate. There is some evidence of few surgical complications when the uterine size is reduced after evacuation of the uterus .
Women who have not completed their childbearing may be considered for fertility-sparing treatment similar to non-pregnant women.
Radical trachelectomy (RT) can be performed either vaginally or abdominally (open or laparoscopically) with pelvic lymph node dissection (PLND) in a non-pregnant woman. The world literature and indeed in our hands, tumours less that 2 cm may be managed safely with the vaginal approach and those between 2 and 4 cm can be managed by abdominal trachelectomy . Trachelectomy in any tumour >2 cm needs to be carefully considered as the oncological outcome may be compromised. The robotic approach for trachelectomy in pregnancy has not been reported yet.
In stage 1A2 tumour, the risk of lymph node metastasis is approximately 10% . A large cone biopsy may be recommended in selected patients with stage 1A2 and small-volume 1B1 tumours with low-risk histology and PLND .
High-stage tumours that are treated non-surgically (stage 1B2 and beyond)
A fertility-sparing option is not appropriate in these advanced tumours. The major focus has to be on ‘evacuation’ of the uterus and commencement of chemo/radiotherapy. Medical TOP is advised in the first trimester, as dilation of a cervix with a large tumour may increase the risk of bleeding, dissemination of disease and perforation.
External beam radiotherapy can be initiated in pregnant women. However, it has been reported that radiation can cause miscarriage, usually between 24 and 34 days after commencement of the treatment . Once the uterus is empty, intracavitary radiotherapy can be performed .
When cancer is detected after 12–14 weeks of gestation, hysterotomy is recommended before starting oncological treatment. However, after hysterotomy, there may be an increased risk of developing adhesions, which could worsen the side effects of radiotherapy. It is believed that the aforementioned risks of dilatation of a diseased cervix far outweigh the risk caused by adhesions.
Management of women wishing to continue their pregnancy
Women who wish to continue their pregnancy or who are beyond the legal TOP limit (>24 weeks of gestation) present an interesting and challenging situation.
Low-stage tumours (stage 1A1–1B1) that are managed surgically
The previous comments regarding the management of minimally microinvasive disease (stage 1A1) apply here. These lesions are usually diagnosed on cone biopsy and no further action is usually required.
Invasive cervical cancer from stage 1A2 to 1B1, which is surgically treated using traditional methods, needs to be assessed on an individual basis. A discussion with the patient and her partner is recommended. It is noteworthy that delaying cancer treatment for foetal lung maturity could affect the prognosis.
In general, TOP should be seriously considered in women in whom cancer is diagnosed in the first or early second trimester. There will be obviously a cohort of women who will have an overwhelming desire to continue their pregnancy, thereby presenting a major challenge for management.
Excellent outcomes are obtained for even extremely premature infants with modern neonatal facilities. The EPIPAGE-2 cohort study reported the following survival rates in preterm children: 59.1% infants born at 25 weeks, 75.3% at 26 weeks, 93.6% at 27 through 31 weeks and 98.9% at 32 through 34 weeks . With these excellent survival rates with minimal morbidity, it would be reasonable to recommend that women in their early third trimester are given steroids to accelerate foetal lung maturity and infants are delivered without delay, so that oncological treatment may be commenced. There will obviously be variations in neonatal services, and thus it is recommended that obstetric, neonatal and oncological services be provided on one site, if possible, even if it requires the gynaecological oncology team to travel to another site .
This group of women presents many challenges for management, and individualisation of care is necessary. Delaying oncological treatment until foetal viability with a good neonatal outcome would involve a significant length of time and may adversely affect maternal survival. It is important to consider whether oncological treatment can be commenced whilst continuing the pregnancy safely. In this regard, there are three main issues that require careful investigation.
Role of NACT
The rationale for administering NACT in locally advanced cervical cancer is to (1) reduce the size of the primary tumour and (2) prevent dissemination of the disease until foetal viability is achieved. The advantages and drawbacks of the treatment should be discussed with the patient and her partner because of the limited number of retrospective studies and the absence of long-term follow-up.
The main agent reported in pregnancy is platinum-based cisplatin (50–100 mg/m 2 ), alone or in combination with paclitaxel (175 mg/m 2 ), bleomycin, vincristine, 5-fluorouracil or vincristine and bleomycin. Carboplatin in combination with paclitaxel has also been reported . The therapy should be administered once every 3 weeks ( Fig. 2 and Table 1 ).
| Authors | GA | FIG O Stage | Histology | Gr | Agent | Response | GA Delivery | Type Delivery | Neonatal Outcome |
|---|---|---|---|---|---|---|---|---|---|
| Rabaiotti, 2010 | 15 | 1B2 | SCC | 3 | P 3 cycles | SD | 32 | CS | Well |
| Chun, 2010 | 28 | 1B2 | SCC | NA | PT 2 cycles | PR | 36 | CS RH PLND PALND | Well |
| Li, 2011 | 29 | 1B2 | SCC | NA | PT 2 cycles | CR | 33 | CS | Well |
| Li, 2011 | 27 | 1B2 | SCC | 3 | PT 2 cycles | PR | 33 | CS | Well |
| Fruscio, 2012 | 18 | 1B2 | SCC | 3 | P | SD | 32 | CS RH | Well |
| Fruscio, 2012 | 16 | 1B2 | SCC | 3 | PT | PR | 33 | CS RH | Well |
| Fruscio, 2012 | 16 | 1B2 | SCC | 3 | PT | PR | 34 | CS RH | Well |
| Fruscio, 2012 | 20 | 1B2 | SCC | 3 | P | SD | 35 | CS RH | Well |
| Gambino 2011 | 20 | 1B2 | SCC | NA | P | NA | 22 | NA | Well |
| Gambino 2011 | 24 | 1B2 | SCC | NA | P 3 cycles | NA | 36 | NA | Well |
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