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Cervical cancer associated with pregnancy: Results of a multicenter retrospective Korean study (KGOG-1006)
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Cervical cancer associated with pregnancy: Results of a multicenter retrospective Korean study (KGOG-1006) Jong-Min Lee, MD, PhD; Kwang-Beom Lee, MD; Young-Tak Kim, MD, PhD; Hee-Sug Ryu, MD, PhD; Young-Tae Kim, MD, PhD; Chi-Heum Cho, MD, PhD; Sung-Eun Namkoong, MD, PhD; Ki-Hun Lee, MD, PhD; Ho-Sun Choi, MD, PhD; Kyung-Tai Kim, MD, PhD OBJECTIVE: The objective of the study was to analyze the characteristics of cervical cancer associated with pregnancy. STUDY DESIGN: Forty patients with cervical cancer associated with pregnancy were retrospectively identified between 1995-2003. Three controls for each case were matched on the basis of age, stage, histology, and date of treatment. RESULTS: Sampling of cervical cytology after the second trimester was
the most common cause of delayed diagnosis. Among 12 patients who delayed treatment for fetal maturity, 2 died of disease. There was no
difference in overall survival between pregnant and nonpregnant patients with stage Ib tumors. In contrast to nonpregnant patients, the depth of stromal invasion was not correlated with the incidence of lymph vascular space involvement and lymph node metastasis in pregnant patients. CONCLUSION: Thorough evaluation is warranted before deciding whether to delay treatment until fetal maturity. Pregnancy does not adversely affect the prognosis of early-stage cervical cancer significantly.
Key words: cervical cancer, pregnancy, prognosis
Cite this article as: Lee J-M, Lee K-B, Kim Y-T, et al. Cervical cancer associated with pregnancy: Results of a multicenter retrospective Korean study (KGOG1006). Am J Obstet Gynecol 2008;198:92.e1-92.e6.
U
terine cervical cancer is the fourth most common malignant disease in Korean women, accounting for 9.8% of total malignancies in Korean women in 2002.1 Because of the increased availability of screening tests, the incidence of cervical cancer has been decreasing in Korea. However, the incidence of earlystage cervical cancer has increased, especially among women in their 20s and 30s for whom child-bearing remains a con-
cern.2 Thus, cervical cancer associated with pregnancy is a clinical challenge. Although cervical cancer is the most common gynecologic malignancy associated with pregnancy, it is relatively rare, with an incidence ranging from 1 per 1200-10,000 pregnancies, depending on whether carcinoma in situ and postpartum patients are included.3 Pregnancy has been found not to adversely affect the prognosis of patients with cer-
From the Departments of Obstetrics and Gynecology, East-West Neo Medical Center, Kyung Hee University, Seoul, Korea (Dr J.-M. Lee); Gachon University, Gil Medical Center, Inchon (Dr K.-B. Lee); University of Ulsan College of Medicine, Asan Medical Center, Seoul (Dr Young-Tak Kim); Ajou University School of Medicine, Suwon (Dr Ryu); Yonsei University College of Medicine, Seoul (Dr Young-Tae Kim); Keimyung University, Dongsan Medical Center, Daegu (Dr Cho); The Catholic University of Korea School of Medicine, Seoul (Dr Namkoong); Cheil General Hospital and Women’s Health Care Center, Sungkyunkwan University School of Medicine, Seoul (Dr K.-H. Lee); Chonnam National University College of Medicine, Gwangju (Dr Choi); and Hanyang University College of Medicine, Seoul (Dr K.-T. Kim), Korea. Presented at the 11th Biennial Meeting of International Gynecologic Cancer Society, Oct. 14-18, 2006, Santa Monica, CA. Received Feb. 5, 2007; revised April 3, 2007; accepted June 29, 2007. Reprints: Kyung-Tai Kim, Department of Obstetrics and Gynecology, College of Medicine, Hanyang University, Seoul, 133-792, Korea; [email protected]. This work was supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412-CR01-0704-0001). 0002-9378/$34.00 • © 2008 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2007.06.077
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vical cancer.3-5 Because of the lack of sufficient data about the effect of pregnancy on tumor biology, the effects of cancer on maternal and fetal outcomes, and the impact of adequate intervention timing on maternal and fetal outcomes, the management guidelines for these patients remain unclear.3,4 To answer some of these questions, we retrospectively evaluated the clinical outcomes of patients having cervical cancer associated with pregnancy. We also describe the results following delays in treatment until fetal maturity, and we assess the effects of pregnancy on the prognosis of patients with cervical cancer.
M ATERIALS AND M ETHODS Forty patients having cervical cancer associated with pregnancy, including 1 patient diagnosed 1 month after vaginal delivery, were identified from tumor registry databases at 13 tertiary medical centers in Korea from 1995-2003. Institutional review board approval was obtained from each of the participating centers. We reviewed their medical records, including medical charts, electronic
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TABLE 1
TABLE 2
Patient characteristics
Causes of delayed diagnosis during or after the second trimester
Variables Mean age (range), y
33.5 (21-46)
..............................................................................................................................................................................................................................................
Mean gravidity (range)
2.1 (0-7)
Mean parity (range)
1.1 (0-3)
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Stage
Ia1
6
Ib1
16
Ib2
9
IIa
4
IIb
3
IIIb
1
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
IVa
1
..............................................................................................................................................................................................................................................
Gestational age at diagnosis
First trimester
18
Second trimester
14
Causes No antenatal care
Number (n ⴝ 22) 2
...........................................................................................................
Delayed cervical cytology
13
...........................................................................................................
Cervical cytology not performed 3 until bleeding
...........................................................................................................
Cytologic underestimation of LSIL or less
3
Inaccurate biopsy
1
........................................................................................................... ...........................................................................................................
LSIL, low-grade squamous intraepithelial lesion. Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Third trimester
7
Postpartum
1
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Histology
Squamous cell carcinoma
30
..............................................................................................................................................................................................................................................
Adenocarcinoma
6
Adenosquamous carcinoma
1
Others
3
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a ..............................................................................................................................................................................................................................................
Delay in treatment for fetal maturity
No
28
Yes
12
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a
Others: small cell neuroendocrine, clear cell, adenoma malignum.
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
records, and follow-up data. Among the data collected were patient age, gestational age, date of diagnosis, histology, type and date of treatment, duration of treatment delay, and follow-up data. Tumor stages were assigned according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. To evaluate the effects of pregnancy on cervical cancer, we identified, for each pregnant patient, 3 nonpregnant women with FIGO stage Ib tumors, matched on the basis of age (⫾ 5 years), FIGO stage (Ib1 and Ib2), histology (squamous cell carcinoma vs adenocarcinoma vs adenosquamous carcinoma vs others), and date of treatment (⫾ 2 years) in this order of priority. For the purposes of the study, the referral date was designated as the date of diagnosis. The date of treatment was calculated from the first date of definitive treatment.
Case-control differences were evaluated using Student t test or the Mann– Whitney U test for continuous variables and 2 test or Fisher’s exact test for categorical variables. Overall survival was evaluated using the Kaplan-Meier method and log-rank tests. The significance level for all analyses was set at 0.05. All analyses were performed using SPSS 11 software (v 11; SPSS, Chicago, IL).
R ESULTS Patient characteristics are shown in Table 1. The mean age at diagnosis of the 40 pregnant patients was 33.5 years (range, 21-46 years); their mean gravidity was 2.1 (range, 0-7) and their mean parity was 1.1 (range, 0-3). Thirty-five patients had FIGO stage I-IIa tumors, including 16 with stage Ib1 and 5 patients with stage IIb or higher. At diagnosis, 18 were in their first trimester, 14 in their second trimester, and 7 in their third trimester,
and 1 was diagnosed at 1 month postpartum. Squamous cell carcinoma was the most frequent histologic subtype. Twelve patients delayed treatment to achieve fetal maturity; the mean delay was 15.7 weeks (range, 3-34 weeks). Of the 22 patients diagnosed during or after the second trimester, 2 had no antenatal care, 13 had cervical cytology after the second trimester, 3 did not have cervical cytology until vaginal bleeding occurred, 3 had cytologic underestimation of low-grade squamous intraepithelial lesion (LSIL) or less, and 1 had an inaccurate colposcopically directed biopsy (Table 2). Table 3 shows the trend of primary treatment according to FIGO stage at diagnosis. Thirty-six patients, including 2 with stage IIb and 1 with stage IVa tumors, underwent primary surgery. Definitive surgery for patients with earlystage disease except stage Ia1 consisted of radical hysterectomy with pelvic lymphadenectomy. Twenty-eight patients underwent immediate treatment; 17 with gestation of 21 weeks or less underwent radical surgery with fetus in situ, 6 with gestation of 20 weeks or longer underwent radical surgery after cesarean delivery, 2 with gestation in the first trimester underwent radiation or chemoradiation with fetus in situ, 1 with gestation of 32 weeks underwent radiation after cesarean delivery, 1 with gestation of 4 weeks underwent conization after artificial abortion,
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TABLE 3
Trend of primary treatment according to FIGO stage Stage
Conization
Type I H
Ia1
4
2
Type II H
Type III H
RT alone
CCRT
..............................................................................................................................................................................................................................................
Ib1
2
14
..............................................................................................................................................................................................................................................
Ib2
9
IIa
2
IIb
2
..............................................................................................................................................................................................................................................
2
..............................................................................................................................................................................................................................................
1
..............................................................................................................................................................................................................................................
IIIb
1
..............................................................................................................................................................................................................................................
IVa
1
..............................................................................................................................................................................................................................................
Total
4
2
2
28
2
2
..............................................................................................................................................................................................................................................
CCRT, concurrent chemoradiation; H, hysterectomy; RT, radiation. Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
and 1 who was diagnosed 1 month after vaginal delivery underwent radical surgery. The patient with stage IVa had no antenatal care and had visited the emergency department because of labor pains; she underwent an emergency cesarean delivery, inadvertent radical hysterectomy, and pelvic lymphadenectomy with low anterior resection of rectum because of erroneous estimation for rectal invasion on preoperative physical examination. Table 4 shows the characteristics of patients in whom treatment was delayed for fetal maturity. Four had
FIGO stage Ia1 tumors, 5 had stage Ib1, and 1 each had stages Ib2, IIa, and IIIb. Histologically, 7 patients had squamous cell carcinoma, 1 had adenocarcinoma, 1 had adenosquamous carcinoma, and 3 had other tumor types. Six patients with a gestation of less than 20 weeks and stage Ia1/Ib1 tumors delayed treatment for 9-34 weeks to increase fetal maturity, and 6 patients with a gestation of 20 weeks or longer and stage Ib1/Ib2/IIa/IIIb tumors delayed treatment for 3-17 weeks to increase fetal maturity. Fetal outcome in both groups was excellent.
Two patients in the latter group died; 1 (case 9) had a stage Ib1 tumor and delayed treatment for 6 weeks. She had pathologic tumor size of 2 cm, deep stromal invasion, and lymph vascular space involvement and did not receive adjuvant treatment. She had disease recurrence at paraaortic lymph nodes 10 months later and died of her disease at 34 months. The other (case 10) had a stage Ib2 tumor and delayed treatment for 4 weeks. She had pathologic tumor size of 4.5cm, lymph vascular space involvement, and multiple pelvic/paraaortic lymph nodes metastases. She received adjuvant chemoradiation, but she died of her disease at 34 months because of disease progression. The remaining 10 patients are alive after a median follow-up of 40 months. Comparison of the pregnant patients with the 3 nonpregnant patients matched for age, FIGO stage Ib, histology, and date of treatment revealed no significant differences in the status of resection margin (P ⫽ .08), parametrial extension (P ⫽ .68), lymph vascular space involvement (P ⫽ .45), lymph node metastasis (P ⫽ .48), and treatment modality (P ⫽ .15; Table 5). The estimated 5 year survival rates of pregnant and nonpregnant patients with stage Ib
TABLE 4
Clinical characteristics of patients managed with planned delay for fetal maturity Age
Stage
Hx
GA at dx (wks)
Delay in tx (wks)
Tx
Patient status (mo)
Infant (g)
1
33
Ia1
S
11
27
Conization
Alive (9)
3610
2
26
Ia1
S
6
9
Conization
Alive (29)
3255
3
21
Ia1
A
6
34
Conization
Alive (40)
3610
4
27
Ia1
O
18
18
Type I H
Alive (40)
2575
5
29
Ib1
S
11
25
Type III H
Alive (58)
2500
6
37
Ib1
O
14
18
Type III H
Alive (15)
2200
7
27
Ib1
O
23
13
Type III H
Alive (22)
2575
8
28
Ib1
S
23
14
Type III H
Alive (12)
2600
9
31
Ib1
AS
25
6
Type III H
Death (34)
2030
10
29
Ib2
S
31
4
Type III H
Death (34)
2100
11
35
IIa
S
20
17
Type III H
Alive (75)
2900
12
36
IIIb
S
32
3
CCRT
Alive (104)
1880
Cases
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
A, adenocarcinoma; AS, adenosquamous carcinoma; CCRT, concurrent chemoradiation; Dx, diagnosis; GA, gestational age; H, hysterectomy; Hx, histology; S, squamous cell carcinoma; O (case 4), adenoma malignum; O (case 6), clear cell carcinoma; O (case 7), small cell neuroendocrine carcinoma; Tx, treatment. Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
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TABLE 5
FIGURE 1
Clinicopathologic variables in pregnant and nonpregnant patients with FIGO stage Ib tumors
Overall survival of pregnant and nonpregnant patients with FIGO stage Ib tumors
Variable
Cases (n ⴝ 21)
Controls (n ⴝ 63)
Age (median, range), y
33 (21-46)
38 (22-50)
P
..............................................................................................................................................................................................................................................
Stage (%)
..............................................................................................................................................................................................................................................
Ib1
12 (57.1)
36 (57.1)
Ib2
9 (42.9)
27 (42.9)
1.00
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
Histology (%)
.....................................................................................................................................................................................................................................
SCC
13 (61.9)
39 (61.9)
Adenocarcinoma
5 (23.8)
15 (23.8)
Adenosquamous
1 (4.8)
3 (4.8)
Others
2 (9.5)
6 (9.5)
1.00
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
RM (%)
.....................................................................................................................................................................................................................................
Negative
20 (95.2)
63 (100)
Positive
1 (4.8)
0 (0)
.08
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
PM (%)
.....................................................................................................................................................................................................................................
Negative
18 (85.7)
57 (90.5)
Positive
3 (14.3)
6 (9.5)
.68
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
DOI (%)
.....................................................................................................................................................................................................................................
Inner 2/3
16 (76.2)
30 (47.6)
Outer 1/3
5 (23.8)
33 (52.4)
.02
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
LVSI (%)
.....................................................................................................................................................................................................................................
Negative
9 (42.9)
33 (52.4)
Positive
12 (57.1)
30 (47.6)
.45
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
Positive LN (%)
.....................................................................................................................................................................................................................................
Negative
14 (66.7)
47 (74.6)
Positive
7 (33.3)
16 (25.4)
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
age at diagnosis of 30-35 years.4,6,7 Generally, cervical cancer diagnosed within 6-12 months of an antecedent pregnancy is considered to have been present during pregnancy.8 Because of the current trend of delaying pregnancy into the later reproductive years and the increased availability of screening tests for cervical cancer, physicians caring for pregnant women may encounter early-stage cervical cancer more frequently.3 In analyzing the causes of delayed diagnosis made during or after the second
.48
.....................................................................................................................................................................................................................................
FIGURE 2
..............................................................................................................................................................................................................................................
Tx modality (%)
.....................................................................................................................................................................................................................................
NACT plus surgery
4 (19.0)
6 (9.5)
Surgery
7 (33.3)
36 (57.1)
10 (47.6)
21 (33.3)
.15
..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................
Surgery plus adjuvant Tx
..............................................................................................................................................................................................................................................
DOI, depth of stromal invasion; LN, lymph node; LVSI, lymph vascular space involvement; NACT, neoadjuvant chemotherapy; PM, parametrial invasion; RM, resection margin; SCC, squamous cell carcinoma; Tx, treatment.
Incidence of lymph vascular space involvement (LVSI) and lymph node metastasis (LNM) relative to depth of stromal invasion in nonpregnant patients
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
cervical cancer were 75.0% and 89.4%, respectively; this difference was not significant (P ⫽ .41; Figure 1). We also evaluated whether the depth of stromal invasion correlated with the incidence of lymph vascular space involvement or lymph node metastasis. In nonpregnant patients, the depth of stromal invasion was significantly correlated with the incidence of lymph vascular space involvement (P ⫽ .00) and lymph
node metastasis (P ⫽ .046; Figure 2). In pregnant patients, however, the depth of stromal invasion did not affect the incidence of lymph vascular space involvement (P ⫽ .34) or lymph node metastasis (P ⫽ .62; Figure 3).
C OMMENT Cervical cancer associated with pregnancy is a rare disease, with a median
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
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www.AJOG.org cal cancer.9 In addition, only 69% of pregnant patients with stage Ib cervical cancer were reported to have had positive cytology leading to their diagnosis.10 Not surprisingly, therefore, carcinoma was suspected on cervical cytology in only 19 of our 40 patients. During pregnancy, both cervical glands and stroma undergo physiologic changes. Decidual cells, endocervical gland hyperplasia, or glandular cells exhibiting an Arias-Stella reaction may appear worrisome on cytologic interpretation.11 However, cytology may be falsely negative because it may pick up only the inflammatory and/or the nonneoplastic cells because of the focal neoplastic lesion. The use of an endocervical brush and spatula to obtain a cytologic specimen, as compared with a cotton applicator and spatula, is safe in pregnancy and reduces the number of suboptimal smears.12,13 This is significant because the fraction of suboptimal smears in pregnant women is as high as 58% when using the conventional cotton swab vs 29% when using the cytobrush.14 Several well-done series have confirmed the safety and accuracy of colposcopy and directed biopsy in pregnancy.15,16 Therefore, colposcopy and directed biopsies, when indicated,
FIGURE 3
Incidence of lymph vascular space involvement (LVSI) and lymph node metastasis (LNM) relative to depth of stromal invasion in pregnant patients
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
trimester in 22 women, we found that 2 had never received antenatal care and 16 had not had or had delayed cervical cytology. Interestingly, delayed diagnosis in 3 patients was because of cytologic underestimation of LSIL or less. The lack of access to health care and noncompliance with recommended cervical cytological screening has been regarded as significant factors in the development of cervi-
should be considered for pregnant patients with abnormal cytology and/or suspicious clinical findings. The surgical treatment guidelines for pregnant women with cervical cancer are similar to those for nonpregnant women.17 Of our 35 patients with stage I-IIa tumors, 33 underwent surgical management without significant complications. Three of the 5 women with locally advanced cervical cancer, including stages IIb-IVa, however, also underwent radical surgery, suggesting the difficulty of preoperative evaluation in pregnant patients with cervical cancer and the surgeon’s inclination to perform surgery at the time of abdominal delivery. Because of a lack of prospective clinical trials, the management of cervical cancer during pregnancy remains unclear and varies according to stage of disease, gestational age at diagnosis, and ethical or religious background. Delaying definitive treatment to improve fetal outcomes, although beneficial to the fetus, may carry an additional risk of tumor progression. A delay in definitive treatment is regarded as feasible and safe in patients with small-sized early-stage disease if there is no evidence of disease progression. However, no firm data are available in patients with advanced dis-
TABLE 6
Review of literature published since 1995 for planned treatment delay in cervical cancer associated with pregnancy FIGO stage (number of cases)
Authors
Period accrued
Sood et al17
1960-1994
4
Sorosky et al
1989-1994
1
Zanetta et al
1992-1995
van Vliet et al
1977-1996
Takushi et al
1978-1997
Germann et al
1985-2000
Current study
1995-2003
Ia1
Ia2 4
Ib1
Ib2
IIa
IIIb
3
Delay (wks)
Outcome (months)
3-32
NED; 12-360
3-40
NED; 13-68
5-18
NED; 40-55
2-10
NED; 16-142
6-25
NED; 52-156
................................................................................................................................................................................................................................................................................................................................................................................ 18
7
................................................................................................................................................................................................................................................................................................................................................................................ 19
3
1
................................................................................................................................................................................................................................................................................................................................................................................ 20 a
3
2
1
................................................................................................................................................................................................................................................................................................................................................................................ 21
8
1
2
1
................................................................................................................................................................................................................................................................................................................................................................................ 5
4-24
5-YS; 100%
5
9
1
1
1
3-34
NED; 9-104
2-40
................................................................................................................................................................................................................................................................................................................................................................................ b c
4
................................................................................................................................................................................................................................................................................................................................................................................
Total cases
17
5
32
5
2
1
0
0
2
1
0
0
................................................................................................................................................................................................................................................................................................................................................................................
Cases of DOD
................................................................................................................................................................................................................................................................................................................................................................................
DOD, died of disease; NED, no evidence of disease; 5-YS, 5-year survival. a
Includes 1 patient who died of disease at 14 months.
b
Includes 1 patient who died of disease at 34 months.
c
Includes 1 patient who died of disease at 34 months.
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www.AJOG.org ease because of the low number reported in the literature (Table 6).5,17-21 It has been recommended that a maximum delay of up to 12 weeks be allowed for stage Ib1 tumors and 6 weeks for stage Ib2 tumors, prior to the start of definitive treatment.3 In addition, recent advances in neonatal intensive care can dramatically decrease the duration of a treatment delay. However, the acceptable duration of treatment delay has not been determined clearly for pregnant patients with stage Ia2 or more advanced tumors because of an absence of substantial objective data.21 In this study, 12 patients delayed definitive treatments for fetal maturity, and 2 with stage Ib tumors died of their disease. Although the current study population was small and heterogeneous for stage and length of treatment delay, the 2 patients who died delayed treatment for only 4 and 6 weeks, respectively. Therefore, thorough evaluation of clinical characteristics prior to deciding on a treatment plan is necessary. Although most studies have found that pregnancy did not adversely affect maternal outcome or tumor biology, most of these studies evaluated a small number of patients, were retrospective in design, and did not match prognostic factors in cases and controls.10,22-24 Although 1 study matched cases and controls for age, year of diagnosis, stage, and tumor type,25 pregnancy-dependent pathologic characteristics were not included. When we matched the pregnant and nonpregnant patients with stage Ib disease, we observed no significant differences in pathologic risk factors and overall survival. However, the depth of stromal invasion was not correlated with the incidence of lymph vascular space involvement and lymph node metastasis in pregnant patients, whereas they were correlated in nonpregnant patients. These findings may suggest that the enlargement of the uterine cervix induced by pregnancy may relatively lessen the depth of stromal invasion in pregnant patients rather than that lymph vascular space involvement and lymph node metastasis may occur early in the progression of disease in pregnant patients. Thus, clinical significance of the depth of stromal invasion in pregnant
patients should be evaluated with more information from a larger number of patients in the future. Because of the limited number of patients and the characteristics inherent to a retrospective design, our results cannot provide definitive guidelines for treating women with cervical cancer associated with pregnancy. Our experiences, however, may contribute to the foundation of knowledge with regard to cervical cancer associated with pregnancy. f ACKNOWLEDGMENTS The following members of Korean Gynecologic Oncology Group also participated in this study: Asan Medical Center Seoul (Jung E. Mok, Joo H. Nam, Yong M. Kim, Jong H. Kim); Donga University Hospital (Goo H. Je); National Cancer Center (Sang Y. Park, Byung H. Nam); and Seoul National University Hospital (Soon B. Kang, Jae W. Kim).
REFERENCES 1. Korea Central Cancer Registry. 2002 annual report of the Korea central cancer registry (2002.1.-2002.12). Republic of Korea: Korea Central Cancer Registry, Ministry of Health and Welfare; 2003. 2. Korean Society of Obstretrics and Gynecology, Gynecologic Oncology Committee. Annual report of the Gynecologic Cancer Registry Program in Korea for 2004 (Jan. 1, 2004 through Dec. 31, 2004). Kor J Obstet Gynecol 2007;50:28-78. 3. Nguyen C, Montz FJ, Bristow RE. Management of stage I cervical cancer in pregnancy. Obstet Gynecol Surv 2000;55:633-43. 4. Method MW, Brost BC. Management of cervical cancer in pregnancy. Semin Surg Oncol 1999;16:251-60. 5. Germann N, Haie-Meder C, Morice P, et al. Management and clinical outcomes of pregnant patients with invasive cervical cancer. Ann Oncol 2005;16:397-402. 6. Hacker NF, Berek JS, Lagasse LD, Charles EH, Savage EW, Moore JG. Carcinoma of the cervix associated with pregnancy. Obstet Gynecol 1982;59:735-46. 7. Norstrom A, Jansson I, Andersson H. Carcinoma of the uterine cervix in pregnancy. A study of the incidence and treatment in the western region of Sweden 1973 to 1992. Acta Obstet Gynecol Scand 1997;76:583-9. 8. Duggan B, Muderspach LI, Roman LD, Curtin JP, d’Ablaing G 3rd, Morrow CP. Cervical cancer in pregnancy: reporting on planned delay in therapy. Obstet Gynecol 1993;82: 598-602. 9. Hacker NF. Cervical cancer. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology. Philadelphia: Lippincott Williams & Wilkins; 2005: 337-95.
Research
10. Hopkins MP, Morley GW. The prognosis and management of cervical cancer associated with pregnancy. Obstet Gynecol 1992;80:9-13. 11. Michael CW, Esfahani FM. Pregnancy-related changes: a retrospective review of 278 cervical smears. Diagn Cytopathol 1997;17: 99-107. 12. McCord ML, Stovall TG, Meric JL, Summitt RL Jr, Coleman SA. Cervical cytology: a randomized comparison of four sampling methods. Am J Obstet Gynecol 1992;166:1772-7. 13. Orr JW Jr, Barrett JM, Orr PF, Holloway RW, Holimon JL. The efficacy and safety of the cytobrush during pregnancy. Gynecol Oncol 1992;44:260-2. 14. Rivlin ME, Woodliff JM, Bowlin RB, et al. Comparison of cytobrush and cotton swab for Papanicilaou smears in pregnancy. J Reprod Med 1993;38:147-50. 15. Baldauf JJ, Dreyfus M, Ritter J, Philippe E. Colposcopy and directed biopsy reliability during pregnancy: a cohort study. Eur J Obstet Gynecol Reprod Biol 1995;62:31-6. 16. Siddiq TS, Twigg JP, Hammond RH. Assessing the accuracy of colposcopy at predicting the outcomes of abnormal cytology in pregnancy. Eur J Obstet Gynecol Reprod Biol 2006;124:93-7. 17. Sood AK, Sorosky JI, Krogman S, Anderson B, Benda J, Buller RE. Surgical management of cervical cancer complicating pregnancy: a case-control study. Gynecol Oncol 1996;63:294-8. 18. Sorosky JI, Squatrito R, Ndubisi BU, et al. Stage I squamous cell cervical carcinoma in pregnancy: planned delay in therapy awaiting fetal maturity. Gynecol Oncol 1995;59:207-10. 19. Zanetta G, Pellegrino A, Vanzulli A, Di Lelio A, Milani R, Mangioni C. Magnetic resonance imaging of cervical cancer in pregnancy. Int J Gynecol Cancer 1998;8:265-9. 20. van Vliet W, van Loon AJ, ten Hoor KA, Boonstra H. Cervical carcinoma during pregnancy: outcome of planned delay in treatment. Eur J Obstet Gynecol Reprod Biol 1998; 79:153-7. 21. Takushi M, Moromizato H, Sakumoto K, Kanazawa K. Management of invasive carcinoma of the uterine cervix associated with pregnancy: outcome of intentional delay in treatment. Gynecol Oncol 2002;87:185-9. 22. Lee RB, Neglia W, Park RC. Cervical carcinoma in pregnancy. Obstet Gynecol 1981;58:584-9. 23. Greer BE, Easterling TR, McLennan DA, et al. Fetal and maternal considerations in the management of stage I-B cervical cancer during pregnancy. Gynecol Oncol 1989;34: 61-5. 24. Baltzer J, Regenbrecht ME, Kopcke W, Zander J. Carcinoma of the cervix and pregnancy. Int J Gynaecol Obstet 1990;31:317-23. 25. Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G. Maternal and fetal outcome after invasive cervical cancer in pregnancy. J Clin Oncol 1991;9:1956-61.
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ONCOLOGY
Cervical cancer associated with pregnancy: Results of a multicenter retrospective Korean study (KGOG-1006) Jong-Min Lee, MD, PhD; Kwang-Beom Lee, MD; Young-Tak Kim, MD, PhD; Hee-Sug Ryu, MD, PhD; Young-Tae Kim, MD, PhD; Chi-Heum Cho, MD, PhD; Sung-Eun Namkoong, MD, PhD; Ki-Hun Lee, MD, PhD; Ho-Sun Choi, MD, PhD; Kyung-Tai Kim, MD, PhD OBJECTIVE: The objective of the study was to analyze the characteristics of cervical cancer associated with pregnancy. STUDY DESIGN: Forty patients with cervical cancer associated with pregnancy were retrospectively identified between 1995-2003. Three controls for each case were matched on the basis of age, stage, histology, and date of treatment. RESULTS: Sampling of cervical cytology after the second trimester was
the most common cause of delayed diagnosis. Among 12 patients who delayed treatment for fetal maturity, 2 died of disease. There was no
difference in overall survival between pregnant and nonpregnant patients with stage Ib tumors. In contrast to nonpregnant patients, the depth of stromal invasion was not correlated with the incidence of lymph vascular space involvement and lymph node metastasis in pregnant patients. CONCLUSION: Thorough evaluation is warranted before deciding whether to delay treatment until fetal maturity. Pregnancy does not adversely affect the prognosis of early-stage cervical cancer significantly.
Key words: cervical cancer, pregnancy, prognosis
Cite this article as: Lee J-M, Lee K-B, Kim Y-T, et al. Cervical cancer associated with pregnancy: Results of a multicenter retrospective Korean study (KGOG1006). Am J Obstet Gynecol 2008;198:92.e1-92.e6.
U
terine cervical cancer is the fourth most common malignant disease in Korean women, accounting for 9.8% of total malignancies in Korean women in 2002.1 Because of the increased availability of screening tests, the incidence of cervical cancer has been decreasing in Korea. However, the incidence of earlystage cervical cancer has increased, especially among women in their 20s and 30s for whom child-bearing remains a con-
cern.2 Thus, cervical cancer associated with pregnancy is a clinical challenge. Although cervical cancer is the most common gynecologic malignancy associated with pregnancy, it is relatively rare, with an incidence ranging from 1 per 1200-10,000 pregnancies, depending on whether carcinoma in situ and postpartum patients are included.3 Pregnancy has been found not to adversely affect the prognosis of patients with cer-
From the Departments of Obstetrics and Gynecology, East-West Neo Medical Center, Kyung Hee University, Seoul, Korea (Dr J.-M. Lee); Gachon University, Gil Medical Center, Inchon (Dr K.-B. Lee); University of Ulsan College of Medicine, Asan Medical Center, Seoul (Dr Young-Tak Kim); Ajou University School of Medicine, Suwon (Dr Ryu); Yonsei University College of Medicine, Seoul (Dr Young-Tae Kim); Keimyung University, Dongsan Medical Center, Daegu (Dr Cho); The Catholic University of Korea School of Medicine, Seoul (Dr Namkoong); Cheil General Hospital and Women’s Health Care Center, Sungkyunkwan University School of Medicine, Seoul (Dr K.-H. Lee); Chonnam National University College of Medicine, Gwangju (Dr Choi); and Hanyang University College of Medicine, Seoul (Dr K.-T. Kim), Korea. Presented at the 11th Biennial Meeting of International Gynecologic Cancer Society, Oct. 14-18, 2006, Santa Monica, CA. Received Feb. 5, 2007; revised April 3, 2007; accepted June 29, 2007. Reprints: Kyung-Tai Kim, Department of Obstetrics and Gynecology, College of Medicine, Hanyang University, Seoul, 133-792, Korea; [email protected]. This work was supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412-CR01-0704-0001). 0002-9378/$34.00 • © 2008 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2007.06.077
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vical cancer.3-5 Because of the lack of sufficient data about the effect of pregnancy on tumor biology, the effects of cancer on maternal and fetal outcomes, and the impact of adequate intervention timing on maternal and fetal outcomes, the management guidelines for these patients remain unclear.3,4 To answer some of these questions, we retrospectively evaluated the clinical outcomes of patients having cervical cancer associated with pregnancy. We also describe the results following delays in treatment until fetal maturity, and we assess the effects of pregnancy on the prognosis of patients with cervical cancer.
M ATERIALS AND M ETHODS Forty patients having cervical cancer associated with pregnancy, including 1 patient diagnosed 1 month after vaginal delivery, were identified from tumor registry databases at 13 tertiary medical centers in Korea from 1995-2003. Institutional review board approval was obtained from each of the participating centers. We reviewed their medical records, including medical charts, electronic
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TABLE 1
TABLE 2
Patient characteristics
Causes of delayed diagnosis during or after the second trimester
Variables Mean age (range), y
33.5 (21-46)
..............................................................................................................................................................................................................................................
Mean gravidity (range)
2.1 (0-7)
Mean parity (range)
1.1 (0-3)
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Stage
Ia1
6
Ib1
16
Ib2
9
IIa
4
IIb
3
IIIb
1
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
IVa
1
..............................................................................................................................................................................................................................................
Gestational age at diagnosis
First trimester
18
Second trimester
14
Causes No antenatal care
Number (n ⴝ 22) 2
...........................................................................................................
Delayed cervical cytology
13
...........................................................................................................
Cervical cytology not performed 3 until bleeding
...........................................................................................................
Cytologic underestimation of LSIL or less
3
Inaccurate biopsy
1
........................................................................................................... ...........................................................................................................
LSIL, low-grade squamous intraepithelial lesion. Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Third trimester
7
Postpartum
1
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Histology
Squamous cell carcinoma
30
..............................................................................................................................................................................................................................................
Adenocarcinoma
6
Adenosquamous carcinoma
1
Others
3
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a ..............................................................................................................................................................................................................................................
Delay in treatment for fetal maturity
No
28
Yes
12
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a
Others: small cell neuroendocrine, clear cell, adenoma malignum.
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
records, and follow-up data. Among the data collected were patient age, gestational age, date of diagnosis, histology, type and date of treatment, duration of treatment delay, and follow-up data. Tumor stages were assigned according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. To evaluate the effects of pregnancy on cervical cancer, we identified, for each pregnant patient, 3 nonpregnant women with FIGO stage Ib tumors, matched on the basis of age (⫾ 5 years), FIGO stage (Ib1 and Ib2), histology (squamous cell carcinoma vs adenocarcinoma vs adenosquamous carcinoma vs others), and date of treatment (⫾ 2 years) in this order of priority. For the purposes of the study, the referral date was designated as the date of diagnosis. The date of treatment was calculated from the first date of definitive treatment.
Case-control differences were evaluated using Student t test or the Mann– Whitney U test for continuous variables and 2 test or Fisher’s exact test for categorical variables. Overall survival was evaluated using the Kaplan-Meier method and log-rank tests. The significance level for all analyses was set at 0.05. All analyses were performed using SPSS 11 software (v 11; SPSS, Chicago, IL).
R ESULTS Patient characteristics are shown in Table 1. The mean age at diagnosis of the 40 pregnant patients was 33.5 years (range, 21-46 years); their mean gravidity was 2.1 (range, 0-7) and their mean parity was 1.1 (range, 0-3). Thirty-five patients had FIGO stage I-IIa tumors, including 16 with stage Ib1 and 5 patients with stage IIb or higher. At diagnosis, 18 were in their first trimester, 14 in their second trimester, and 7 in their third trimester,
and 1 was diagnosed at 1 month postpartum. Squamous cell carcinoma was the most frequent histologic subtype. Twelve patients delayed treatment to achieve fetal maturity; the mean delay was 15.7 weeks (range, 3-34 weeks). Of the 22 patients diagnosed during or after the second trimester, 2 had no antenatal care, 13 had cervical cytology after the second trimester, 3 did not have cervical cytology until vaginal bleeding occurred, 3 had cytologic underestimation of low-grade squamous intraepithelial lesion (LSIL) or less, and 1 had an inaccurate colposcopically directed biopsy (Table 2). Table 3 shows the trend of primary treatment according to FIGO stage at diagnosis. Thirty-six patients, including 2 with stage IIb and 1 with stage IVa tumors, underwent primary surgery. Definitive surgery for patients with earlystage disease except stage Ia1 consisted of radical hysterectomy with pelvic lymphadenectomy. Twenty-eight patients underwent immediate treatment; 17 with gestation of 21 weeks or less underwent radical surgery with fetus in situ, 6 with gestation of 20 weeks or longer underwent radical surgery after cesarean delivery, 2 with gestation in the first trimester underwent radiation or chemoradiation with fetus in situ, 1 with gestation of 32 weeks underwent radiation after cesarean delivery, 1 with gestation of 4 weeks underwent conization after artificial abortion,
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TABLE 3
Trend of primary treatment according to FIGO stage Stage
Conization
Type I H
Ia1
4
2
Type II H
Type III H
RT alone
CCRT
..............................................................................................................................................................................................................................................
Ib1
2
14
..............................................................................................................................................................................................................................................
Ib2
9
IIa
2
IIb
2
..............................................................................................................................................................................................................................................
2
..............................................................................................................................................................................................................................................
1
..............................................................................................................................................................................................................................................
IIIb
1
..............................................................................................................................................................................................................................................
IVa
1
..............................................................................................................................................................................................................................................
Total
4
2
2
28
2
2
..............................................................................................................................................................................................................................................
CCRT, concurrent chemoradiation; H, hysterectomy; RT, radiation. Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
and 1 who was diagnosed 1 month after vaginal delivery underwent radical surgery. The patient with stage IVa had no antenatal care and had visited the emergency department because of labor pains; she underwent an emergency cesarean delivery, inadvertent radical hysterectomy, and pelvic lymphadenectomy with low anterior resection of rectum because of erroneous estimation for rectal invasion on preoperative physical examination. Table 4 shows the characteristics of patients in whom treatment was delayed for fetal maturity. Four had
FIGO stage Ia1 tumors, 5 had stage Ib1, and 1 each had stages Ib2, IIa, and IIIb. Histologically, 7 patients had squamous cell carcinoma, 1 had adenocarcinoma, 1 had adenosquamous carcinoma, and 3 had other tumor types. Six patients with a gestation of less than 20 weeks and stage Ia1/Ib1 tumors delayed treatment for 9-34 weeks to increase fetal maturity, and 6 patients with a gestation of 20 weeks or longer and stage Ib1/Ib2/IIa/IIIb tumors delayed treatment for 3-17 weeks to increase fetal maturity. Fetal outcome in both groups was excellent.
Two patients in the latter group died; 1 (case 9) had a stage Ib1 tumor and delayed treatment for 6 weeks. She had pathologic tumor size of 2 cm, deep stromal invasion, and lymph vascular space involvement and did not receive adjuvant treatment. She had disease recurrence at paraaortic lymph nodes 10 months later and died of her disease at 34 months. The other (case 10) had a stage Ib2 tumor and delayed treatment for 4 weeks. She had pathologic tumor size of 4.5cm, lymph vascular space involvement, and multiple pelvic/paraaortic lymph nodes metastases. She received adjuvant chemoradiation, but she died of her disease at 34 months because of disease progression. The remaining 10 patients are alive after a median follow-up of 40 months. Comparison of the pregnant patients with the 3 nonpregnant patients matched for age, FIGO stage Ib, histology, and date of treatment revealed no significant differences in the status of resection margin (P ⫽ .08), parametrial extension (P ⫽ .68), lymph vascular space involvement (P ⫽ .45), lymph node metastasis (P ⫽ .48), and treatment modality (P ⫽ .15; Table 5). The estimated 5 year survival rates of pregnant and nonpregnant patients with stage Ib
TABLE 4
Clinical characteristics of patients managed with planned delay for fetal maturity Age
Stage
Hx
GA at dx (wks)
Delay in tx (wks)
Tx
Patient status (mo)
Infant (g)
1
33
Ia1
S
11
27
Conization
Alive (9)
3610
2
26
Ia1
S
6
9
Conization
Alive (29)
3255
3
21
Ia1
A
6
34
Conization
Alive (40)
3610
4
27
Ia1
O
18
18
Type I H
Alive (40)
2575
5
29
Ib1
S
11
25
Type III H
Alive (58)
2500
6
37
Ib1
O
14
18
Type III H
Alive (15)
2200
7
27
Ib1
O
23
13
Type III H
Alive (22)
2575
8
28
Ib1
S
23
14
Type III H
Alive (12)
2600
9
31
Ib1
AS
25
6
Type III H
Death (34)
2030
10
29
Ib2
S
31
4
Type III H
Death (34)
2100
11
35
IIa
S
20
17
Type III H
Alive (75)
2900
12
36
IIIb
S
32
3
CCRT
Alive (104)
1880
Cases
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
A, adenocarcinoma; AS, adenosquamous carcinoma; CCRT, concurrent chemoradiation; Dx, diagnosis; GA, gestational age; H, hysterectomy; Hx, histology; S, squamous cell carcinoma; O (case 4), adenoma malignum; O (case 6), clear cell carcinoma; O (case 7), small cell neuroendocrine carcinoma; Tx, treatment. Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
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TABLE 5
FIGURE 1
Clinicopathologic variables in pregnant and nonpregnant patients with FIGO stage Ib tumors
Overall survival of pregnant and nonpregnant patients with FIGO stage Ib tumors
Variable
Cases (n ⴝ 21)
Controls (n ⴝ 63)
Age (median, range), y
33 (21-46)
38 (22-50)
P
..............................................................................................................................................................................................................................................
Stage (%)
..............................................................................................................................................................................................................................................
Ib1
12 (57.1)
36 (57.1)
Ib2
9 (42.9)
27 (42.9)
1.00
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
Histology (%)
.....................................................................................................................................................................................................................................
SCC
13 (61.9)
39 (61.9)
Adenocarcinoma
5 (23.8)
15 (23.8)
Adenosquamous
1 (4.8)
3 (4.8)
Others
2 (9.5)
6 (9.5)
1.00
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
RM (%)
.....................................................................................................................................................................................................................................
Negative
20 (95.2)
63 (100)
Positive
1 (4.8)
0 (0)
.08
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
PM (%)
.....................................................................................................................................................................................................................................
Negative
18 (85.7)
57 (90.5)
Positive
3 (14.3)
6 (9.5)
.68
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
DOI (%)
.....................................................................................................................................................................................................................................
Inner 2/3
16 (76.2)
30 (47.6)
Outer 1/3
5 (23.8)
33 (52.4)
.02
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
LVSI (%)
.....................................................................................................................................................................................................................................
Negative
9 (42.9)
33 (52.4)
Positive
12 (57.1)
30 (47.6)
.45
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
Positive LN (%)
.....................................................................................................................................................................................................................................
Negative
14 (66.7)
47 (74.6)
Positive
7 (33.3)
16 (25.4)
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
age at diagnosis of 30-35 years.4,6,7 Generally, cervical cancer diagnosed within 6-12 months of an antecedent pregnancy is considered to have been present during pregnancy.8 Because of the current trend of delaying pregnancy into the later reproductive years and the increased availability of screening tests for cervical cancer, physicians caring for pregnant women may encounter early-stage cervical cancer more frequently.3 In analyzing the causes of delayed diagnosis made during or after the second
.48
.....................................................................................................................................................................................................................................
FIGURE 2
..............................................................................................................................................................................................................................................
Tx modality (%)
.....................................................................................................................................................................................................................................
NACT plus surgery
4 (19.0)
6 (9.5)
Surgery
7 (33.3)
36 (57.1)
10 (47.6)
21 (33.3)
.15
..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................
Surgery plus adjuvant Tx
..............................................................................................................................................................................................................................................
DOI, depth of stromal invasion; LN, lymph node; LVSI, lymph vascular space involvement; NACT, neoadjuvant chemotherapy; PM, parametrial invasion; RM, resection margin; SCC, squamous cell carcinoma; Tx, treatment.
Incidence of lymph vascular space involvement (LVSI) and lymph node metastasis (LNM) relative to depth of stromal invasion in nonpregnant patients
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
cervical cancer were 75.0% and 89.4%, respectively; this difference was not significant (P ⫽ .41; Figure 1). We also evaluated whether the depth of stromal invasion correlated with the incidence of lymph vascular space involvement or lymph node metastasis. In nonpregnant patients, the depth of stromal invasion was significantly correlated with the incidence of lymph vascular space involvement (P ⫽ .00) and lymph
node metastasis (P ⫽ .046; Figure 2). In pregnant patients, however, the depth of stromal invasion did not affect the incidence of lymph vascular space involvement (P ⫽ .34) or lymph node metastasis (P ⫽ .62; Figure 3).
C OMMENT Cervical cancer associated with pregnancy is a rare disease, with a median
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
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www.AJOG.org cal cancer.9 In addition, only 69% of pregnant patients with stage Ib cervical cancer were reported to have had positive cytology leading to their diagnosis.10 Not surprisingly, therefore, carcinoma was suspected on cervical cytology in only 19 of our 40 patients. During pregnancy, both cervical glands and stroma undergo physiologic changes. Decidual cells, endocervical gland hyperplasia, or glandular cells exhibiting an Arias-Stella reaction may appear worrisome on cytologic interpretation.11 However, cytology may be falsely negative because it may pick up only the inflammatory and/or the nonneoplastic cells because of the focal neoplastic lesion. The use of an endocervical brush and spatula to obtain a cytologic specimen, as compared with a cotton applicator and spatula, is safe in pregnancy and reduces the number of suboptimal smears.12,13 This is significant because the fraction of suboptimal smears in pregnant women is as high as 58% when using the conventional cotton swab vs 29% when using the cytobrush.14 Several well-done series have confirmed the safety and accuracy of colposcopy and directed biopsy in pregnancy.15,16 Therefore, colposcopy and directed biopsies, when indicated,
FIGURE 3
Incidence of lymph vascular space involvement (LVSI) and lymph node metastasis (LNM) relative to depth of stromal invasion in pregnant patients
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
trimester in 22 women, we found that 2 had never received antenatal care and 16 had not had or had delayed cervical cytology. Interestingly, delayed diagnosis in 3 patients was because of cytologic underestimation of LSIL or less. The lack of access to health care and noncompliance with recommended cervical cytological screening has been regarded as significant factors in the development of cervi-
should be considered for pregnant patients with abnormal cytology and/or suspicious clinical findings. The surgical treatment guidelines for pregnant women with cervical cancer are similar to those for nonpregnant women.17 Of our 35 patients with stage I-IIa tumors, 33 underwent surgical management without significant complications. Three of the 5 women with locally advanced cervical cancer, including stages IIb-IVa, however, also underwent radical surgery, suggesting the difficulty of preoperative evaluation in pregnant patients with cervical cancer and the surgeon’s inclination to perform surgery at the time of abdominal delivery. Because of a lack of prospective clinical trials, the management of cervical cancer during pregnancy remains unclear and varies according to stage of disease, gestational age at diagnosis, and ethical or religious background. Delaying definitive treatment to improve fetal outcomes, although beneficial to the fetus, may carry an additional risk of tumor progression. A delay in definitive treatment is regarded as feasible and safe in patients with small-sized early-stage disease if there is no evidence of disease progression. However, no firm data are available in patients with advanced dis-
TABLE 6
Review of literature published since 1995 for planned treatment delay in cervical cancer associated with pregnancy FIGO stage (number of cases)
Authors
Period accrued
Sood et al17
1960-1994
4
Sorosky et al
1989-1994
1
Zanetta et al
1992-1995
van Vliet et al
1977-1996
Takushi et al
1978-1997
Germann et al
1985-2000
Current study
1995-2003
Ia1
Ia2 4
Ib1
Ib2
IIa
IIIb
3
Delay (wks)
Outcome (months)
3-32
NED; 12-360
3-40
NED; 13-68
5-18
NED; 40-55
2-10
NED; 16-142
6-25
NED; 52-156
................................................................................................................................................................................................................................................................................................................................................................................ 18
7
................................................................................................................................................................................................................................................................................................................................................................................ 19
3
1
................................................................................................................................................................................................................................................................................................................................................................................ 20 a
3
2
1
................................................................................................................................................................................................................................................................................................................................................................................ 21
8
1
2
1
................................................................................................................................................................................................................................................................................................................................................................................ 5
4-24
5-YS; 100%
5
9
1
1
1
3-34
NED; 9-104
2-40
................................................................................................................................................................................................................................................................................................................................................................................ b c
4
................................................................................................................................................................................................................................................................................................................................................................................
Total cases
17
5
32
5
2
1
0
0
2
1
0
0
................................................................................................................................................................................................................................................................................................................................................................................
Cases of DOD
................................................................................................................................................................................................................................................................................................................................................................................
DOD, died of disease; NED, no evidence of disease; 5-YS, 5-year survival. a
Includes 1 patient who died of disease at 14 months.
b
Includes 1 patient who died of disease at 34 months.
c
Includes 1 patient who died of disease at 34 months.
Lee. Cervical cancer associated with pregnancy. Am J Obstet Gynecol 2008.
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Oncology
www.AJOG.org ease because of the low number reported in the literature (Table 6).5,17-21 It has been recommended that a maximum delay of up to 12 weeks be allowed for stage Ib1 tumors and 6 weeks for stage Ib2 tumors, prior to the start of definitive treatment.3 In addition, recent advances in neonatal intensive care can dramatically decrease the duration of a treatment delay. However, the acceptable duration of treatment delay has not been determined clearly for pregnant patients with stage Ia2 or more advanced tumors because of an absence of substantial objective data.21 In this study, 12 patients delayed definitive treatments for fetal maturity, and 2 with stage Ib tumors died of their disease. Although the current study population was small and heterogeneous for stage and length of treatment delay, the 2 patients who died delayed treatment for only 4 and 6 weeks, respectively. Therefore, thorough evaluation of clinical characteristics prior to deciding on a treatment plan is necessary. Although most studies have found that pregnancy did not adversely affect maternal outcome or tumor biology, most of these studies evaluated a small number of patients, were retrospective in design, and did not match prognostic factors in cases and controls.10,22-24 Although 1 study matched cases and controls for age, year of diagnosis, stage, and tumor type,25 pregnancy-dependent pathologic characteristics were not included. When we matched the pregnant and nonpregnant patients with stage Ib disease, we observed no significant differences in pathologic risk factors and overall survival. However, the depth of stromal invasion was not correlated with the incidence of lymph vascular space involvement and lymph node metastasis in pregnant patients, whereas they were correlated in nonpregnant patients. These findings may suggest that the enlargement of the uterine cervix induced by pregnancy may relatively lessen the depth of stromal invasion in pregnant patients rather than that lymph vascular space involvement and lymph node metastasis may occur early in the progression of disease in pregnant patients. Thus, clinical significance of the depth of stromal invasion in pregnant
patients should be evaluated with more information from a larger number of patients in the future. Because of the limited number of patients and the characteristics inherent to a retrospective design, our results cannot provide definitive guidelines for treating women with cervical cancer associated with pregnancy. Our experiences, however, may contribute to the foundation of knowledge with regard to cervical cancer associated with pregnancy. f ACKNOWLEDGMENTS The following members of Korean Gynecologic Oncology Group also participated in this study: Asan Medical Center Seoul (Jung E. Mok, Joo H. Nam, Yong M. Kim, Jong H. Kim); Donga University Hospital (Goo H. Je); National Cancer Center (Sang Y. Park, Byung H. Nam); and Seoul National University Hospital (Soon B. Kang, Jae W. Kim).
REFERENCES 1. Korea Central Cancer Registry. 2002 annual report of the Korea central cancer registry (2002.1.-2002.12). Republic of Korea: Korea Central Cancer Registry, Ministry of Health and Welfare; 2003. 2. Korean Society of Obstretrics and Gynecology, Gynecologic Oncology Committee. Annual report of the Gynecologic Cancer Registry Program in Korea for 2004 (Jan. 1, 2004 through Dec. 31, 2004). Kor J Obstet Gynecol 2007;50:28-78. 3. Nguyen C, Montz FJ, Bristow RE. Management of stage I cervical cancer in pregnancy. Obstet Gynecol Surv 2000;55:633-43. 4. Method MW, Brost BC. Management of cervical cancer in pregnancy. Semin Surg Oncol 1999;16:251-60. 5. Germann N, Haie-Meder C, Morice P, et al. Management and clinical outcomes of pregnant patients with invasive cervical cancer. Ann Oncol 2005;16:397-402. 6. Hacker NF, Berek JS, Lagasse LD, Charles EH, Savage EW, Moore JG. Carcinoma of the cervix associated with pregnancy. Obstet Gynecol 1982;59:735-46. 7. Norstrom A, Jansson I, Andersson H. Carcinoma of the uterine cervix in pregnancy. A study of the incidence and treatment in the western region of Sweden 1973 to 1992. Acta Obstet Gynecol Scand 1997;76:583-9. 8. Duggan B, Muderspach LI, Roman LD, Curtin JP, d’Ablaing G 3rd, Morrow CP. Cervical cancer in pregnancy: reporting on planned delay in therapy. Obstet Gynecol 1993;82: 598-602. 9. Hacker NF. Cervical cancer. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology. Philadelphia: Lippincott Williams & Wilkins; 2005: 337-95.
Research
10. Hopkins MP, Morley GW. The prognosis and management of cervical cancer associated with pregnancy. Obstet Gynecol 1992;80:9-13. 11. Michael CW, Esfahani FM. Pregnancy-related changes: a retrospective review of 278 cervical smears. Diagn Cytopathol 1997;17: 99-107. 12. McCord ML, Stovall TG, Meric JL, Summitt RL Jr, Coleman SA. Cervical cytology: a randomized comparison of four sampling methods. Am J Obstet Gynecol 1992;166:1772-7. 13. Orr JW Jr, Barrett JM, Orr PF, Holloway RW, Holimon JL. The efficacy and safety of the cytobrush during pregnancy. Gynecol Oncol 1992;44:260-2. 14. Rivlin ME, Woodliff JM, Bowlin RB, et al. Comparison of cytobrush and cotton swab for Papanicilaou smears in pregnancy. J Reprod Med 1993;38:147-50. 15. Baldauf JJ, Dreyfus M, Ritter J, Philippe E. Colposcopy and directed biopsy reliability during pregnancy: a cohort study. Eur J Obstet Gynecol Reprod Biol 1995;62:31-6. 16. Siddiq TS, Twigg JP, Hammond RH. Assessing the accuracy of colposcopy at predicting the outcomes of abnormal cytology in pregnancy. Eur J Obstet Gynecol Reprod Biol 2006;124:93-7. 17. Sood AK, Sorosky JI, Krogman S, Anderson B, Benda J, Buller RE. Surgical management of cervical cancer complicating pregnancy: a case-control study. Gynecol Oncol 1996;63:294-8. 18. Sorosky JI, Squatrito R, Ndubisi BU, et al. Stage I squamous cell cervical carcinoma in pregnancy: planned delay in therapy awaiting fetal maturity. Gynecol Oncol 1995;59:207-10. 19. Zanetta G, Pellegrino A, Vanzulli A, Di Lelio A, Milani R, Mangioni C. Magnetic resonance imaging of cervical cancer in pregnancy. Int J Gynecol Cancer 1998;8:265-9. 20. van Vliet W, van Loon AJ, ten Hoor KA, Boonstra H. Cervical carcinoma during pregnancy: outcome of planned delay in treatment. Eur J Obstet Gynecol Reprod Biol 1998; 79:153-7. 21. Takushi M, Moromizato H, Sakumoto K, Kanazawa K. Management of invasive carcinoma of the uterine cervix associated with pregnancy: outcome of intentional delay in treatment. Gynecol Oncol 2002;87:185-9. 22. Lee RB, Neglia W, Park RC. Cervical carcinoma in pregnancy. Obstet Gynecol 1981;58:584-9. 23. Greer BE, Easterling TR, McLennan DA, et al. Fetal and maternal considerations in the management of stage I-B cervical cancer during pregnancy. Gynecol Oncol 1989;34: 61-5. 24. Baltzer J, Regenbrecht ME, Kopcke W, Zander J. Carcinoma of the cervix and pregnancy. Int J Gynaecol Obstet 1990;31:317-23. 25. Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G. Maternal and fetal outcome after invasive cervical cancer in pregnancy. J Clin Oncol 1991;9:1956-61.
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