Cervical Cancer in Pregnancy and Cervical Cancer Dysplasia (CIN I – II –III) Management
Cervical Cancer in Pregnancy and Cervical Cancer Dysplasia (CIN I – II –III) Management Cervical cancer is one of the frequently seen cancers in pregnancy. One third of the women who are diagnosed with cervical cancer are either pregnant or in postpartum period (1,2). Half of these cases have diagnosed prenatal however the other half are diagnosed within the 12 months following the 12 months after birth (2,3).
The cervical cancers detected during pregnancy are generally detected in early stage. A reason is that pap-smear is taken as a part of routine examination in early pregnancy and the cervix is assessed or the possibility of advanced stage cervical cancer preventing pregnancy (3).
Yes you heard it right. You should be examined form below in pregnancy and if you are not giving smears regularly you must give one. It is a part of the routine examination and NO the examination NEVER causes miscarriages. The most meaningless rumor in Turkey is that the examination from below or ultrasound causing miscarriages.
I wish the life was that easy, you do not lift heavy things, not have examination from below, not lift high and not miscarriages at all! But the life and scientific truth are not as such. Important ratio of the miscarriages seen in the first trimester (85%) is due to chromosomal abnormalities and cannot be prevented. Anyway, back to the subject.
The stages and progress of the cervical cancer during pregnancy are not different form the non-pregnant patient. And unfortunately there are no studies about approach to the cervical cancer in pregnant women yet and it seems to be difficult to conduct, at least for ethical problems.
Therefore, usually observatory studies and personal experiences shape the treatment plans.
The moral is that in pregnant women when cervical cancer is detected and when the treatment is planned it is required that a person specific plan should be done and the whether the patient wants to continue the pregnancy, the stage of the illness and what risks every option may bring, all these should be considered one by one.
The clinical indications; cervical cancer suspicion generally starts with an abnormality detected in the pap smear scan test. There is no difference for pregnant and non-pregnant women regarding pap smear however when sending to pathology whether the patient is pregnant or not must be indicate. If you look at the literature, in 5-8% of all pregnant women abnormal smear results are seen, but these are American data and are not so different than the data of the non-pregnant women in the same geography (4,5).
When the subject is the indications, symptoms of the illness, the most important indicator factors in the cervical cancer are the stage of the illness and the tumor diameter. In fact early stage cervical cancer rarely gives indications. In none of the Stage IA patients and in only half of the stage IB patients symptoms are seen (5).
In these patients the illness can show itself through vaginal leakage and bleeding however as these conditions can be confused with the normal findings during pregnancy there is a possibility that they are generally overlooked. In the advanced stage cervical cancer, indistinct and again usual in pregnancy, groin pain, leg pain is added to the picture. Thus, in the pregnant patient with cervical cancer, as the mentioned indications can be seen also in healthy pregnant women, there is a possibility of delay in diagnosis (1).
The same situation is valid also for examination and laboratory findings. In any stage of pregnancy a mass can be seen at cervix. For example desidual bleeding masses (endometrium, in womb tissue special to pregnancy) can be detected. Moreover, the cellular changes in cervix are also show similarities to the changes due to cancer and this is why the pathologist must know that the patient is pregnant. This condition can make it harder to distinguish a healthy pregnancy from a pregnancy with cervical cancer (4, 5).
Cervical Cancer Diagnosis In Pregnancy
In a pregnant women with suspicious symptoms for cervical cancer, first of all physical examination, the gynecological examination what you pregnant women do not like, is a must. This examination is required to rule out a possible cervical cancer. Also, identifying pathologies that are different like polyps but benign that cause bleeding in cervix for a pregnant woman is another must for the protection it provides.
Subsequently, a pap smear must be taken and send to pathology. The only difference from a non-pregnant woman is that one must not use sitobrush to take smear from inside the cervix canal. Otherwise a conventional smear should be taken.
If there is a suspicious lesion, a biopsy must be taken. As the possibility of bleeding of the cervix is higher in pregnant women, an experienced gynecologist or a gynecologist oncologist is preferred to take the biopsy.
According to the biopsy result the patient is directed.
A. Cervical Cytology (Pap Smear Results) Assessment in Suspicious Pregnancies
The Algorithms indicated below are taken from the directives created according to the 2006 Bethesda guide.
1. Pregnant women under 20: In women under 20 years of age the rate of seeing an HPV infection, prevalence of ASC-US (Atypical Squamous Cell of Unknown Significance) or LSIL (CIN I) is high however as the 90 per cent of the cases selfheal, colposcopy is not necessary. However the cytology results must be repeated after delivery.
2. Pregnant women over 20: In pregnant women detected with ASC-UC and LSIL (CIN I), the approach is no different than non-pregnant women. Thus a colposcopy and if necessary a biopsy under colposcopy can be performed. The most important difference is that the colposcopy should be repeated in the 6 weeks following the delivery (1, 4).
3. In the presence of ASC-H, HGSIL or atypical glandular cells (AGC), even if in adolescence a colposcopy must be done. ASC-H means that there are most probably high grade cervical intraepithelial neoplasic (HGSIL or CIN 2-3) cells. As a result, in case of detection of ASC-H, HGSIL or AGC in the smear taken from a pregnant woman, colposcopy and subsequently a biopsy must be done.
B. Colposcopy in Pregnancy During
Colposcopy on the patient if CIN 2/3 or cervical cancer is considered a biopsy from the lesion is a must. In case that no suspicious areas are detected in colposcopy, it shall be sufficient to repeat the cytology and colposcopy within 6 weeks after delivery.
Taking biopsies under colposcopy is a safe invasion in experienced hands, there is no need for anesthesia and it does not increase the frequency of miscarriages or premature delivery. The most important problem is the risk of bleeding and it can be taken under control mainly with cautery or “Monsel solution”.
You can think like this, in cervical failure we stitch the cervix to prevent miscarriage with a surgical method much more aggressive than biopsy.
In fact the only difference in assessment of premalignant or malignant possible lesions in cervix in pregnancy from non-pregnant women is that no endocervical curettage is done. “Endo” means inside. “Endocervical curettage” is taking biopsy from the canal in the middle of the cervix.
The reason for this procedure is to sample the entire canal and not to miss tumors rooted in the region close to the womb even if they are rare. However this application has the risk to increase complication risk in pregnant women.
Even though there is no proven connection between this and fetal loss, as it carries miscarriage risk the endocervical curettage is not recommended.
Sometimes not sufficient results are gained during colposcopy. The region fundamentally examined in colposcopy is the transformation zone where endometrium and squamous epithelia meet. Sometimes the transition zone cannot be assessed clearly. We call this condition “Insufficient Colposcopy”.
In that case after 20 pregnancy weeks, the colposcopy should be repeated because at that time the Transition Zone gets closer to the outer side of the cervix and a better result is acquired (6). However due to the physiology of the pregnancy, the “insufficient colposcopy” is a rarely seen situation.
The changes at the cervix due to pregnancy can be confused with the malignancy findings at the cervix. For example extreme vascularization due to pregnancy will react more with acetic acid and this shall lead to suspicious lesions. A similar situation is also valid for the first trimester of the pregnancy.
In this period, as hormonal changes due to pregnancy show similarities with the neoplastic changes, a possible malignancy can be missed. Thus the colposcopy is better to be done by an experienced person. (6, 7).
C. Confiscation Operation in Pregnancy and Possible Complications:
Cervical conization indications show differences between pregnant and non-pregnant patients. However, firstly, let us see what is conization.
You know that the cervix is a special organ, it is composed of combination of two completely different tissues, squamous epithelia of vagina and columnar epithelia of the womb. We call the zone they meet the transition zone.
In this area metaplasic cells are present which are developed as the result of combination of two tissues. Our infamous HPV likes to settle down in these cells. Thus, classical cervical cancer roots in this transition zone.
Conization is a method we use for treatment of cervical intraepithelial neoplasia, i.e. CIN 2 and CIN 3, and also the early stage cervical cancer (Stage IA1), that is based on removing the transition zone. In conization transition zone is removed where the tumors and precursors are most frequently seen.
However performing conization is a serious decision in pregnancy. It can cause miscarriage, premature delivery and early membrane tearing, i.e. water break.
Normally in non-pregnant patients, as the only way to understand how deep the lesion goes is to examine the entire lesion, conization is recommended to be done in the presence of microinvasive or adenocarcinoma in situ.
But in pregnant women on the contrary, the conization should be delayed to post-delivery if the condition shall not change the time and way of the delivery, in order to understand whether there is an invasion or not.
Let me explain more clearly. If the results of the biopsy from cervix require that information should be gathered about the spreading of the tumor as to change the time of delivery, conization should be done during pregnancy (8).
KIf the labor shall not be wait for, a date between 14 to 20 weeks should be preferred for conization. Additionally, due to risk of re-bleeding of the conization area or the scar getting bigger, the operation must be performed at least 4 weeks before the planned date of labor.
However, there is a big “but” here that some new publications suggest that the conization should be done in the first trimester and this decreases the complication risk (9).
Technically, squamo-columnar epithelia (transition zone) getting closer to outer side during pregnancy is a factor facilitating conization.
In the 6th edition of the book of DiSaia, it is indicated that instead of a cone, a piece in the size of a coin to be taken shall not be problem and it may decrease the complication risk (10).
In the case where this condition is not possible stitching around the cervix right after operation is another choice. Here, it is not right to discuss the surgical technique however conization to be done after clearly setting the section to be removed in colposcopy and avoiding unnecessary aggressiveness shall minimize the complication risk.
While fetal loss is not seen much after conization, the complications with higher prevalence can be listed as blood loss, fetal membrane early rupture, premature delivery, miscarriage and infection (1).
Reported fetal losses are mainly related with chorioamnionitis. The frequency of blood losses over 500ml changes depending on the stage of the pregnancy. Accordingly, in the first trimester, when conization is performed the risk is too low, however in second trimester the risk is reported as 5% and in third as 10%.
This is where the view let us do the conization in the first trimester depends that emerged in the recent years and I mentioned above. The counter view, the classical view is that the first trimester is the organogenesis period so that surgical intervention should be done around 18th week.
In the most extensive study performed on the matter, in 8 of 27 pregnant women (4.5 per cent) fetal loss is seen due to conization. 3 of these are reported in the 14th week of the pregnancy around 1 to 4 weeks later than the conization operation. Among the pregnancies in the same study, 11 of them in the third trimester, total of 13 has suffered over 500 ml blood loss during pregnancy (11).
However this research is a very old publication done in Miami University. On the other hand, I could not find a better one, one done with a wider case group in the literature.
Cervical Cancer Staging in Pregnancy:
The staging of cervical cancer is very important for the accurate guidance of the patient whether pregnant or not and for planning of the treatment. Staging is performed clinically according to the criteria set by FIGO International Federation of Gynecology and Obstetrics. It is not different than the non-pregnant patient.
The problem is that in the pregnant women, depending on the pregnancy week, sometimes the clinical staging is very hard to do. However, if the patient is in the condition to perform a clinical staging then the detail we shall get to in the treatment section below which are especially important for the fetus shall be determinant in the prognosis of the patient and the baby.
1. Physical examination, gynecological examination: During gynecological examination it is important that the womb, vagina and parametrium, both sides of the cervix, are assessed. In cases where the examination cannot be performed ideally, if needed, the patient should be anesthetized and the examination shall be repeated.
2. Imaging Techniques: When cervical cancer is present in pregnant women, it ideal is the magnetic resonance imaging method. It does not contain radiation but should be assessed with an experienced radiologist. In pregnancies, during utilization of the imaging techniques it should be preferred that the fetus is exposed to minimal ionized radiation while obtaining maximum possible information on the condition of the mother.
Treatment Approach in Pregnant Patients with Preinvasive Cervical Cancer
In this case it is recommended that the end of pregnancy is waited and in 6 to 8 weeks after delivery the assessment is repeated and the treatment is planned accordingly. Even if the lesion is at an advanced stage, if there is no invasion, transformation to invasive cancer is very rare during pregnancy (0 to 0.4 percent) (12).
Moreover, disease can regress after delivery. As there is no exact information on whether this regression is related to the birth or not, it is recommended that while deciding normal delivery or C-section it should be done according to the routine criteria.
Treatment Approach in Pregnant Patients with Invasive Cervical Cancer
In this case there are many factors to be considered in determination of the approach. Progress of the illness, the methods used for diagnosis and especially assessment of the findings of MRI, the spiritual condition of the mother, how much the family wants the baby (for example a family with 3 living children shall have a very different behavior than a mother and her spouse being pregnant for the first time), the approach of the patient and her family towards the termination of pregnancy, and many similar issues should be assessed and at the final decision stage the issue should be discussed with a consultant group.
However in some cases, without considering the stage of the pregnancy, an emergency and definite treatment should be applied (13):
1. Lymph node metastasis
2. Disease advancing during pregnancy. For example, in the examination and MRI of a patient with CIN III at her 28th week of pregnancy, presence of parametrial or vaginal involvement.
3. Patient taking the decision of termination of pregnancy. Here many ethical rules come in to discussion besides pregnancy week and the livability of the child. Extremely hard decisions may have to be taken.
For example, in a family with 2 children the father can say “My god bless my wife to her children, please terminate this pregnancy” but at that time the pregnancy can be at 26th week. 3-4 weeks later termination of the pregnancy shall not create a problem regarding the progress of the tumor and the child may become livable.
On the other hand for the gynecologist to explain this situation to the family can be extremely difficult.
The approach to the patient and the treatment process in advanced stage cervical cancer and about pregnancy is same as the non-pregnant women. Only the stage that is accepted as advanced is Stage IIB and beyond, and the classical treatment is systemic chemotherapy and radiotherapy.
In advanced stage cervical cancers detected before the 20th week of pregnancy, the ideal thing is to terminate the pregnancy.
In the patients who do not wish to or cannot terminate the pregnancy due to ethical or medical reasons, the treatment approach should be determined special to the individual considering the stage of the illness, treatment options, preferences of the patient and the possibility of the living in the fetus.
Thus during the assessment of all these should be directed via utilizing the psychological consultancy in cooperation with a gynecologist oncologist, mother-fetus health expert (perinatalogist) and new born specialist.
Approach in Pregnancies with Cervical Cancer Requiring Surgery according to the Stages
Microinvasive cancer (Stage IA-1)
The patients in this group are recommended conization application. Few amount of data show that this method is sufficient and safe. It was showed that in 8 pregnant women with Stage IA-1 cervical cancer, there is no advancement in the illness in the time passes until the final treatment after the cervical conization performed in weeks 9 to 25 (14).
For patients with conization to be applied, it is important to give information on the complications of this operation.
The examples are 5 to 15 percent bleeding risk and in cold conization (it is never my choice and it increases risk unnecessarily) spontaneous miscarriages up to 15 %. The complication risk increases as the pregnancy week advances and depending on the size of the tissue extracted.
Therefore, in order for the endocervical canal to be damaged less, coin excision method is also among the recommendations (13, 14).
Despite the issue is extremely controversial, in the presence of stage IA1adenocarcinoma, treatment can be organized similarly.
Stage IA2-IB1 (<2 cm)
In this group the probability of the illness to spread to parametrium is less than 1 percent (15). Thus, conservative interferences like simple trachelectomy or extended conization are considered sufficient. In radical trachelectomy as the miscarriage and bleeding risks are very high this should not be done (1, 13, 15).
The thing to be discussed here is whether the lymph node should be taken or not. When the pregnancy is less than 22-25 weeks, as the complication risk is not much lymphadenectomy is recommended to be performed (safest terms are first and second trimester). Moreover, this application can also be done perfectly as laparoscopic (13).
Whether there is a lymph node invasion or not is determined during the surgery with frozen and subsequently if there is no invasion the treatment is determined according to the size of the lesion in the cervix.
Stage IB1 (tumor larger than 2 cm) and more advance cases should be treated immediately, neoadjuvant chemotherapy (application of chemotherapy to stop the illness and to protect the progress of the pregnancy and the fetus before radical surgery or radiotherapy) should be applied.
If the pregnancy is at a margin for the fetus like 24-26 weeks, the family should be consulted and the risks should be explained to them then respecting their decision the treatment should be planned.
All in all, for the women who wish to continue their pregnancy, chemotherapy or premature labor options can be assessed. However, at this point the evaluation of the ethical and medical aspects, determination of the methods to be applied considering the advanced stage illness properties, the choices of the patient, the living chance of the fetus and premature birth possibility with a multidisciplinary approach and informing the patient on her condition are essential.
In Stages IA and IB1 (<2 cm) some studies argue that it is better to delay the treatment post-delivery in patients with tumor size less than 2 cm.
Some studies on the matter have really well results. However there are so few data on the subject that at the decision stage the family and the woman to understand the risks and the issue to be explained to the family countless times by the gynecologist oncologist and necessary legal papers (consent forms) to be signed by the patient are crucial (13, 16).
How the Pregnant Woman with Cervical Cancer should Deliver?
The time of birth should be determined according to the pregnancy week, stage of the illness, whether the illness is in advancement or not. The ideal thing is to have birth on term (37th week and later) but if it is necessary to deliver earlier due to medical reasons, necessary treatments to adjust the wellness of the fetus (e.g. Giving steroids) should be applied.
The studies, when the microscopic cervical cancer is in question, i.e. IA1 and IA2, show that the vaginal birth does not affect the prognosis of the patient. Thus, in those patients selection of vaginal birth or C-section should be done independent of the illness (1, 2, 13).
However, with a great BUT, if possible, episiotomy should be avoided. It is reported that in more than 15 cases, implantation is observed as the result of episiotomy performed during vaginal birth. It should be emphasized that in these studies, 5 of 11 women where the cervical cancer has relapsed as the result of episiotomy have been lost (17).
In stage IB1 and more advanced cervical cancers, the vaginal birth should not be performed. Abdominal birth, C-Section, is the best choice!
In the presence of a microscopic tumor (Stage IA1 and IA2) in the patients who wish to protect fertility after birth, if no cancer trace is seen during follow ups and if it is definite that the patient is in Stage IA1 then there shall be no need for additional treatment. If in the conization performed during pregnancy the margins are positive in pathology C-section birth and repetition of the conization 6-8 weeks after birth are recommended (1, 13).
In Stage IA2 patients or patients with tumor diameter up to 4 cm, radical trachelectomy and in addition lymphadenectomy (if not performed before) are recommended. This operation can be done up to 6-8 weeks after delivery.
Besides these, in the patients with the size of the tumor below and equal to 60 cm3 or patients with larger, advanced stage tumor, the treatment is same with the patients with no pregnancy and it is shaped in line with the gynecologist oncologist and medical oncologist’s choices.
The worst picture is the pregnancy and metastatic cervical cancer.
The approach to these patients that can be seen, even though they are rare, is that the cervical cancer spread to the organs out of cervix is called as stage 4.
In this case where prognosis is not good, the condition of the pregnancy affects more negatively the patient and her family. It is very crucial that the patient, in addition to the planned treatment, is also supported psychologically. Our goal is not definite treatment but to keep the illness under control so that it is proper that the patients are treated with the chemotherapic agents used in patients that are not pregnant. It is recommended to start classically with cisplatin and paclitaxel combination (13).
In many of the studies performed there is no difference seen in the prognosis of the patients that are pregnant and not pregnant. However it must be stressed again that the data in hand is limited. The effects of the cervical cancer on the pregnancy and fetal health is indeterminate under the current knowledge. In two retrospective studies, it is shown that this illness does not affect the prognosis of the pregnancy, and it is determined that the premature birth ratios, intrauterine growth and stillbirth ratios do not change between the pregnant women with cervical cancer and healthy pregnant woman.
1. Amer Karam. Cervical cancer in pregnancy. UpToDate web site (https://www.uptodate.com/conten…/cervical-cancer-in-pregnancy)
2. Nguyen C, Montz F.J., Bristow R.E. Management of stage I cervical cancer in pregnancy. Obstet Gynecol Surv. 2000;55(10):633.
3. Creasman W.T. Cancer and pregnancy. Ann N Y Acad Sci. 2001;943:281.
4. Van Calsteren K, Vergote I., Amant F. Cervical neoplasia during pregnancy: diagnosis, management and prognosis. Best Pract Res Clin Obstet Gynaecol. 2005;19(4): 611.
5. Zemlickis D, Lishner M, Degendorfer P. Et al. Maternal and fetal outcome after invasive cervical cancer in pregnancy. J Clin Oncol. 1991;9(11):1956. (Önemli yayın fetal prognoz açısından!)
6. Economos K., Perez Veridiano N., Delke I. et al. Abnormal cervical cytology in pregnancy: a 17-year experience. Obstet Gynecol. 1993;81(6):915
7. 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(1):31.
8. Douvier S, Filipuzzi L, Sagot P. Management of cervical intra-epithelial neoplasm during pregnancy. Gynecol Obstet Fertil. 2003;31:851.
9. Siegler E., Amit A., Lavie O., et al. Cervical intraepithelial neoplasia 2, 3 in pregnancy: time to consider loop cone excision in the first trimester of pregnancy? J. Low Genit. Tract Dis. 2014; 18(2):162-168.
10. Clinical Gynecologic Oncology, 6th, DiSaia PJ, Creasman WT (Eds), Mosby, 2002.
11. Averette HE, Nasser N, Yankow SL, Little WA. Cervical conization in pregnancy. Analysis of 180 operations. Am J Obstet Gynecol. 1970;106(4):543.
12. Paraskevaidis E., Koliopoulos G., Kalantaridou S. et al. Management and evolution of cervical intraepithelial neoplasia during pregnancy and postpartum. Eur J Obstet Gynecol Reprod Biol. 2002;104: 67.
13. Amant F., Halaska M.J., Fumagalli M. Et al. ESGO task force‘Cancer in Pregnancy’ Gynecologic cancers in pregnancy: guidelines of a second international consensus meeting. Int J Gynecol Cancer. 2014;24: 394.
14. Takushi M, Moromizato H, Sakumoto K. Et al. Management of invasive carcinoma of the uterine cervix associated with pregnancy: outcome of intentional delay in treatment. Gynecol Oncol. 2002; 87: 185.
15. Rob L., Skapa P., Robova H. Fertility-sparing surgery in patients with cervical cancer. Lancet Oncol. 2011 Feb;12(2):192-200.
16. Karam A., Feldman N., Holschneider CH. Neoadjuvant cisplatin and radical cesarean hysterectomy for cervical cancer in pregnancy. Nat. Clin. Pract. Oncol. 2007; 375.
17. Van den Broek N.R., Lopes A.D., Ansink A., Monaghan J.M. “Microinvasive” adenocarcinoma of the cervix implanting in an episiotomy scar. Gynecol Oncol. 1995; 59: 297.