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Cancer in Pregnancy: Cervical Cancer in Pregnancy

Introduction
Although it occurs infrequently, cervical cancer is the most commonly diagnosed malignancy during pregnancy 1. 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.

The exact incidence of invasive cervical cancer during pregnancy is unknown and may range form .01 to .1 percent 1. It is estimated that between 1 and 3 percent of patients with invasive cervical cancer are pregnant at the time of diagnosis 2, 3.

Diagnosis
Pregnancy represents a unique opportunity for the early diagnosis of cervical cancer since visual inspection, cytologic examination of the ecto/endocervix and bimanual palpation are considered part of routine antenatal care.

Reports suggest that the majority of women with early cervical cancer are asymptomatic and are diagnosed by abnormal cytology 4, 5. Other patients may have symptoms similar to the nonpregnant population i.e. vaginal bleeding, discharge and pain.

Evaluation of the cervix by Papanicolaou (Pap) smear (including endocervical sampling) and biopsy of all suspicious lesions is 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 pregnant state. Interpretation of Pap smears obtained during pregnancy is somewhat problematic since several common physiologic changes associated with the gravid state can lead to false positive results. For example, eversion of the transformation zone and exposure of columnar cells to the acid pH of the vagina causes squamous metaplasia which may be interpreted as dysplasia. The Arias-Stella reaction may resemble an adenocarcinoma 6, 7 and in one study examining gravid hysterectomy specimens, was found to occur in 9% of specimens 8. Trophoblast cells may be retrieved on the smear and resemble low grade dysplasia. It is essential that the cytopathologist be made aware that the smear has been obtained from a pregnant patient.

A patient with an abnormal Pap test and a normal cervix on routine examination should undergo colposcopy. The technique of colposcopic directed biopsies has been shown to be a less morbid yet accurate alternative to the traditional practice of random biopsies and conization 2,9-17. Conization is indicated in those cases where colposcopy is unsatisfactory and cytology is highly suggestive of invasive cancer. Conization during pregnancy should be viewed as diagnostic and not therapeutic due to a high rate of positive margins and residual disease as demonstrated by Hannigan et al .18

Other limitations to this procedure include complications such as bleeding, spontaneous abortion, infection and preterm labour. Studies suggest that hemmorhage and miscarriage occur in the minority of patients and perinatal death rates range from 3 to 6 percent 19.

Staging
Cervical carcinoma is clinically staged using the FIGO classification 20 which is a summary of information derived mainly from physical examination and radiologic investigations. During pregnancy, decisions regarding the use of radiological investigations must take into account the age of the fetus and the estimated dose of radiation delivered with the respective imaging study. In the pregnant patient, ultrasound and MRI should be considered as alternatives to CT scans since both are noninvasive and are not associated with ionizing radiation 21.

Pathology and Biology
Similar to the nonpregnant population, the majority of cases of invasive cervical cancer have a squamous histology (>80%). Of the remaining cases, the majority are adenocarcinomas 22,23. Other, less common histologies such as neuroendocrine tumor of the cervix have been described 24.

There is no conclusive evidence that the pregnant state alters the biology of cervical cancer. However, some authors have found a higher proportion of early stage tumors in pregnant patients which is likely a consequence of the increased cervical cancer screening performed during routine antenatal care 2,25,26. In contrast, studies suggest that those cases diagnosed late in the pregnancy or postpartum tend to be associated with a more advanced clinical stage and worse prognosis 27,29.

Treatment

Noninvasive Cervical Carcinoma
Studies have shown that treatment/follow-up of noninvasive carcinoma can be safely deferred until the postpartum period provided that careful colposcopic evaluation is performed in addition to cytology 2, 9-14.

Invasive Cervical Carcinoma
Early Stage Disease - FIGO Stages IA, IB, IIA

Radical hysterectomy with retroperitoneal
lymphadenectomy and definitive radiation are both effective modalities in early stage disease 2,28,30,31. Recent evidence suggests that cisplatinum-based combination chemo/radiotherapy improves survival for patients with FIGO stages IB2 to IV A and stages I to IIA with poor prognostic factors32. For young patients, surgery has the added benefits of preservation of ovarian and sexual functions and for these reasons may be considered the treatment of choice 1. Postoperative radiotherapy is recommended in patients with high risk disease (positive margins, node positive or parametrial extension)33.

Surgery
For those patients presenting 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 30,34,40. 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. Repeat examination every 6-8 weeks (including colposcopy) is recommended until surgery. For higher stages i.e. IB2 and IIA, the authors suggest early treatment 1.

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 5,35,37,40,41.

In a small series42, two patients were treated with 4 - 6 courses of neoadjuvant vincristine and cisplatin prior to definitive surgery. One patient had stage IIA disease; the other had bulky stage IB2. Treatment occurred between 21 and 29 weeks gestation in both patients. Both had a reduction in tumor size and underwent delivery by cesarean section followed by radical hysterectomy and pelvic lymphadenectomy. Both neonates had favorable outcomes. The patient with stage IIA disease recurred at 5 months time; the other one was disease free at 2 years. Although the results are promising, the use of neoadjuvant chemotherapy in this situation is still considered experimental.

Radiation Therapy
External beam radiation followed by intracavitary radiation is recommended for early stage invasive carcinoma in pregnant patient as an alternative to surgery33. When administered in the first trimester, spontaneous abortion usually occurs at a cumulative dose of 30 - 50 Gy. Treatment in the second trimester results in abortion at a higher cumulative dose and less reliably. 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 23,34.

FIGO Stages>IIB
In the higher stage categories, radiation is the treatment of choice and consists of external beam irradiation combined with intracavitary brachy therapy as indicated by tumor extent 28,33,43,44. Recent evidence suggests that cisplatinum-based combined chemo/radiotherapy improves survival for patients with FIGO stages IB2 to IVA32. Experience with 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 this 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 26. Others have suggested that routine pretherapy uterine evacuation or hysterotomy not be performed due to complications and treatment delays associated with these procedures 23,33.

Outcome of pregnant patients treated primarily with radiation therapy is largely unknown due to small patient numbers and differing radiation techniques. Using a case control methodology, The outcome of 26 patients treated with external beam and intracavitary radiation using average doses of 46.6 Gy by external beam radiation followed by an average of 56.5 Gy to Point A 20 has been recorded. Twenty of the pregnant patients had Stage<IB2. There were no differences in short or long term toxicities between the pregnant patients and their matched controls with a mean follow-up time > 13 years for both groups. No difference in recurrence rates were seen.

Early studies have suggested increased morbidity with radiation treatment in pregnant patients compared to the nonpregnant population 5,31,35. 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 23,30.

Treatment for cervical cancer that has spread to distant organs is palliative. Various chemo therapeutic agents have been used with varying success. These include cisplatinum, ifosfamide, paclitaxel and ironotecan.

Mode of Delivery
Little data exists examining the safety of cesarean section versus vaginal delivery. Non randomized studies suggest that there is no difference in survival rates 2,25,45. However, the risks of obstructed labour, hemorrhage and episiotomy site recurrence with vaginal delivery has led to the recommendation of cesarean delivery as the preferred method 1,22,46,48,49.

Chemotherapy
Cancer chemotherapeutic drugs are very potent teratogens. Currently, there is very little information on the effect of cancer chemotherapy on the fetus50. The risk of malformations when chemotherapy is administered in the first trimester has been estimated to be around 10% for single agent chemotherapy 51and 25% for combination chemotherapy 48. It is generally suggested that chemotherapy be avoided during first trimester, when cells are actively dividing. Use of these agents in the second and third trimesters has been associated with an increased risk of stillbirth, intrauterine growth retardation and low birth weight50,53,54.

>When chemotherapy is administered during pregnancy, timing of delivery of the infant 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 complications of this 55. Long term neurodevelopmental complications of in utero chemotherapy exposure have not been extensively studied. Limited data exists to suggest that this may be normal in the offspring of patients with haematologic malignancies treated during various stages of the pregnancy 56. Tewari et al described two cases of neoadjuvant chemotherapy for invasive squamous cell carcinoma of the cervix in pregnancy59.

Prognosis
Due to small numbers and methodologic flaws of the existing literature, the effect of pregnancy on prognosis is controversial, especially in the higher stages of disease 2,23,28,31,34,57. It appears that pregnancy associated cervical carcinoma has an overall better prognosis than in the nonpregnant population due to the relatively higher proportion of patients with early stage disease. After stratifying for stage, survival analyses generally do not show a difference between the two groups 23. Treatment of noninvasive cervical cancer can be postponed until postpartum. Due to diagnostic and therapeutic difficulties associated with it in pregnancy, reevaluation after delivery is crucial 58.

Fetal Outcome
Cervical cancer does not appear to affect the outcome of pregnancy. Laser vaporisation of the uterine cervix does not influence the outcome of subsequent pregnancy 60. In a study performed by Zemlickis et al. 25 no statistically significant differences in mean gestational age or proportion of preterm deliveries were seen when infants born to women with invasive cervical cancer were compared to controls. Also the risk of prematurity increased after conization for CIS and did not increase when women with CIS had other procedures 61. Mean birth weight was slightly lower for infants in the cancer group. None of the infants were exposed to therapy in utero. Favorable outcome was reported in two cases treated with neoadjuvant chemotherapy in the second trimester 59.

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