Cervical cancer is one of the most common malignancies in pregnancy, and with the rejuvenation of cervical cancer and the delayed age of childbirth, combined cervical cancer in pregnancy has become a concern for obstetricians and gynecologists. Due to the need to consider the patient’s fertility requirements, extensive hysterectomy in anticipation of treatment until the fetus is viable in vitro and preservation of the fetus is the trend of treatment in recent years, but there is still no unified two-pronged treatment plan, and the progress of diagnosis and treatment of combined cervical cancer in pregnancy is reviewed.
Cervical cancer is the most common gynecologic malignancy in pregnancy, with an incidence rate of 1-12/10,000 pregnancies [1,2]. The current findings suggest that pregnancy has no effect on the prognosis of cervical cancer, and the prognosis of cervical cancer during pregnancy is similar to that of non-pregnancy [3,4]. With the younger age of cervical cancer and delayed age of childbirth, combined cervical cancer during pregnancy has become a concern for obstetricians and gynecologists. The clinical management of combined cervical cancer in pregnancy has special characteristics that require consideration of both the disease treatment itself and the pregnant woman and fetus, and requires a comprehensive consideration taking into account multiple factors. Considering the patient’s fertility requirements, extensive hysterectomy in anticipation of treatment until the fetus is viable in vitro and preservation of the fetus is the trend of treatment in recent years, but there is no unified two-pronged treatment plan so far, and we would like to review the progress of diagnosis and treatment of cervical cancer in pregnancy.
The symptoms of cervical cancer in pregnancy are not different from those of non-pregnancy, and the study of relevant literature confirms that most patients with stage I are asymptomatic and have symptoms such as irregular vaginal bleeding (mostly post-coital bleeding) and fluid discharge. months [5]. Since the squamocolumnar junction is often displaced during pregnancy due to the effects of high estrogen, i.e., the appearance of “erosions” observed visually, cytologic and histopathologic examinations can accurately and rapidly diagnose cervical lesions during pregnancy. The diagnosis of cervical lesions in pregnancy is the same as in non-pregnancy and follows a three-step ladder of cytopathology, colposcopy and histopathology biopsy.
1.1.1 Cervical cytology examination of the cervix during pregnancy in a high estrogen environment can result in cervical cell abnormalities of 10% to 15%, which can easily be misdiagnosed as atypical hyperplasia or cervical cancer, resulting in overdiagnosis. Therefore, the cytology specimens sent for examination must be marked as pregnant or not to avoid overdiagnosis.
I.2. HPV testing during pregnancy is also used as an adjunct to cytology to improve the detection rate of cervical lesions.
I.3. Colposcopy evaluation during pregnancy is aimed at ruling out cervical invasive cancer, and colposcopy performed during pregnancy by an experienced colposcopist is safe and will not harm the pregnancy or the fetus [5].
1.4. In pregnant women with abnormal cervical cytology smears, colposcopy should be performed with direct biopsy at the most significant abnormal site if the possibility of invasive cancer cannot be ruled out. Cervical biopsy during pregnancy will not cause hemorrhage or serious pregnancy complications, but the sampling site should be accurate and should not be too deep or too wide, and after sampling, pressure can be applied to the biopsy site to stop bleeding or medication. Cervical canal scraping is strictly prohibited during pregnancy because it can cause prostaglandin secretion, resulting in premature rupture of fetal membranes, episodic infection, bleeding and other potential risks.
1.5. Cervical conization is suitable for patients whose biopsies cannot exclude invasive cancer. Cervical conization during pregnancy is more dangerous and has more complications, such as miscarriage, preterm labor, infection and maternal hemorrhage, so it is necessary to strictly grasp the indications and restrict it to the middle of pregnancy, and the depth should preferably be <10mm.
Ultrasound and MRI examination can help to solve this problem. Ultrasound and MRI can also assist in determining the size of the tumor, the depth of infiltration, the presence of metastases and enlarged pelvic lymph nodes in the parametrium, and the risk to the fetus is low.
In 2005, the European Society of Urogenital Radiology concluded that the use of gadolinium-containing contrast agents in pregnant women is safe. Studies have shown that… The dose used in contrast examinations is not sufficient to pass through the placenta, and even small amounts of gadolinium pass through the placenta and are rapidly metabolized in the fetus [6]. Therefore, the application of MRI imaging in patients with cervical cancer combined with pregnancy is beneficial in improving the detection rate of metastases, providing accurate staging and formulating effective treatment plans for patients.Choi et al. evaluated 1 15 patients with cervical cancer combined with pregnancy using MRI preoperatively, and the negative predictive values for infiltrating parametrial, vaginal, and pelvic lymph nodes were 95%, 96%, and 93%, respectively [7]. More and more scholars advocate the use of MRI in cervical cancer combined with pregnancy. Positron emission tomography (PET) is still contraindicated in pregnancy.
Management of combined cervical intraepithelial neoplasia in pregnancy Low-grade intraepithelial neoplasia combined in pregnancy regresses in 48-62% and does not change in 29-38% [8,9]. Combined high-grade intraepithelial neoplastic lesions have a low regression rate of 27.4-34.2% and a progression rate of 2.7-9.7% [10]. In the absence of invasive cervical cancer, treatment is not required during pregnancy and can wait until after delivery. If disease progression is suspected, colposcopy can be performed again.
Management of pregnancy with stage IA and stage IB1 invasive cervical cancer Previously, it was considered that early and mid pregnancy were the mainstay of timely treatment of maternal cancer, while treatment of the latter at 24 weeks of gestation could be postponed to cesarean section at 32-34 weeks of gestation with intraoperative radical hysterectomy. It is generally accepted that the treatment of small lesions of IA or IB diagnosed after 20 weeks of gestation can be postponed until fetal maturity if there is an urgent need to continue the pregnancy; vaginal delivery is feasible in IA1 and total hysterectomy is performed after delivery; in IA2, cesarean delivery is preferred and radical hysterectomy is performed intraoperatively [11].
In recent years, there have been major advances in fetal preservation treatment, which is feasible even for early cervical cancer in early pregnancy. The options for conservative treatment are delayed treatment, extensive cervical hysterectomy or neoadjuvant chemotherapy.
3.1 The relevant factors to decide whether fetal preservation is possible in cervical cancer combined with pregnancy depend on four main aspects: the histological type of the tumor, whether the lymph nodes are metastatic, the degree of tumor dissemination (stage and size of the tumor) and the gestational week of the fetus.
3.1.1. The histological type of the tumor is similar in the healing of squamous, adenocarcinoma and squamous adenocarcinoma of the cervix, so they are treated in a similar way. However, small cell carcinoma of the cervix has a poor healing and must be treated after termination of pregnancy [2].
3.1.2, whether lymph nodes are metastatic Early cervical cancer detected in early and early mid pregnancy, MRI and laparoscopic lymph node dissection can help to understand the extent of tumor dissemination and decide whether fetal preservation treatment can be performed according to the condition. Laparoscopic lymph node dissection before 20 weeks is feasible. The literature reports 31 cases of pelvic lymph node dissection during pregnancy with no intermediate openings and no fetal or maternal complications [12,13].
If lymph node metastasis is present, the prognosis is different, so the treatment modality is different, and preservation of the fetus is generally not advocated.
3.1.3, Staging and size of tumor 70% of cervical cancers are found to be FIGO stage I [14,15]. stage I patients with small tumors (<4 cm) and MRI examination suggesting no lymph node metastasis can be treated with fetal preservation, and there are two main treatment options. One is delayed treatment, during which close clinical and imaging follow-up is performed, except for tumor progression, until fetal maturity and simultaneous radical hysterectomy during cesarean section. The second is to perform an extensive hysterectomy with preservation of the uterus and the fetus. As mentioned below, there are also individual papers that use neoadjuvant chemotherapy followed by expectation until fetal maturity.
The management of locally advanced cervical cancer combined with pregnancy is controversial. Neoadjuvant chemotherapy can be performed to preserve the pregnancy or radiotherapy can be performed after termination of pregnancy, depending on the size of the tumor, imaging findings, fetal gestational age and the patient’s wishes.
3.1.4. Regardless of the gestational age of the fetus, if the pregnant woman and her family have a strong demand for childbirth, the fetus can be preserved according to the aforementioned criteria, and the fetus can be followed closely clinically and imaging-wise, except for the progression of the tumor, and when the fetus is mature, appropriate measures can be taken according to the stage of cervical cancer and maternal condition at the same time or later when the pregnancy is terminated.
Treatment modalities for fetus-preserving cervical cancer 3.2.1 Fetus-preserving delayed treatment Duggan et al [16] et al reported eight cases of pregnancy combined with stage I cervical cancer, including squamous, adenocarcinoma, and squamous adenocarcinoma, in which patients at 11-27 weeks of gestation were treated with a delay of 6-15 weeks, with a mean delay of 144 days (20 weeks) for surgery, and patients were followed up for a mean of 23 months after surgery, with no evidence of recurrence. The authors concluded that delaying treatment in the case of cervical cancer stages IA and IB (lesions <4 cm in diameter) combined with pregnancy does not increase maternal risk.Germann et al [17] performed delayed treatment in 21 patients (13, 5, 2, and 1 in early, intermediate, and late pregnancy and postpartum patients, respectively; 15, 5, and 1 in stages IB, IIB, and IVA, respectively) with a mean delay of 5 months in early pregnancy (3-6 months) before treatment, and 3 months (1-4 months) for intermediate pregnancies, with a mean follow-up of 64 months (2-165 months), which showed an overall survival rate and 5-year disease-free survival rate of 82% and 79%, respectively; it is believed that treatment can be delayed until fetal maturity for early pregnancies with stage IB lesions <2 cm in diameter and without lymph node metastases.
The prognosis of cervical cancer in pregnancy combined with stage IA is expected to be better, and preservation of the fetus has now become the norm of treatment [2]. although the treatment of stage IB1 cervical cancer combined with pregnancy can be postponed, caution must be exercised, and the risks of postponement must be made known to the patient, as the possibility of cervical cancer progression over time is high, and the risk to the mother and fetus is high. bokhman et al. reported that for every month of postponement, survival would decrease by 5% [18].
3.2.2 Radical hysterectomy in non-pregnancy has four modalities: open, transvaginal, laparoscopic, and radical hysterectomy + pelvic lymphatic dissection with robotic surgery. In contrast, the only two reported radical hysterectomies in pregnancy are transabdominal and transvaginal. Due to the small number of reported cases and the short follow-up period, no conclusions can be drawn about the merits of this procedure.
Ungar et al [19] in 2006 reported the first report of this procedure in 5 patients with IA2-IB1 stage, who underwent open extensive hysterectomy in pregnancy (7, 8, 9, 13, and 18 weeks of gestation, respectively) and ended up with 2 full-term live fetuses delivered with healthy newborns; 2 cases (7 and 8 weeks of gestation) spontaneously aborted 1 d after the procedure and 1 case (13 weeks of gestation) spontaneously aborted 17 d after the procedure, for Van de Nieuwenhof HP et al [20] reported in 2008 the first transvaginal radical hysterectomy for mid-pregnancy combined with cervical cancer in a patient with stage Ib1 hypofractionated squamous carcinoma with intravascular infiltration. The authors concluded that transvaginal may reduce the rate of miscarriage by reducing the manipulation of the pregnant uterus.
A total of 15 cases of extensive hysterectomy in pregnancy have been reported in the literature [19-24], 14 ≤ stage IB1 and 1 in stage IB2), all with intraoperative pelvic lymph node dissection. 7 cases were performed transvaginally and 8 were open procedures. patients with stage IB2 miscarried a few hours after surgery and no follow-up data are available in the literature. None of the general authors recommend extensive hysterectomy in patients with stage IB1 or higher. In 14 other patients (2 with stage IA2 and 12 with stage IB1), the operation was completed between 4 and 19 weeks of gestation, and intraoperative lymph node metastases were found in only one patient, who underwent cesarean section and hysterectomy at 30 weeks of gestation, with postoperative radiotherapy. The postoperative miscarriage rate was high, with 5 cases miscarrying between 0-16 days postoperatively. Thirteen patients with negative lymph nodes were followed up for 9-54 days, and no recurrence was detected except for one case for which no follow-up data were available. However, given the limited number of cases reported so far, it is difficult to clarify the impact of fetal preservation on patient prognosis.
Management of locally advanced cervical cancer in combination with pregnancy For locally advanced cervical cancer, the main treatment modalities are neoadjuvant chemotherapy (NACT), or radiotherapy. The latter cannot preserve the fetus; if the patient and family have the desire to preserve the fetus, some investigators perform neoadjuvant chemotherapy followed by radical surgery or radiotherapy after delivery.
The effect of chemotherapy drugs on the fetus depends on the time of administration, the week of gestation, and the type and dose of the drug. After 13 weeks of gestation, most of the organs have completed development except for the central nervous system and gonads, and the rate of fetal malformation with chemotherapy decreases, but it may increase the rate of non-malignant disease, resulting in fetal growth restriction, low birth weight, transient myelosuppression and central nervous system effects, etc. The long-term effects on the newborn need further study. Since neonates, especially preterm infants, have not fully developed liver and kidney functions and have limited ability to metabolize and excrete drugs, the application of chemotherapy drugs should be ended 2-3 weeks before delivery to reduce the residual chemotherapy drugs in neonates and also to avoid neonatal infections due to myelosuppression and neutropenia [25]. In addition, breastfeeding should be prohibited during chemotherapy.
In conclusion: due to the special nature of cervical cancer in pregnancy, diagnosis and screening should take a positive attitude, and routine cytological examination during pregnancy and colposcopy if necessary are advocated to improve the prenatal diagnosis rate, and the management of cervical cancer in pregnancy should take all factors into consideration, combining clinical stage, lesion size, number of weeks of pregnancy, maternal physical condition and desire for childbirth and medical conditions to develop individualized treatment plans In order to achieve a satisfactory outcome. In case of cervical intraepithelial neoplasia without invasive cervical cancer, treatment is not needed during pregnancy and can wait until postpartum. vaginal delivery is feasible in stage IA1 and total hysterectomy is performed after delivery. patients in stages IA2 and IB1 who have a strong desire to preserve the fetus and have no high-risk factors can choose to delay treatment or perform extensive hysterectomy with preservation of the uterus and fetus depending on the gestational weeks. However, given the limited number of cases reported so far, it is difficult to clarify the impact of fetal preservation on patient prognosis, and future studies with large samples are pending. The management of locally advanced cervical cancer combined with pregnancy is controversial. Radiotherapy can be administered after termination of pregnancy or neoadjuvant chemotherapy can be attempted by preserving the pregnancy, depending on the size of the tumor, imaging findings, fetal gestational age and the patient’s wishes. However, patients with neoadjuvant chemotherapy and deferred treatment have poor prognosis and need to be chosen with caution.