TINJAUAN PUSTAKA

Pregnancy with Cervical Cancer

Denny Khusen, Gatot Purwoto, Trijatmo Rachimhadhi
YPK Mandiri Mother and Child Hospital, Jakarta, Indonesia

ABSTRAK Although infrequent, cervical cancer is the most commonly diagnosed malignancy during pregnancy. The overall incidence of cervical cancer in pregnancy ranging from 7.5 to 45.0 cervical cancers per 100,000 pregnancies. The aim of this review was to provide information about the difficulties in diagnosing and managing cervical cancer during pregnancy. A systematic review of the literature was undertaken using the following words: cervical cancer and pregnancy. The result showed that there was a consensus in the literature regarding diagnosis and management of cervical cancer during pregnancy. However, the management of invasive cervical carcinoma during pregnancy depends on the stage of the disease, the gestational age at diagnosis, and the womans desire to continue pregnancy. In conclusion, invasive cervical cancer during pregnancy is rare but is a dilemma for patients and their physicians. The management of invasive cervical carcinoma during pregnancy depends on the situation and condition. Key words: cervical cancer, pregnancy, invasive carcinoma

ABSTRACT Meskipun jarang, kanker serviks merupakan kanker yang paling sering didiagnosis selama kehamilan. Secara keseluruhan kejadian kanker serviks pada kehamilan berkisar 7,5-45,0 kasus kanker serviks per 100.000 kehamilan. Tujuan tinjuan pustaka ini adalah untuk memberikan informasi tentang kesulitan mendiagnosis dan mengelola kanker serviks selama kehamilan. Peninjauan sistematis literatur dilakukan dengan menggunakan kata-kata berikut: kanker leher rahim dan kehamilan. Hasilnya memperlihatkan bahwa sebenarnya ada konsensus dalam literatur mengenai diagnosis dan manajemen kanker serviks selama kehamilan. Namun, untuk pengelolaan karsinoma invasif, manajemen selama kehamilan tergantung pada stadium penyakit, usia kehamilan saat diagnosis, dan keinginan untuk melanjutkan kehamilan. Simpulannya, kanker serviks invasif selama kehamilan jarang tetapi merupakan dilema bagi wanita dan dokter. Pengelolaan karsinoma serviks invasif selama kehamilan tergantung pada situasi dan kondisi. Denny Khusen, Gatot Purwoto, Trijatmo Rachimhadhi. Kehamilan dengan Kanker Serviks. Kata kunci: kanker serviks, kehamilan, karsinoma invasif

INTRODUCTION Cervical cancer is one of the most common cancer in womens reproductive period. The median age of cervical cancer diagnosed in pregnancy has been reported to be 30 to 35 years old. Reports from tumor registries and large maternity hospitals worldwide show an overall incidence of cervical cancer in pregnancy ranging from 7.5 to 45.0 cervical cancers per 100,000 pregnancies.1 Although infrequently occurs, cervical cancer is the most commonly diagnosed malignancy during pregnancy. Important issues to be considered include treatment of the cancer, the well-being of the fetus and the impact of the therapy on the reproductive capacity of the patient.2,3 Current evidence indicates that the chance of being diagnosed in initial stages among
Alamat korespondensi email: dennyddk09@yahoo.com

Table 1 Comparison of staging at the time of diagnosing cervical cancer in pregnant and non-pregnant women Staging Stage I Stage II Stage III Stage IV Pregnant 70-80% 11-20% 3-8% 0-3% Non-pregnant 42% 35% 21% 2%

pregnant women is three times greater than in controls. This is based on inspections and cervical cytological tests conducted among women in countries where these examinations are part of routine prenatal care. Several studies have shown that 76% of lesions diagnosed during pregnancy are in stage IB.4,5 (Table 1) MATERIALS AND METHODS The present review discusses the current

guidelines about cervical cancer associated with pregnancy. A systematic review of literature was undertaken by searching the PubMed, Cochrane, Excerpta Medica (Embase), Literatura Latino Americana e do Caribe em Cincias da Sade (Lilacs), and Scientific Electronic Library Online (SciELO) databases. The search used the following key words: cervical cancer and pregnancy. Articles were selected according to the following criteria: literature reviews, prospective studies, and case reports presenting approaches for diagnosing cervical cancer during pregnancy, particularly using innovative treatments, protocols, and consensuses from institutions specializing in this disease. DIAGNOSIS The presenting symptoms of cervical cancer in pregnant women are the same as in nonpregnant women. Vaginal bleeding is the

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Table 2 FIGO staging of cervical cancer 0 I IA IA1 IA2 IB IB1 IB2 II IIA IIA1 IIA2 IIB III IIIA IIIB IVA IVB Carcinoma in situ (preinvasive carcinoma) Cervical carcinoma confined to the uterus; invasive carcinoma diagnosed by microscopy All macroscopically visible lesionseven with superficial invasionare stage IB Stromal invasion 3.0 mm in depth and 7.0 mm in horizontal spread Stromal invasion >3.0 mm and 5.0 mm with a horizontal spread 7.0 mm Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2 Clinically visible lesion 4.0 cm in greatest dimension Clinically visible lesion >4.0 cm in greatest dimension Tumour beyond the uterus but not to pelvic wall or to lower third of the vagina without parametrial extension clinically visible lesion 4.0 cm in greatest dimension clinically visible lesion >4.0 cm in greatest dimension with parametrial extension Tumour extends to pelvic wall and/or involves lower third of the vagina and/or with hydronephrosis or nonfunctioning kidney Tumour involvement of the lower third of the vagina without extension to the pelvic wall Tumour extension to the pelvic wall and/or causes hydronephrosis or non-functioning kidney Tumour involvement of rectal and/or bladder mucosa and/or extends beyond true pelvis Distant metastasis

TREATMENT The management of invasive cervical carcinoma during pregnancy depends on the stage of the disease, the gestational age at diagnosis, and the womans desire to continue pregnancy.13,14 Noninvasive Cervical Carcinoma Studies have shown that treatment/follow-up of noninvasive carcinoma can be safely deferred until postpartum period, provided that careful colposcopic evaluation is performed in addition to cytology.5,9 Invasive Cervical Carcinoma Surgery For those patients who were present prior to 20 weeks gestation, treatment options include immediate surgery with the fetus left in situ or a delay in treatment to allow for fetal viability and definitive surgery postpartum. In general, there are few reports on delaying therapy in pregnancy. Studies to date have not shown adverse maternal outcomes after treatment delays of 5-40 weeks. Cell type, depth of penetration, and tumor size should be considered in the decision to recommend treatment delay in early disease. It has been suggested that delay can be considered in stages IA1, IA2, and IB1. It is recommended to repeat examination every 6-8 weeks (including colposcopy) until surgery. For higher stages i.e. IB2 and IIA, it should be suggested early treatment.15 Concerns regarding the safety of surgery for cervical carcinoma in pregnant patients have been raised. Although increased operative time, blood loss and fistulae formation have been reported, recent studies have not demonstrated an increase in blood transfusion requirements or major complications.16 The choice of therapeutic modality for pregnant women with cervical cancer should be decided in the same manner as for non-pregnant patients. The treatment is individualized, based on the stage of the disease according to the International Federation of Gynecology (FIGO), the stage of pregnancy, desire to continue the pregnancy and risks of modifying or delaying cancer treatment during the pregnancy. When the pregnancy is terminated, patient can be treated according to the stage of the disease. In case of continuation of the pregnancy, patient is non-invasively staged with MRI without gadolinium contrast or inva-

most common symptom (43%-54%), while 30% to 50% of pregnant women experience no symptoms whatsoever. Diagnosis is based on an examination of the cervix and on taking a cytological cervical smear, colposcopic findings and if necessary a targeted cervical biopsy.2,6 Early pregnancy gives a unique opportunity for diagnosing premalignant and malignant disease of cervix. A womans suspicion on pregnancy is a reason to see a gynecologist, and part of a routine examination in early pregnancy is a speculum examination for cervical visualization and taking a cervical smear for the cytological examination, apart from a bimanual palpatory examination and an ultrasound for fetus viability. Taking ecto- and endocervical smear for cytological examination is the most important in a diagnosis.1,6 Evaluation by Papanicolaou (Pap) smear (including endocervical sampling) and biopsy of all suspicious lesions are mandatory in all pregnant patients. Complete visualization of the transformation zone is usually possible due to the eversion of the squamocolumnar junction that occurs as part of the normal physiologic changes associated with the pregnancy.7,8 A patient with an abnormal Pap test and a normal cervix on routine examination should undergo colposcopy. The tech-

nique of colposcopic directed biopsies has been shown to be a less morbid yet accurate alternative to the traditional practice of random biopsies and conization.9 Conization is indicated in those cases where colposcopy is unsatisfactory and cytology is highly suggestive of invasive cancer.10,11 Other limitations to this procedure include complications such as bleeding, spontaneous abortion, infection, and preterm labour. Studies suggest that hemorhage and miscarriage occurred in the minority of patients and perinatal death rates range from 3 to 6 percent.11,12 STAGING Stage of the disease during pregnancy is defined according to FIGO classification, which is a summary of information derived mainly from physical examination and radiologic investigations (Table 2).7 During pregnancy, decisions regarding the use of radiological investigations must consider the age of fetus and the estimated dose of radiation delivered. In pregnant patient, ultrasound and MRI should be considered as alternatives to CT scans since both are noninvasive and are not associated with ionizing radiation. The most frequent histological type of cervical cancer in pregnant women, as in nonpregnant women, is squamous cell carcinoma (80%); less frequently is cervical adenocarcinoma (approximately 11%).7,11

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(laparoscopic) lymphadenectomy before considering therapy delay. For pregnant women with stage IB/IIA and IIBIVA during gestational weeks 120, the standard treatment for cervical cancer is radical hysterectomy and chemoradiation respectively with pregnancy termination or spontaneous abortion. Neoadjuvant cisplatin-based chemotherapy in selected cases beyond the first trimester after careful counselling might be an option to allow for fetal maturation. Cisplatin crosses the placenta but more than 10 cases of fetal exposure to the drug without untoward effects have been published.17 Radiation Therapy External beam radiation followed by intracavitary radiation is recommended for early stage invasive carcinoma in pregnant patient as an alternative to surgery. When being administered in first trimester, spontaneous abortion usually occurs at a cumulative dose of 30 - 50 Gy. Treatment in second trimester results in abortion at a higher cumulative dose and less reliable. As with surgery, planned therapy delays (3 - 17 weeks) to await fetal maturity and delivery prior to treatment have not been shown to adversely affect maternal outcome.19,20 FIGO Stages >IIB In the higher stage categories, radiation is optional and consists of external beam irradiation combined with intracavitary brachy therapy as indicated by tumor extent. Recent evidence suggests that cisplatinumbased combined chemo/radiotherapy improves survival for patients with FIGO stages IB2 to IVA14. Experience of this treatment in pregnant patients is generally lacking. The timing of treatment may be affected by gestational age. For a viable fetus, delivery by cesarean section followed by radiation is recommended. For a nonviable fetus, treatment with the fetus in situ is administered. For first trimester pregnancies these reliably results in abortion. In second trimester, it has been recommended that teletherapy followed by hysterotomy be performed as part of the therapy to avoid delivery of a viable but badly damaged neonate. Others have suggested that routine pretherapy uterine evacuation or hysterotomy not be performed due to complications and treatment delays associated with these procedures7,8,10,16.

Stage IA-IB

Pregnancy desired

Yes

No

Delay treatment until fetal maturity

Appropriate surgical intervention with fetus - in - situ

Termination

IA1 (no LVS1)

IA1 (+ LVSI); IA2 IB1 or IB2

IB2

Appropriate intervention

Deliver vaginally

Cesarean radical hysterectomy* +/- ovarian preservation

Cesarean section with ovarian transposition

Conization post partum

Adjuvant tailored therapy as needed

Chemo radiation

Margins (-); (+) dysplasia

Margins (+) cancer; more advanced disease

Observation

Completion hysterectomy

Radical hysterectomy*

Figure 1 Algorithm for possible treatment options in patients with early stage invasive cervical cancer diagnosed at <20 weeks of gestation. *Consider radical trachelectomy 6 weeks post-partum in very selected cases (Reproduced with permission from: Muller CY, Smith HO. Cervical neoplasia complicating pregnancy. Obstet Gynecol Clin North Am 2005; 32: 533. Copyright _2005 Elsevier)

sively staged with laparoscopic nodal evaluation when indicated.17 When the patient is diagnosed with carcinoma in situ or stage IA1 disease without Lymphovascular Space Involvement (LVSI), no further treatment is indicated after Large Loop Excision of the Transfer Zone (LLETZ) or conization. For pregnant women with early stage disease (FIGO: IA2, IB1, IIA) diagnosed after 20 weeks of gestation, treatment may be delayed until the fetus has matured. Upon fetal maturation a caesarean section is performed, followed by radical hysterectomy with bilateral pelvic lymphadenectomy and adjuvant radiation treatment when indicated. For patients with

cervical cancer stage IB2 after 20 weeks of gestation, it is acceptable to delay treatment for 8 weeks to allow fetal maturation. The treatment options are outlined in Figure 1. In selected patients with stage IA, IB, IIA tumours who have a desire for fertility preservation, radical trachelectomy with lymphadenectomy is an alternative to conventional radical hysterectomy. Antepartum trachelectomy is accompanied by a high rate of fetal loss.17,18 A difficult dilemma arises when fetal immaturity requires prolongation of pregnancy which could negatively affect the mothers survival. In such cases women should receive a complete evaluation including MRI and

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Early studies have suggested increased morbidity with radiation treatment in pregnant patients compared to the nonpregnant population. However, with the use of modern techniques and the avoidance of routine pretreatment uterine evacuation, it appears that the complication rates between the two populations are similar. Treatment for cervical cancer that has spread to distant organs is palliative. Various chemotherapeutic agents have been used with varying success. These include cisplatinum, ifosfamide, paclitaxel and ironotecan.15,16 Chemotherapy Cancer chemotherapeutic drugs are very potent teratogens. Currently, there is very little information on cancer chemotherapy effect on the fetus. The risk of malformations when
REFERENCES 1. Bisseling KC, Bekkers RL, Rome RM, Quinn MA. Treatment of microinvasive adenocarcinoma of the uterine cervix: A retrospective study and review of the literature. Gynecol Oncol. 2007;107:424-30. 2. Traen K, Svane D, Kryger-Baggesen N, Bertelsen K, Mogensen O. Stage Ib cervical cancer during pregnancy: planned delay in treatment--case report. Eur J Gynaecol Oncol. 2006;27:615-7. 3. 4. Goncalves CV, Duarte G, Costa JS, Marcolin AC, Bianchi MS, Dias D et al. Diagnosis and treatment of cervical cancer during pregnancy. Sao Paulo Med J. 2009;127:359-65. Nygrd M, Daltveit AK, Thoresen SO, Nygrd JF. Effect of an antepartum Pap smear on the coverage of a cervical cancer screening programme: A population-based prospective study. BMC Health Serv Res. 2007;7:10. 5. 6. 7. 8. 9. Van Calsteren K, Vergote I, Amant F. Cervical neoplasia during pregnancy: Diagnosis, management and prognosis. Best Pract Res Clin Obstet Gynecol. 2005;19:611-30. Nowak-Markwitz E, Spaczynski M. Carcinoma of the uterine cervix during pregnancy. Ginekol Pol. 2007;78:727-32. Sarkar S, Yusif S, Egan D. Cervical screening during pregnancy. Ir Med J. 2006;99:284-5. He GF, Bian ML, Wang Y, Liu XY. Cervical cytological screening and management in pregnant and postpartum women. Chin Med Sci J. 2005;20:242-6. Kyrgiou M, Tsoumpou I, Vrekoussis T, Martin-Hirsch P, Arbyn M, Prendeville W, et al. The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia: The Cochrane colposcopy & cervical cytopathology collaborative group (C5 group) approach. Cancer Treat Rev. 2006;32:516-23. 10. Zoundi-Ouango O, Morcel K, Classe JM, Burtin F, Aundrain O, Levque J. Lsions cervicales utrines pendant la grossesse: Diagnostic et prise en charge [Uterine cervical lesions during pregnancy: diagnosis and management. J Gynecol Obstet Biol Reprod. 2006;35:227-36. 11. Rambocas N, Olah K. Microinvasive carcinoma of the cervix. J Obstet Gynecol. 2010; 30:515-6. 12. Robova H, Rob L, Pluta M, Kacirek J, Halaska M, Strnad P et al. Squamous intraepithelial lesion-microinvasive carcinoma of the cervix during pregnancy. Eur J Gynaecol Oncol. 2005;26:611-4. 13. Rabaiotti E, Sigismondi C, Montoli S, Mangili G, Candiani M, Vigano R. Management of locally advanced cervical cancer in pregnancy: a case report. Tumori. 2010;96:623-6. 14. Karam A, Feldman N, Holschneider CH. Neoadjuvant cisplatin and radical cesarean hysterectomy for cervical cancer in pregnancy. Nat Clin Pract Oncol. 2007;4:375-80. 15. Jakobsson M, Gissler M, Sainio S, Paavonen J, Tapper AM. Preterm delivery after surgical treatment for cervical intraepithelial neoplasia. Obstet Gynecol. 2007;109:309-13. 16. Germann N, Haie-Meder C, Morice P, Lhomme C, Duvillard P, Hacene K, et al. Management and clinical outcomes of pregnant patients with invasive cervical cancer. Ann Oncol. 2005;16:397402. 17. Pentheroudakis G, Orecchia R, Hoekstra HJ, Pavlidis N. Cancer, fertility and pregnancy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21:v26673. 18. Muller CY, Smith HO. Cervical neoplasia complicating pregnancy. Obstet Gynecol Clin North Am. 2005;32:533-46. 19. Kal HB, Struikmans H. Radiotherapy during pregnancy: Fact and fiction. Lancet Oncol. 2005;6:328-33. 20. Aldrich JE, Bilawich AM, Mayo JR. Radiation doses to patients receiving computed tomography examinations in British Columbia. Can Assoc Radiol J. 2006;57:79-85. 21. Van Calsteren, K, Vergote I, Amant F. Cervical neoplasia during pregnancy: Diagnosis, management and prognosis. Best Pract Res Clin Obstet Gynaecol. 2005;19:611-30. 22. Baloglu A, Uysal D, Aslan N, Yigit S. Advanced stage of cervical carcinoma undiagnosed during antenatal period in term pregnancy and concomitant metastasis on episiotomy scar during delivery: A case report and review of the literature. Int J Gynecol Cancer. 2007;17:1155-9. 23. Caluwaerts S, VAN Calsteren K, Mertens L, Lagae L, Moerman P, Hanssens M, et al. Neoadjuvant chemotherapy followed by radical hysterectomy for invasive cervical cancer diagnosed during pregnancy: Report of a case and review of the literature. Int J Gynecol Cancer. 2006;16:905-8. 24. Bader AA, Petru E, Winter R. Long-term follow-up after neoadjuvant chemotherapy for high-risk cervical cancer during pregnancy. Gynecol Oncol. 2007;105:269-72. 25. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004;5:283-91.

chemotherapy is administered in the first trimester has been estimated to be around 10% for single agent chemotherapy and 25% for combination chemotherapy. It is generally suggested that chemotherapy be avoided during first trimester, when cells are actively dividing.21-23 The use of chemotherapy during the second and third trimesters increases the risk of low birth weight and intrauterine growth restriction.7 A platinum-based regimen is the most active and is associated with only a slightly increased risk of congenital abnormalities.14 In most of available reports, toxicity to mother is not specified. Dilutional and iron-deficiency anemia during pregnancy combined with chemotherapy- induced cytopenia increases the risk of anemia. Epoietin alfa does not cross the placenta and is safe in pregnant patients with anemia.13 When che-

motherapy is administered during pregnancy, delivery timing should take into account the expected bone marrow depression and potential problems such as bleeding or infections. Self-limiting fetal haematopoetic depression has been described and the neonate should be monitored for this complications.24,25 CONCLUSION Cervical cancer in pregnancy is curable if diagnosed and treated on time i.e. in its early stages. The treatment depends not only on the stage of the disease, but also on the gestational age at diagnosis i.e. on the ability of the fetus to survive outside the uterus at that moment. The patients wish to carry pregnancy to term can also significantly postpone the treatment and consequently affect its outcome and result.

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