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CERVICAL CANCER DURING PREGNANCY

Sarah D. McDonald, MD,' Wylam Faught, MD, FRCSC,2 Andree Gruslin, MD, FRCSC',3
I Department of Obstetrics, Gynecology and Newborn Care, University of Ottawa, Ottawa ON

2 Gyneoncologist and Chair, Department of Obstetrics and Gynecology, University of Alberta, Edmonton AB

J Assistant Professor, Division of Maternal Fetal Medicine, University of Ottawa, Ottawa ON

Abstract: Cervical cancer is one of the most devastating condi- INTRODUCTION


tions that can complicate a pregnancy. Stage for stage, treat-
ment for squamous cell cervical cancer is the same as that
given in the non-pregnant patient. Radical surgery is the treat- Contrary to popular belief, cancer complicates pregnancy more
ment of choice for the early stages of the disease. Although a frequently than appendicitis, thyrotoxicosis, and nephrolithia-
planned delay in therapy may be considered for up to 20 sis. 1 Cancer is the leading cause of death among women aged
weeks, for stages IA and IB I, it should be implemented cau- 35 to 54 years and the second most common cause among
tiously and with the patient's full awareness of the risks. If women aged 15 to 34 years. 2 With the exception of breast can-
delay is considered for higher stages, the patient must be
cer, which occurs in 113000 pregnancies, gynaecologic neo-
aware of the paucity of data to support this plan. Chemo-
radiation is the standard treatment for advanced cancer of the plasms constitute the most common cancers that complicate
cervix. When acceptable fetal maturity has been reached, a pregnancy (see Table 1).3 Cervical cancer is the most common
classical Caesarean section is usually performed prior to defin- of these, with an incidence of 1/2200 pregnancies. 4 This review
itive treatment. outlines the diagnosis and management of squamous cell cer-
vical cancer during pregnancy, in contrast to the older literature
Resume: Le cancer du col est I'une des complications les plus
devastatrices pouvant apparaitre pendant la grossesse. Le term of "cervical cancer associated with pregnancy," which
traitement administre contre Ie cancer du col a cellules included patients diagnosed up to one year postpartum.
squameuses, a chacun de ses stades, est Ie meme que pour les
patientes qui ne sont pas enceintes. La chirurgie radicale est SCREENING
Ie traitement de preference aux stades precoces de la ma-
ladie. Bien que, pour les stades IA et IB I, on puisse envisager
Routine antenatal care presents an important opportuniry to
la possibilite de retarder Ie traitement pour une periode allant
jusqu'a 20 semaines, cela doit se faire avec prudence et en screen women for cervical cancer and its precursors. The
s'assurant que la patiente est pleinement consciente des squamocolumnar junction is usually readily accessible due to the
risques que cela com porte. Si on envisage un delai a des natural eversion of the transformation zone under the influence
stades plus avances, la patiente doit savoir qu'iI existe peu de of high estrogen levels during pregnancy.s The use of a cyrobrush
preuves scientifiques permettant de justifier ce choix. La
is not contraindicated in pregnancy, however, endocervical cur-
chimiotherapie par radiation est Ie traitement habituel pour
les cas de cancer du col avance. Quand Ie fretus a atteint une rettage should be avoided as it is associated with increased bleed-
maturite suffisante, on pratique generalement une cesarienne ing and the possibility of disruption of the amniotic membranes.
normale avant de commencer I'administration d'un traitement Abnormal cervical cytology complicates 5% of pregnan-
definitif. cies. 6 Twenty percent of Pap smears during pregnancy under-
estimate, and 24% overestimate, the final histopathologic
J Obstet Gynaecol Can 2002;24(6):491-8.

TABLE I
INCIDENCE OF CANCERS
DURING PREGNANCy3,4

Site Incidence

Cervical 1:2200
KeyWords Breast 1:3000
Pregnancy, cervical carcinoma, surgery, radiation, chemotherapy Ovary 1:5000-25,000
Vulvar 1:8000
Competing interests: None declared. Vaginal 1:37,000
Leukemia 1:75,000
Received on November 10, 2001
Colorectal I: 100,000
Revised and accepted on February 19, 2002

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diagnosis,? which compares well with the 20-45%7 false neg- "normal" were actually CIN (cervical intraepithelial neoplasia)
ative rate in the non-pregnant population. I or II, and 14% oflesions called "low-grade" dysplasia were actu-
ally CIN III.8 Sugimori et aL9 found that 7% of patients with
COLPOSCOPY AND BIOPSY micro invasive cancer had no colposcopic abnormality, and in
The management of an abnormal Pap smear during pregnan- another study, 5 of9 patients with invasive cancer who were fol-
cy has evolved dramatically during the last three decades. Col- lowed colposcopically during the antepartum were not diagnosed
poscopy combined with selective directed biopsy has largely until the postpartum. 10
replaced cone biopsy and the associated significant morbidity. Colposcopically directed biopsy has been proven reliable
Pregnancy-related physiological cervical changes can mimic during pregnancy. A comparison of 117 pregnant women with
neoplastic changes and hence colposcopy should be performed 234 controls found that the reliability of biopsy was similar,
by an experienced colposcopist. Physiological changes during and colposcopy was rarely unsatisfactory in pregnant women. 1
pregnancy include increased vascularity and edema and hyper- Several large reviews have supported the safety of colpos-
plasia of the endocervical glands, as well as eversion of the trans- copic biopsy in the pregnant population. A review of 1064
formation zone. 1 pregnant patients evaluated with colposcopic biopsy reported a
Colposcopy alone without biopsy frequently underestimates &lse negative rate of 0.5% and a complication rate of 0.6%.11 Two
the severity of the cervical lesion during pregnancy. 6 In a retro- other studies totalling 175 patients found no major morbidity
spective review from a tertiary care centre, 35% of women who associated with colposcopically directed biopsy during
had carcinoma in situ (CIS) were judged by colposcopy to have pregnancy. 6, 12
only mild to moderate changes. 6 Economos et aL reported from The management of abnormal Pap smears is outlined in
their retrospective study of 612 pregnant women with abnormal Figure 1. Women whose Pap smears demonstrate low-grade
Pap smears, that 54% oflesions evaluated by colposcopists as squamous intraepitheliallesions (LGSIL) should be assessed

FIGURE I
MANAGEMENT OF THE ABNORMAL PAP SMEAR DURING PREGNANCY

LGSIL HGSIL

Once or twice duri>


antepartum ng ~ Colposcopy
/
<8-12
~ntepartum
weeks

directed biopsy

Unsatisfactory colposcopy,
suspected early invasion, or
adenocarcinoma in situ

Consider coin,
wedge, or cone
biopsy*

Repeat colposcopy
and biopsy 6 weeks
postpartum

LGSIL: Low-grade squamous intraepithelial lesion


HGSIL: High-grade squamous intraepithelial lesion
'Intervention will be influenced by patient's wishes regarding definitive therapy
with colposcopy (and directed biopsy as indicated) upon ini- cohort study found that women who had had a cone biopsy
tial receipt of the Pap smear report. Reassessment may be con- for carcinoma in situ were more likely to deliver prematurely
sidered during the early third trimester. Women whose Pap in their subsequent pregnancy, with an odds ratio of 1.6 (95%
smears demonstrate high-grade squamous intraepitheliallesions CI 1.2-2.0).23 In a case-control study, which matched for risk
(HGSIL) should be assessed with colposcopy (and directed factors for preterm delivery, women with a cone height of at
biopsy as indicated) upon receipt of the Pap smear report and least 10 mm had a higher rate of preterm delivery (OR 11.1)
every eight to twelve weeks. Once invasion has been ruled out, than those with a height less than 10 mm. 24
the natural history of cervical dysplasia permits delaying treat- The significant morbidity associated with cone biopsy has
ment until postpartum. 6 It has been suggested that cone bi- prompted the development of alternative biopsy techniques.
opsy should be performed in the event of an unsatisfactory Both wedge biopsy for discrete lesions and coin bioPsT5 for ecto-
colposcopy,5 and suspected early invasion,5 or adenocarci- cervical lesions have been suggested, to avoid excessive trauma
noma in situ. However, should the patient, after having been to the endocervical canal and hence to attempt to decrease the
fully educated and counselled on the issues, choose to delay risk of both pregnancy loss and maternal blood loss. An uncon-
treatment for invasive cervical cancer under all circumstances, trolled trial of cone cerclage in 15 patients suggested a decrease
cone biopsy may be avoided until her fetus reaches maturity. in hemorrhage. 26 In this series, vasopressin was injected prior to
For many years it was believed that cervical dysplasia was the cone biopsy, a McDonald suture was placed immediately
sloughed with the trauma of vaginal delivery. Disease persis- after, and the vagina was packed overnight. There were no trans-
tence following 88% of vaginal deliveries effectively refutes this fusions, readmissions for bleeding, or abortions. Two patients
notion. 6 Because rates of regression are unclear during preg- underwent spontaneous preterm delivery at 35 and 36 weeks,
nancy, it is mandatory that all pregnant women with any respectively, neither of which was precipitous. Three other
degree of dysplasia have a repeat Pap smear and colposcopy patients had planned preterm deliveries, undergoing Caesarean
6 to 12 weeks after delivery. I sections when cone biopsies diagnosed invasion.
The initial optimism that the loop electrosurgical excision
CONE BIOPSY OF THE CERVIX procedure (LEEP) would be a better alternative to cone biopsy
has not been sustained. 27 In a study of20 women at 8-34 weeks
Cone biopsy (conization) may be required for diagnosis of inva- gestational age undergoing LEEP, 14 had dysplasia on LEEP
sive cancer during pregnancy. 13 In the non-pregnant popula- specimen (6 were either normal or had cervicitis) and 8 of these
tion, the occurrence of positive margins varies greatly by series involved surgical margins. 27 Nine had residual dysplasia at three
(7.8%_31.8%),14-16 with 14.5%-38%15,17 of these having months postpartum. Two patients required blood transfusions
residual lesions on retesting. 15-18 While an association seems to and there was 1 unexplained intrauterine fetal demise (IUFD)
exist between conization in the non-pregnant state and preterm four weeks post-LEEP.
delivery in a subsequent pregnancy, it is difficult to quantif}r.l
Hence, follow-up colposcopy and appropriate biopsies during CERVICAL CANCER
the postpartum are critical. 19
Risks associated with cone biopsy include an abortion rate The average age of pregnant women with cervical cancer is
ranging from 0_26.7%20,21 when performed during the first 31 years,28 compared with 51 years in non-pregnant women. 29
trimester and a perinatal loss of apptoximately 3--6%.2l Coniza- The reasons for the earlier age of development of cervical car-
tion during pregnancy is associated with preterm delivery in as cinoma in pregnant women are not yet completely delineated
many as 30.6% of cases. 22 Excessive bleeding, most common- but likely involve earlier exposure to risk factors, such as early
ly in the third trimester, occurs in 5-14%1 of cone biop- age at first intercourse and multiple sexual partners 30 and pos-
sies performed during pregnancy, with an average blood loss sibly the relative immune system suppression during pregnan-
in one study of 428 mL. I cy. Ten to 15% of women diagnosed with cervical cancer are in
While an association seems to exist between conization in their childbearing years. 31 Approximately 1-3% of patients with
the non-pregnant state and subsequent preterm delivery in a cervical cancer are diagnosed during pregnancy.28,32
subsequent pregnancy, it is difficult to quantif}r.1 Many stud- The majority of patients with cervical cancer during preg-
ies fail to describe the amount of tissue removed at the opera- nancy (50-70%)28,30,33 are asymptomatic. In the remainder, vagi-
tion and the technique that was employed. Furthermore, they nal bleeding is the most common symptom, followed by vaginal
fail to control for other confounding factors known to be asso- discharge and pain.28 Hence, vaginal bleeding in a pregnant
ciated with both cervical dysplasia and preterm delivery, such patient should be investigated with a speculum examination of
as smoking, age at first intercourse, number of sexual partners, the cervix and a Pap smear if one has not been recently obtained.
and history of sexually transmitted disease. l After adjusting for The histologic distribution of cervical cancer during preg-
confounding factors, a recent retrospective population-based nancy is similar to that in non-pregnant patients, with squamous

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cell carcinoma representing 81-87%, adenocarcinoma 7-16%, IA2, a modified radical hysterectomy with lymphadenectomy
and others 4_5%.34-36 is usually performed. For stage !BllIA, a radical hysterectomy
The frequency of diagnosis of cervical cancer is approxi- with lymphadenectomy is usually preferred to radiation thera-
mately equal among the three trimesters. A large American study py in young women because it preserves sexual and ovarian
noted that 31 % of women were diagnosed in the first trimester, functions. 4o In addition, pregnancy-induced edema makes the
34% in the second, and 35% in the third. 34 Of note was a trend identification of tissue planes easier. 33,41,42 For bulky !BllIA dis-
toward later diagnosis among non-insured patients. 34 ease, chemoradiation is generally preferred. For stage lIB or
Clinical stage is the most important prognostic factor in higher, chemoradiation is recommended. 29
cervical cancer. 37 ,38 In the above study, 83% of the women were In early stage disease, at a gestational age less than 20 weeks,
stage I (29% were stage IA and 54% IB). 34 Cancers more the radical hysterectomy is usually done with the fetus in situ
advanced than stage IB were almost all diagnosed in the sec- to decrease blood loss. 1,28 Mter 20 weeks gestational age, the
ond or third trimester. An increase in the percentage of cancers uterus should be evacuated first, improving the operative expo-
being diagnosed as late stage disease (stages lIB to IVB), from sure for the hysterectomy.28 Depending on the gestational age,
6.7% in 198434 to 15% in 1990, is disturbing. either a high vertical hysterotomy or a classical Caesarean are
No fetal or placental metastases have ever been reported recommended to avoid extension into the cancer and a risk of
with cervical cancer. 33 increased blood loss or dissemination of disease. 28 Recur-
rence of disease in abdominal wall incisions following low
TREATMENT OF CERVICAL CANCER transverse Caesarean sections has been reported. 43

Stage for stage, the treatment of squamous cell cervical cancer COMPLICATIONS OF SURGERY
during pregnancy is the same as in the non-pregnant patient. 32
For stage IAI disease with no evidence of lymphatic or vascu- It is difficult to assess the true rate of complications in pregnant
lar space invasion, either a LEEP,39 a cone, or a simple hys- patients undergoing radical surgery because many of the stud-
terectomy is performed. 29 A cone biopsy or LEEP with negative ies are of carcinoma of the cervix "associated" with pregnancy
margins for stage IAI would effectively treat the disease,29 allow- and include patients up to 18 months postpartum. Further-
ing a term vaginal delivery with follow-up postpartum. For stage more, many studies lack a control group of non-pregnant

FIGURE 2
PLANNED DELAY IN THERAPY OF CERVICAL CANCER DURING PREGNANCY

Cone biopsy:
STAGE IA2,IBI STAGE ~ IB2
STAGE IAI
I I
~ ~ / ~
EXAM + COLPO EXAM + COLPO $20 WEEKS >20 WEEKS
Q 4-6 weeks Q 2-4 weeks Deliver and treat Deliver and treat
within 4 weeks of

~ ~
diagnosis

TERM DELIVERY,
CONSIDER DELAY
Treat 6 weeks
IN TREATMENT
postpartum

Consider SERIAL
MRI q 3-4 weeks

Reprinted from Sood 28 with minor modifications, by permiSSion of the publishers,W. B. Saunders Company.

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patients. 41 However, available data suggest that the radical paucity of evidence supporting such a delay; the data are retro-
surgical management of cervical cancer has mortality and early spective, and the outcomes remain unclear, given the short
morbidity rates (mainly fever and lower urinary tract infections) duration of follow-up and the limited numbers.
comparable to those for non-pregnant patients. 28 ,30,41 There
may be slight increases in operating time and blood loss, CISPLATIN CHEMOTHERAPY AS PART
although transfusion does not appear to be increased. 30,36 Venous OF DELAY OF DEFINITIVE TREATMENT
thromboembolism is the leading maternal cause of death44 and
consideration should be given to heparin prophylaxis. Cisplatin neoadjuvant chemotherapy has been administered in
several case reports for patients with stage IB or higher diseases
PLANNED DELAY OF TREATMENT who delayed treatment to await fetal maturity.32,56 Three cycles
of single-agent cisplatin chemotherapy for invasive cervical car-
Since 1966, the concept of delaying treatment for squamous cell cinoma at 22, 25, and 28 weeks, followed by Caesarean sec-
cervical cancer to await fetal maturity has emerged (Figure 2). tionlradical hysterectomy and lymphadenectomy at 32 weeks,
Although many reports 30 ,35,41,43,45-55 provide little evidence of resulted in a healthy infant weighing 2120 g.57 A patient with
tumour progression during pregnancy, significant concerns stage IB disease, who received cisplatin and vincristine while her
remain. First, the literature consists of a small number of patients, treatment was delayed from 21 to 32 weeks, was disease-free at
approximately 34 women with stage IA, 58 with stage IB, and two years of follow-up.43 A woman with stage IIA cervical can-
7 with stage II. Second, the literature is clouded by variable def- cer, who also received cisplatin and vincristine while her treat-
initions of "delay," ranging from 1 to 32 weeks, with the typical ment was delayed from 20 to 34 weeks, was found to have
interval being significantly less47 ,48 than the 16-20-week inter- recurrent tumour within five months of delivery.43 Both of these
val proposed in some of the more aggressive reports. 45 Third, the patients experienced a sufficient reduction in tumour volume
greatest concern is over the lack of adequate published follow- to render radical hysterectomy feasible at the time of Caesar-
up studies, with some patients followed for as little as 2 months ean section. Chemotherapy should be timed to avoid a
postpartum. 43 A retrospective review from 1980 to 1991 on hematopoietic nadir at delivery.
delayed therapy in 3 patients with stage IAI and 5 with stage IB Fetal growth restriction and hearing loss have been report-
diseases reported them as tumour-free after a median follow-up ed following cisplatin administration in the second and third
of only 23 months. 45 Another study on delayed therapy in 8 trimesters. 58 In a review of 10 pregnant women given multi-
patients with stage IB cervical cancer reported them as disease- agent chemotherapy for ovarian cancer, 2 infants were growth
free after a mean of only 37 months (range 13-68 months).49 restricted and 1 suffered moderate bilateral hearing loss. 58 How-
While disease would most likely recur within three years of treat- ever, no such effects were reported in two subsequent papers
ment, it is a concern that results are being reported for patients describing neoadjuvant cisplatin-based multi-agent chemother-
who have not received the conventional five-year follow-up. The apy for cervical (2 cases)43 and ovarian (3 cases)59 cancers. The
single case-control study of 11 patients, who delayed for a mean discrepancies may have been due to higher dosages or more
of 16 weeks with follow-up ranging from 12 to 360 months advanced disease in the first group. Because cisplatin is excret-
(mean of 148 months), concluded that for early stage I squa- ed in breast milk, breastfeeding is contraindicated. 60
mous cell carcinoma, planned delay in therapy was safe with no
long-term adverse effects on maternal survival. 36 CHEMORADIATION
Particularly concerning are suggestions to delay treatment in
stage II cancer. 43 ,48,52 Although 7 patients with stage II had no Chemoradiation is the standard treatment of stage IIB (or
progression of disease during pregnancy,43,48,52 postpartum out- higher) squamous cell cervical cancer. Weekly platinum-based
comes were unspecified in 5 patients. The sixth patient, who chemotherapy is paired with daily external beam radiation
showed no evidence of disease after 11 years, had a "delay" of only (teletherapy) and internal beam radiation (brachytherapy) with
2 weeks. 48 The seventh patient, who received six cycles of plat- both intracavitary (tandem) and vaginal applicators (ovoids).
inum-based chemotherapy while delaying therapy for 18 weeks, Radiation, with or without chemotherapy, is also employed as
experienced recurrent disease at five months postpartum and was adjuvant therapy following simple or radical hysterectomy in
receiving salvage chemotherapy at last published follow-up.43 high-risk situations, such as positive surgical margins, as well as
In summary, a delay of therapy for up to 20 weeks until for palliation. 61
fetal maturity is attained does not seem to put the patient at
risk for tumour progression, but even for stage IA and non- RADIATION
bulky stage IB 1 disease, the available outcome data are not
strong enough to warrant a blanket recommendation for this Teletherapy results in spontaneous abortion in the majority of
management option. The patient must be made aware of the first trimester pregnancies within four to five weeks of initiation,

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TABLE 2
MANAGEMENT OF SQUAMOUS CELL CERVICAL CANCER DURING PREGNANCY
Stage Management Level of Evidence 66

LGSILlHGSIL Colposcopy and selected directed biopsy antepartum and 6 weeks postpartum. 11-2A
Given the risk of preterm delivery associated with more aggressive cone
biopsies, techniques aiming to remove the least amount of tissue possible for
appropriate diagnosis and treatment should be employed if a cone biopsy is
performed.

Stage I A I cancer Term delivery with Caesarean section for obstetric indications. III
(diagnosed on a cone
biopsy)

Stage IA2 cancer Delayed therapy is a treatment option, followed by Caesarean section and 11-2B
modified radical hysterectomy and lymphadenectomy.

Stage IB I cancer Delayed therapy is a treatment option, followed by Caesarean section or radical 11-2B
hysterectomy and lymphadenectomy.

Non-bulky stage Minimal delay, if any, then radical hysterectomy and lymphadenectomy. Bulky III
IB2111A cancer IB2/11A is probably best treated with chemoradiation.

Stage ~ liB cancer Minimal delay, if any, then chemoradiation. III

Neoadjuvant chemotherapy may be considered for any patient who refuses III
immediate treatment for advanced stage disease.

at doses of 30-50 G y35 and brachytherapy is given afterwards. ! restriction, sterility, and malignancy.6! Doses less than 0.05 Gy
Seventy percent of second trimester pregnancies will abort after (5 rads), an amount usually sufficient for the pretreatment imag-
five to nine weeks of radiation. The remainder can be managed ing investigation of cervical cancer, have not been associated
with either a uterine curettage6! or a vertical hysterotomy! prior with any fetal complications. 62
to brachytherapy. When the fetus has reached acceptable matu-
rity, classical Caesarean section is usually performed prior to MODE OF DELIVERY
definitive therapy.
The optimal route for delivery in pregnant patients with early stage
MATERNAL COMPLICATIONS squamous cell cervical cancer remains undetermined,34 although
OF RADIATION THERAPY Caesarean section is generally favoured.!,32,63 Maternal risks with
Recent studies suggest no increase in maternal radiation com- vaginal delivery include: cervical dystocia, hemorrhage, dissemi-
plication rates among pregnant patients over non-pregnant nation of malignancy into the lymphatic and vascular spaces, recur-
patients, reflecting the advent of newer radiation techniques and rence in episiotomy sites, and compromised survival. 32 In one
the avoidance of combining surgical procedures with radiation. 6! study with only 7 patients in the vaginal delivery group and 26 in
A retrospective case-control study comparing pregnant and non- the Caesarean section group,34 a lower five-year cumulative sur-
pregnant patients receiving radiation therapy for invasive cervi- vival was reported with vaginal delivery in comparison with Cae-
cal cancer found no significant differences in short-term sarean section (55% vs. 75%, p-value not reported).34 A
radiation-induced toxicity, such as diarrhea, weight loss, nausea, multivariate analysis showed a possible trend (p = 0.08) toward
and cystitis, nor in long-term complications including fistulae, decreased survival after vaginal delivery.32 In a case-control study
bowel obstruction, and necrosis. 35 Moreover, no statistically sig- of 56 women with cervical carcinoma during pregnancy (and 27
nificant differences in recurrence or survival rates were found. 35 diagnosed within 6 months of delivery), a multivariate analysis
revealed that vaginal delivery was the most significant predictor of
FETAL COMPLICATIONS OF RADIATION THERAPY recurrence (OR6.91, 95% CI 1.45-32.8), with 1 of7 (14%)
There is a 40% risk of mental retardation when 1 Gy (100 rads) recurring post Caesarean section and 10 of 17 (59%) recurring
is delivered between 8 and 15 weeks' gestation. 6! After 20 to 25 post vaginal delivery (p = 0.046).63 The authors concluded that
weeks' gestation, radiation may damage the fetal bone marrow, women who deliver vaginally have a significantly worse survival
liver, and kidneys, and may increase risks of intrauterine growth than those who deliver by Caesarean section (p = 0.001), with a

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