Cervical carcinoma during pregnancy: outcome of planned delay in treatment

European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 153–157

Cervical carcinoma during pregnancy: outcome of planned delay in treatment Wim van Vliet*, Aren J. van Loon, Klaske A. ten Hoor, Henk Boonstra Department of Obstetrics and Gynaecology, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands Received 28 August 1997; received in revised form 1 December 1997; accepted 15 January 1998

Abstract Objective: To assess maternal mortality after delayed treatment for invasive carcinoma of the uterine cervix during pregnancy and to improve fetal outcome. Study Design: Invasive cervical cancer was diagnosed in 12 pregnant women between 1 January 1977 and 1 January 1996. The medical records were examined retrospectively, and a literature survey was performed. Results: The incidence of cervical carcinoma in our population was 1.1 per 10 000 pregnancies. Ten patients had FIGO (International Federation of Gynaecology and Obstetrics) stage IB lesions, two patients stage IIA / B. Eight patients had squamous cell carcinoma, four adenocarcinoma. In six patients with a gestation of .20 weeks and stage IB / IIA we postponed treatment for 2 to 10 weeks to optimize fetal outcome. In six patients with a gestation of ,20 weeks and stage IB / IIB we recommended immediate radical hysterectomy. Fetal outcome in the delayed-treatment group was excellent. Two patients, one in each group, died after a relapse. The remaining five patients of the delayed-treatment group are disease-free after a median follow-up of 82 months. Conclusion: Delayed treatment to achieve greater fetal maturity is a reasonable option for patients with cervix carcinoma of ,stage IIB, non-bulky tumours and a gestation of .20 weeks.  1998 Elsevier Science Ireland Ltd. Keywords: Cervical carcinoma; Pregnancy; Delayed treatment

1. Introduction In November 1995 a pregnant woman with a gestation of 23 weeks was referred to the University Hospital Groningen with adenocarcinoma of the uterine cervix, stage IB. She asked us to delay treatment until the risk of prematurity was small enough to be acceptable, as long as it would not seriously increase her own risk. Cervical carcinoma is an important cancer-related cause of death in women worldwide, also during pregnancy [1]. However, the combination is still rare: 1–3% of patients with cervical cancer are also found to be pregnant, and

*Corresponding author. Tel.: 131 50 3613000; fax: 131 50 3611694.

0.05% of all pregnancies are complicated by cervical cancer [2]. Several authors have reported on the influence of pregnancy and the mode of delivery on cervical cancer [2–5]. The question that remains to be answered is: how long can treatment be delayed in order to achieve sufficient fetal maturity without increasing the maternal risk? Traditionally, immediate treatment is recommended before 20 weeks of gestation without any further regard for the pregnancy. In the late third trimester, delayed treatment is recommended until sufficient fetal maturity has been reached, which is rarely a problem. But what about the late second or early third trimester? Several reports have been published on the impact of delayed treatment to achieve greater fetal maturity [6–14]. We reviewed our data

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concerning invasive cervical carcinoma diagnosed in women during pregnancy, in order to advise the patient described above.

2. Patients and methods We reviewed all the cases of invasive cervical carcinoma during pregnancy at our hospital diagnosed between 1 January 1977 and 1 January 1996. According to the morbidity and mortality statistics of the Department of Obstetrics and Gynaecology of the University Hospital Groningen, cervical cancer was diagnosed in twelve women during pregnancy. These patients were residents of the four northern provinces of the Netherlands. All the patients were staged according to the International Federation of Gynaecology and Obstetrics criteria (FIGO) [15]. They were examined under general anaesthesia and only those with histologically confirmed invasive carcinoma of the uterine cervix were included in this study. The choice of treatment was based on tumour stage, lesion size and the woman’s wish to continue the pregnancy or not. Immediate treatment (radical hysterectomy) was advised if invasive cervical cancer was diagnosed before 20 weeks of gestation. After 20 weeks of gestation, our advice depended on tumour stage, lesion size and the amount of weeks of delay needed to achieve sufficient fetal maturity. Patients with early-stage carcinoma (,IIB) and non-bulky tumours (diameter of ,4 cm) received the counseling that treatment delay formed a reasonable option. Patients with bulky IB or late-stage cervical carcinoma (.IIA) were advised that treatment delay was likely to involve increased maternal risk. We grouped the patients according to whether treatment was postponed or started immediately. In both groups, we

determined the gestational age at the time of diagnosis, tumour histology, stage, the interval between diagnosis and treatment, and the duration of follow-up. Neonatal parameters were determined from maternal charts and neonatal charts. For comparison, we reviewed 11 reports in the literature in which the same parameters had been used.

3. Results The diagnosis of invasive cervical cancer was made by cone biopsy or loop excision of the transformation zone (LETZ) in six patients (50%) and by biopsy in the other six patients (50%). Squamous cell carcinoma was the histological cell type in eight cases (67%), while adenocarcinoma was diagnosed in four cases (33%). Vascular space invasion was found in eight patients (67%) and positive malignant lymph node involvement in three patients (25%). The results are summarised in Table 1.

3.1. Delayed-treatment group ( patients 1 – 6) The median diagnosis-to-treatment interval in the delayed-treatment group was 3.5 weeks (range 2–10). Patient 4 presented with invasive cervical cancer at term, was allowed a trial of labour and delivered vaginally. At 2 weeks postpartum, this patient underwent radical hysterectomy and radiotherapy. Four patients underwent radical caesarean hysterectomy. One patient underwent postpartum radiotherapy, because radical hysterectomy was impossible due to severe adhesions. Patients 2, 3 and 5 were found to have vascular space invasion. Patient 3 was also found to have positive lymph nodes. Patient 4 died after a disease-free interval of 12 months, due to a relapse. The remaining five patients are disease-free after a median

Table 1 Delayed (Patients 1–6) and immediate (Patients 7–12) treatment group Patient

Gestational age (wk) at diagnosis

Stage

Interval (wk) between diagnosis and treatment

Treatment

Follow-up (mo)

1 2 3 4 5 6 7 8 9 10 11 12

34 26 28 40 32 23 16 12 15 6 20 11

IIA IB IB IB IB IB IB IB IB IIB IB IB

2 6 4 2 3 10 1 1 1 1 1 1

CS / ppRT CS / RH CS / RH / RT VD/ ppRH / RT CS / RH CS / RH RH RH / RT / CT RH / RT RH / RT / CT RH RH

142 106 92 14 a 54 16 248 192 68 a 130 102 48

RH5radical hysterectomy. RH / RT(/ CT)5radical hysterectomy followed by radiotherapy (and chemotherapy). CS / RH(/ RT)5caesarean section followed by same-session radical hysterectomy (and radiotherapy). CS / ppRT5caesarean section followed by radiotherapy (no RH possible due to severe adhesions). VD/ ppRH / RT5vaginal delivery followed 2 weeks later by radical hysterectomy and radiotherapy. a Died.

W. van Vliet et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 153 – 157

follow-up of 82 months (range 16–142). The mean gestational age at delivery was 34 weeks and 5 days. Four patients received betamethasone injections for fetal lung maturation. Except for the baby who was delivered at term, all the infants spent some time in the Neonatal Intensive Care Unit (NICU). Besides prematurity, there was no other morbidity.

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means deep infiltration, while tumour diameter .4cm represents bulky disease. The results of our review of the literature are presented in Table 3. Treatment was postponed in all the patients, in order to achieve sufficient fetal maturity.

4. Discussion

3.2. Immediate-treatment group ( patients 7 – 12) All six patients in the immediate-treatment group were treated by radical hysterectomy (Wertheim–Meigs). Except for patient 9, all the patients had vascular space invasion. Patients 9 and 10 were found to have positive lymph nodes. In patients 8–10, radical hysterectomy was followed by radiotherapy. After radical hysterectomy and radiotherapy, patients 8 and 10 received chemotherapy, for a lung metastasis and stage IIB disease, respectively. Patient 9 died after 68 months, following a disease-free interval of 32 months, due to a relapse.The remaining five patients in this group are disease-free after a median follow-up of 164 months (range 48–248). Six fetal deaths occurred as a result of maternal treatment before they had reached viable maturity. Patient 6 was referred to our department in November 1995. We delayed her treatment by 10 weeks, gave corticosteroids for fetal lung maturation and performed radical caesarean hysterectomy at 33 weeks gestation. She delivered a son with a birth weigth of 1800 grams, who stayed in the NICU for 3 weeks because of prematurity. Histology confirmed adenocarcinoma and showed no parametrial or lymph node metastases. After a follow-up of 16 months, they are both doing well. Table 2 presents the clinicopathological characteristics of our group of patients. The tumours are classified into well (grade 1), moderately (grade 2) and poorly (grade 3) differentiated carcinoma. Stromal infiltration .5 mm

Worldwide it is estimated that 500 000 women / year suffer from cervical carcinoma, of whom 250 000 die from the disease [5]. Especially in the Third World, it is the leading cause of cancer-related death in women of reproductive age. Currently, the number of new cases of invasive cervical cancer per year in women in the Netherlands is 750. The predominant histological cell type is squamous cell carcinoma (80–85%), followed by adenocarcinoma (15–20%). Although the mortality rate is declining slowly, 300 patients per year die from cervical carcinoma. On the basis that 3% of cervical cancers are diagnosed during pregnancy, this means that there will be 22–24 new cases per year in the Netherlands. With approximately 200 000 deliveries each year, the incidence of cervical cancer as a complication of pregnancy would be 1.1 cases per 10 000 pregnancies. If cervical cancer complicates pregnancy, both the mother and fetus are at risk. It is not possible to apply immediate radical cancer treatment to the mother and, at the same time, continue the pregnancy. The reported incidence of cervical cancer in pregnancy varies from 1.6–10.6 cases in 10 000 pregnancies. Our population is a referral population from the four northern provinces of the Netherlands. During the past 19 years, 1070 women have been diagnosed with invasive cervical cancer; twelve of them were pregnant at the time of diagnosis. In our series of six patients in the delayed-treatment group, one patient died with a stage IB tumour. The

Table 2 Clinicopathological characteristics Patient

Vascular invasion

Grade

Lymph node involvement

Stromal invasion (mm)

Diameter tumor (cm)

Pretreatment SCC-ag (ng / ml)

1 2 3 4 5 6 7 8 9 10 11 12

2 1 1 2 1 2 1 1 2 1 1 1

2 3 2 3 2 1 2 2 1 2 3 3

2 2 1 2 2 2 2 2 1 1 2 2

? 5(25)a .5 .5 4(14)a 1(20)a 3(10)a .5 .5 .5 .5 3(10)a

.4 ,4 .4 ,4 .4 ,4 ,4 .4 .4 ,4 .4 ,4

3.3 1.1 3.0 1.5 0.7 1.4 ? 2.3 2.3 10.0 1.2 0.4

SCC-ag5squamous cell carcinoma antigen (upper normal limit 1.9 ng / ml) [16]. Stromal invasion and Diameter tumor according to the FIGO-classification. a The linear extension is given between brackets.

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156 Table 3 Literature survey Year

Author (ref. no.)

No. of patients

Stage

Delay (wk)

Outcome

Follow-up (mo)

1966 1966 1972 1973 1975 1981 1981 1983 1989 1992 1993

Prem et al. [6] Prem et al. [6] Boutselis [12] Dudan et al. [9] Thompson et al. [13] Lee et al. [7] Lee et al. [7] Nisker et al. [10] Greer et al. [8] Monk et al. [14] Duggan et al. [11]

4 5 5 2 7 1 8 1 5 5 8

I I IA IB IA IB I / II IB IB IA / IB IA / IB

6 11–17 ? 8–24 5–28 12 5 24 6–17 5–16 8–30

NED NED NED IIB / IIIB NED NED ? DOD 4 NED/ 1 DOD NED NED

60 34–64 72–180 ? 3–120 120 ? ? 13–35 5–16 23

NED5no evidence of disease. DOD5died of disease.

remaining five patients were disease-free after a median follow-up of 82 months (range 16–142). In five patients there was no evidence of lymph node involvement. Delaying treatment to achieve fetal maturity did not affect the maternal outcome in five out of the six (83%) patients. When we combined our series of 6 patients with the 51 patients described in the literature, we obtained a total group of 57 patients, in whom treatment had been postponed; 26 patients had stage IA, 25 stage IB and 6 stage II. All 26 patients with stage IA described by Duggan et al. were reported to be disease-free, twenty of them (77%) had a disease-free interval of more than 2 years [11]. From the total group, twenty out of the 25 (80%) patients with stage IB were disease-free; nine of them (45%) had a follow-up of more than 2 years. Two out of the remaining five patients (20%) had undergone progression to stage IIB / IIIB, and three had died from the disease. Nisker et al. reported on a patient with stage IB in whom treatment was delayed for 24 weeks: the patient died after an unspecified period of follow-up [10]. Greer et al. reported on a patient with a stage IB glassy cell tumor and positive lymph nodes who died from the disease [8]. Our patient with stage IB who died, was diagnosed just before delivery with a grade 3 clearcell adenocarcinoma. Lee et al. reported on five patients with stage II lesions [7]. There was no progression during pregnancy, but they did not specify follow-up. Our patient with stage IIA has now been disease-free for 11 years. The results of our study show that the definitive prognosis of invasive cervical cancer seems to be more dependant on factors such as positive lymph nodes, vascular space invasion and lesion size (bulky or not), than on the duration of postponement of treatment to achieve sufficient fetal maturity. Patient 3 in the delayed-therapy group and patients 9 and 10 of the immediate-treatment group had lymph node metastases. Patients 4 and 9 died. In a study, on squamous cell carcinoma antigen (SCCag), Duk et al. investigated the prognostic value of pretreatment serum SCC-ag in relation to more conventional risk factors (stage, tumour size, tumour grade,

stromal infiltration, vascular invasion and lymph node metastasis) with special emphasis on patients with earlystage (IB or IIA) disease [16]. SCC-ag is a tumour marker for patients with (adeno)squamous cancer of the uterine cervix. Particularly in patients with a small tumour size, ,4cm, the SCC-ag level provides a new prognostic factor. They showed that lesion size, stromal infiltration, vascular invasion and lymph node metastases were strongly interrelated: larger tumours infiltrated more deeply, while deep stromal infiltration was associated with an increased incidence of lymphovascular space involvement and lymph node metastases. Further analysis showed a strong correlation between these tumour parameters and elevated (.1.9 ng / ml) pretreatment SCC-ag levels. In our, small, series two patients (4 and 9) died but their SCC-ag was not elevated. However, they both had an adenocarcinoma. Magnetic Resonance Imaging (MRI) was performed on patient 6 to gain an impression of possible lymph node metastases and invasion depth of the tumour. This extra information, besides the many other factors such as tumour stage, lesion size, number of weeks necessary to achieve sufficient fetal maturity, and last but not least, patients wish to continue their pregnancy, could be of use when counseling patients with cervical cancer during pregnancy.

5. Conclusion The results of our study combined with the patients described in the literature survey suggest that delaying treatment for invasive cervical carcinoma, to achieve sufficient fetal maturity, is a reasonable option, if the gestational age is .20 weeks, the stage is ,IIB and the tumour size is ,4 cm. The total number of patients with low-stage cervical cancer as a complication of pregnancy and their length of follow-up are still insufficient to draw any definitive conclusion, but there is no evidence that a delay impairs the maternal prognosis, while it certainly improves the fetal prognosis.

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6. Condensation In selected pregnant patients, a delay in the treatment of cervical carcinoma, to improve fetal outcome, does not appear to adversely affect the maternal prognosis.

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