LITHUANIAN UNIVERSITY OF HEALTH SCIENCES Faculty of Medicine Department of Obstetrics and Gynaecology

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1 LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

Faculty of Medicine

Department of Obstetrics and Gynaecology

Paulina Jagłowska, MF

Title of the Master’s Thesis:

Fertility-Sparing Options for Early-Stage Cervical Cancer

Thesis supervisor PhD. Dr. Eimantas Švedas

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1. Summary………..3-5 2. Conflicts of Interest………...6 3. Abbreviations……….6 4. Terms………...7 5. Introduction……….8-9 6. Aim and objectives………....10 7. Literature Review………..11 7.1 Epidemiology and Etiology of CC……….11 7.2 Diagnostic and screening methods of CC………...12-13 7.3 Staging of CC ………....13 7.4 Fertility Preservation in CC………..14-15 8. Research Methodology and Methods………....16 9. Results and Discussion of the Results………...16 9.1 Cervical cancer screening………..16-18 9.2 Fertility-sparing options depending on FIGO classification ………....19-23 9.3 Obstetrical outcome after fertility-sparing treatment of cervical cancer………...22-25 10. Conclusion………..…..25 11. References………...26-30

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1. Summary

Author: Paulina Jagłowska

Research title: Fertility-Sparing Options for Early-Stage Cervical Cancer

Aim: To describe fertility-sparing methods of treatment for the early-stage cervical cancer and

their obstetrical outcomes

The objectives:

1. To review the actual knowledge about cervical cancer screening

2. To analyze fertility-sparing methods used in early-stage cervical cancer treatment 3. To find out the obstetrical outcomes after fertility-sparing surgeries

The methodology:

The search was done in PubMed, and the most recent and relevant papers were selected in English language. All articles used in this work were published in the last 10 years.

The following keywords were used: “ cervical cancer”, “cervical cancer screening”, “cervical cancer staging”, “ fertility sparing management in cervical cancer”. “ cervical conisation”, “ trachelectomy”, “ fertility outcomes after trachelectomy”, “HPV-related cancers”.

Articles related to cervical cancer screening, staging, fertility-sparing management and their outcomes were selected.

Papers that were not in alignment with the objectives of this thesis were excluded.

Results:

The results show that regular cervical cancer (CC) screening, using Papanicolaou and Human Papillomavirus Deoxyribonucleic acid (HPV DNA ) test, that should start at age 21 and

continue according to the age group, risk factors and associated diseases is an effective method to diagnose CC in early stage, and offer women fertility-sparing methods of treatment that will allow conception in the future.

Cervical Conisation and Radical Vaginal Trachelectomy (RVT) are the main methods of fertility-sparing surgeries (FSS) with satisfying oncological outcomes, comparable to Radical Hysterectomy procedure. Premature labor and delivery seem to be the main obstetrical complications after FSS.

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Conclusion:

• Regular CC screening testing starting at age 21 may lead to early detection of the disease and as a result non-invasive methods of treatments might be applied,

• Cervical Conisation and RVT are the main treatment options in case of low risk, early-stage cervical cancer for women with a strong desire for future pregnancy,

• The main concern with pregnancies following FSS is the increase rate of premature labor and delivery, as well as miscarriages, caused by cervical incompetence, and ascending infections with premature rupture of membranes.

1. Santrauka

Autorė: Paulina Jaglowska

Tyrimo pavadinimas: Vaisingumo išsaugojimo galimybės ankstyvoje gimdos kaklelio vėžio

stadijoje.

Tikslas: Apibūdinti vaisingumą tausojančius gydymo metodus ir jų akušerinius rezultatus esant

ankstyvoje gimdos kaklelio vėžio stadijoje.

Tikslai:

1. Faktinių žinių ir šaltinių apžvalga gimdos kaklelio vėžio patikros tema.

2. Išanalizuoti vaisingumą tausojančius metodus, naudojamus ankstyvoje gimdos kaklelio vėžio

stadijoje.

3. Sužinoti akušerinius rezultatus po vaisingumą tausojančių operacijų.

Metodika:

Paieška buvo atliekama naudojantis „PubMed“ sistema, pasirenkant naujausius ir tema atitinkančius darbus anglų kalba. Visi šiame darbe naudoti straipsniai buvo publikuoti per pastaruosius dešimt (10) metų.

Šiame darbe buvo naudotasi šiais raktiniais žodžiais: „gimdos kaklelio vėžys“, „gimdos kaklelio vėžio patikra“, „gimdos kaklelio vėžio stadija“, „gimdos kaklelio vėžio vaisingumas“, „gimdos kaklelio konizacija“, „trachelektomija“, „vaisingumo rezultatai po trachelektomijos“, “ Su ŽPV susiję vėžiniai susirgimai“.

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5 Šiame darbe atrinkti straipsniai, susiję su gimdos kaklelio vėžio patikra, stadijomis, vaisingumo išsaugojimo būdais ir jų rezultatais.

Straipsniai, kurie neatitiko šiame darbe keliamų tikslų, buvo atmesti.

Rezultatai:

Rezultatai atskleidė, kad reguliari gimdos kaklelio vėžio patikra, naudojant Papanicolaou ir ŽPV DNR tyrimus, kurie turėtų prasideti nuo 21-erių metų amžiaus ir tęstis atsižvelgiant į paciento amžių, rizikos veiksnius ir susijusias ligas, yra veiksmingas būdas diagnozuoti gimdos kaklelio vėžį (CC – gimdos kaklelio vėžys) ankstyvoje stadijoje ir pasiūlyti moterims efektyvius vaisingumą tausojančius gydymo metodus, kurie leistų pastoti ateityje.

Gimdos kaklelio konizacija ir radikalios makšties trachelektomija (RMT) yra pagrindiniai vaisingumą tausojančių operacijų (FSS) metodai, kurių onkologiniai rezultatai yra teigiami, priliginami radikaliai gimdos pašalinimo procedūrai.

Priešlaikinis gimdymas, gimdymas ir kūdikio (vaisiaus) išstūmimas yra pagrindinės akušerinės komplikacijos po FSS.

Išvada:

• Reguliarūs gimdos kaklelio vėžio patikros tyrimai, pradedant nuo 21-erių metų amžiaus, gali padėti nustatyti ligą ankstyvoje stadijoje ir taikyti neinvazinius gydymo metodus;

• Gimdos kaklelio konizacija ir radikali makšties trachelektomija yra pagrindiniai gydymo variantai moterims, turinčioms stiprų norą būsimam nėštumui, esant mažos rizikos, ankstyvos stadijos gimdos kaklelio vėžiui.

• Didžiausias rūpestis dėl nėštumo po vaisingumą saugančių operacijų, yra išaugusi rizika: priešlaikiniui gimdymui, persileidimui sukeltam dėl gimdos kaklelio nepakankamumo ir infekcijoms kylančioms dėl anksčiau laiko plyšusios membranos.

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2. Conflicts of interest

The author reports no conflicts of interest.

3. Abbreviations

CC- Cervical carcinoma HPV- Human Papillomavirus

HPV DNA test- Human Papillomavirus Deoxyribonucleic acid test SCC- Squamous Cervical Carcinoms

CIN 2- Cervical Intraepithelial Neoplasia grade 2

ASCUS cytology- Atypical Squamous Cells of Undetermined significance LEEP- Loop Electro surgical Excision Procedure

FSS- Fertility-Sparing Surgery

RVT- Radical Vaginal Trachelectomy ART- Abdominal Radical Trachelectomy PROM- Premature Rupture of Membranes

pPROM- Pre-term Premature Rupture of Membranes IVF- In Vitro Fertilization

IUI- Intrauterine Insemination

ART- Assisted Reproductive Technologies MRI- Magnetic resonance imaging

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4. Terms

Papanicolaou test- one of the cervical screening method, used to detect potentially

precancerous and cancerous processes in the cervix.

Colposcopy- medical diagnostic procedure used to visualize and magnify the cervix.

Fertility-Sparing Surgeries- medical procedure that preserves the uterus and at least part of

one ovary with the goal of fertility preservation.

Early stage cervical cancer- is defined by FIGO as stage IA to IB1 disease

Cervical Conisation- medical procedure during which a cone-shaped portion of cervix is

removed. Might be used for either diagnostic purposed as part of a biopsy or therapeutic purposes to remove pre-cancerous cells.

Radical Trachelectomy- curative conservative procedure in which the cervix, upper 1-2 cm of

the vagina, parametria are removed, while preserving the uterine corpus and fundus.

Aptima HPV mRNA essay – test approved for cervical screening for the detection of 14

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5. Introduction

HPV ( Human Papillomavirus) infection is very common among sexually active individuals regardless of the age. Usually, it is self-curable and does not lead to cervical abnormalities. However, chronic infection with high risk Human Papillomavirus Deoxyribonucleic acid (HPV DNA) types is the most important risk factor for future development of pre-malignant cervical changes that might lead to cervical carcinoma. HPV genotypes most commonly involved in cervical cancer (CC) development are types 16 and 18.

Although CC might be preventable through well-known screening tests, it still remains one of the most common cancer-related morbidity and mortality throughout the world.

Nowadays there are two screening options: Papanicolaou test and HPV DNA test. Screening should start at age 21 and be continued according to the particular age group. Usually, when there are no special indications for more frequent testing, the screening test should be repeated every 3 years. It might be discontinued in women over 65 years with negative prior screening and no history of Cervical Intraepithelial Neoplasia grade 2 (CIN 2 ) during the last 20 years. For women younger then 65 years, further testing might be needed in case of positive cytology or HPV DNA test results.

Women are usually offered to repeat the test or perform colposcopy with biopsy for further testing and confirmation of the malignant changes. Imaging studies are often used to evaluate the extent of the disease and involvement of the lymph nodes.

Treatment strategy is based upon FIGO staging for CC.

Cancer located anywhere in the body may affect reproductive system due to treatment, which usually includes radio or chemotherapy that might cause ovarian damage.

The situation is even more complicated if malignant process is located in the reproductive system, however in case of early diagnosis of CC there are few Fertility sparing surgeries (FFS) that might be offered to a patient with a strong desire to become pregnant in the future.

Fertility-sparing options include Cervical Conisation, Simple or Radical Trachelectomy. During those procedures the uterus is not removed and women have a chance to become pregnant in the future.

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9 Early stage CC includes disease that is confined to the cervix, 2 cm or less with no spread to adjacent structures or distant organs (FIGO stages IA to IB1).

Pregnancy after successful FSS is possible and usually women conceive without help of the Assisted Reproductive Technologies (ART).

Premature deliveries are the main obstetric complication following FSS, however abundant successful pregnancies have been reported.

Cervical stenosis and shortening, seems to be the leading cause of the premature deliveries.

The general aim of this thesis is to review fertility-sparing treatment options for early stage CC and find out the possible obstetrical complications in future pregnancies.

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6. Aim and objectives

Aim of the study: To describe fertility-sparing methods of treatment for the early-stage

cervical cancer and their obstetrical outcomes.

Objectives:

1. To review the actual knowledge about cervical cancer screening

2. To analyze fertility-sparing methods used in early-stage cervical cancer treatment 3. To find out the obstetrical outcomes after fertility sparing surgeries

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7. Literature review

7.1 Epidemiology and Etiology of CC

Widespread screening programs in developed countries contributed to decrease in incidence and mortality rate of cervical cancer (CC) by greater then fifty percent over the past fifty years. CC can be prevented if screening methods including Pap smear and HPV DNA test are

performed according to the age-specific guidelines. However, the CC still remains the most frequent gynecological cancer in developing countries leading to many deaths annually. There are some factors that might contribute to increasing incidence rate of this disease in many developing countries. That includes early beginning of sexual activity, high number of sexual partners, infrequent use of condoms, immunosuppression caused by HIV infection. Use of the oral contraceptive pills for more then 5 years increase the risk of CC, but only in women who carry the HPV.

A factor responsible for CC development is chronic mucosal infection caused by oncogenic HPV genotypes, including 16,18,33,45,31,58, with 16th and 18th being the most common types involved in the development of CC. The virus is transmitted by the direct contact, most

commonly during sexual intercourse with the infected person. Infection with HPV is very common among sexually active individuals, and it usually resolves spontaneously in nearly 90 % of cases within several months without causing any symptoms. However, in some cases the organism is not able to get rid of the infection, which lead to persistent exposure to the virus which is a main risk factor for the development of the high-grade dysplasia and progression to cervical cancer.

Squamous cervical carcinoma (SCC), Adenocarcinoma and Adenosquamous carcinoma are three histological types of cervical cancer. SCC is the most common type, representing nearly 70% of cases. Cervical Adenosquamous carcinoma is a relatively uncommon histologic subtype of cervical malignant neoplasm.

CC is not the only disease linked to HPV infection. The chronic infection with the virus might lead to the cancer of oropharynx, anus, vulva, vagina, and penis.

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7.2 Diagnostic and screening methods of CC

The purpose of CC screening is to diagnose precancerous lesions and malignant changes that would not require invasive methods of treatment, give high chance of recovery and preserve fertility in young patients who wish to have children in the future. Currently there are two types of screening tests that are used. Papanikolaou test and HPV test. Screening should begin at age 21. It is not recommended for younger women to be screened either with Pap smear or HPV test before that age.

Women between 21- 29 years should be screened every 3 years. If the Pap smear results are abnormal, HPV test should be recommended. Both Pap smear and HPV test (co-test) should be done every 5 years as a screening method for women between 30 and 65 years.

For the Pap smear to be correctly performed patients should be informed not to perform the test during the menstrual bleeding, and to avoid sexual intercourse 48 hours before Pap test.

There is no need for further screening in women over the age of 65 with with three prior negative Pap smears or two prior negative Pap smears together with two negative HPV test results, and no abnormalities in the Pap test over a period of 10 year.

After total hysterectomy procedure and no history of cervical cancer or severe precancerous lesions there is no need for further screening.

Women who underwent vaccination against the HPV are still at risk of infection and should continue the screening against CC according for their age group.

Further investigations depend on the Pap smear and HPV test results.

In case of positive HPV test in the presence of normal cytological findings, the woman should be either offered to repeat co-test in 12 months or perform HPV genotype specific testing for HPV 16 alone or together with HPV18. Colposcopy should be offered for women with positive co-test repeated in 12 months or if immediate HPV genotyping is positive for HPV16 or

HPV16 and HPV18. During colposcopic examination the sample of cervical cells might be taken for laboratory testing.

In case of Atypical Squamous cells of Undetermined Significance (ASCUS) cytology with negative HPV test, women should be recommended to continue screening according to the age.

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13 When the invasive CC is suspected, pelvic Magnetic Resonance Imaging (MRI) or Positron Emission Tomography (PET-CT) should be performed to determine the extent of the original disease.

7.3 Staging of CC

Table 1. FIGO staging of cervical cancer (2020)

Stage I Tumor is limited to the cervix.

Stage IA Microinvasive carcinoma limited to the cervix that is only

microscopically visible. The maximum invasion depth is <5 mm. Stage IA1 Stromal invasion <3mm

Stage IA2 Stromal invasion ≥ 3 mm and ≤ 5 mm

Stage IB Invasive carcinoma limited to the cervix with stromal invasion of _{≥ 5mm or a clinically visible tumor.} Stage IB1 Clinically visible tumor <2 cm or microscopically visible lesion

with an invasion depth of ≥ 5mm.

Stage IB2 Invasive carcinoma with a diameter of ≥ 2cm and ≤ 4 cm.

Stage IB3 Invasive carcinoma with a diameter of ≥ 4cm.

Stage II The tumor is not limited to the cervix and infiltrates the upper 2/3 of the vagina or the parametria.

Stage IIA1 Maximum diameter is <4cm.

Stage IIA2 Maximum diameter is ≥ 4 cm.

Stage IIB Infiltration of the parametria but the pelvic wall is not affected.

Stage III Infiltration of the lower 1/3 of the vagina or the pelvic wall. Stage IIIA Tumor extends to the lower 1/3 of the vagina but does not reach

the pelvic wall.

Stage IIIB

Infiltration of the pelvic wall or the ureters resulting in

hydronephrosis. Per definition, pelvic wall infiltration is present when the iliac vessels, the obturator internus muscle, the

piriformis muscle, or the levator ani muscle is infiltrated.

Stage IIIC Pelvic and/or retroperitoneal lymph node metastases, regardless of the tumor size or extent

Stage IIIC1 Pelvic lymph node metastases

Stage IIIC2

Retroperitoneal lymph node metastases in the TNM classification, involvement of retroperitoneal lymph nodes is categorized as distant metastasis (M1).

Stage IV

Detection of infiltration of the bladder and/or rectum or extension of the tumor beyond the borders of the small pelvis. To be

classified as stage IV, the tumor tissue must infiltrate the wall layers of the bladder and/or rectum to the mucosa ( infiltration of the mesorectal fat tissue is not stage IV per definition).

Stage IVA Infiltration of the bladder and/or rectum to the mucosa.

Stage IVB Presence of the distant metastases.

[3] Chhabra S, Kutchi I. Fertility Preservation in Gynecological Cancers, Clinical Medicine Insights: Reproductive Health[internet].2013[cited 2020 Dec 12];7:49-59.

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7.4 Fertility preservation in CC

CC is still continuing to be the leading cause of cancer-related deaths in many countries. All age groups are effected, including young patients in their fertile years. This is why a closer look at fertility-sparing options is so important. Due to effective screening methods, many women can be diagnosed at early stage of the disease. Less radical, FSS are available for low risk, early-stage CC.

The standard, well-known treatment option for women diagnosed with early stage CC is Radical, or Simple Hysterectomy with pelvic lymphadenectomy with or without radiotherapy. However, those options may result in permanent infertility.

FST options include Cervical Conisation, Simple Trachelectomy and Radical Trachelectomy, where the uterine body is leaving intact.

Patients need to fulfill certain criteria to be offered FSSs. Those criteria are as following: Squamous carcinoma, Adenocarcinoma or Adenesquamous carcinoma on histological examination, tumor size < 2 cm, stromal invasion <10 mm, and no lymph-vascular space invasion.

Radical trachelectomy is a fertility-sparing option for CC in stage IA or IB (less the 2 cm), without evidence of pelvic metastasis.

Radical vaginal trachelectomy (RVT) is a treatment option for stages IA and IIA. In case of stage IA1 CC, Cervical Conisation should be considered.

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Fig1. Radical vaginal trachelectomy

Red line: resection line of the radical vaginal trachelectomy;

Red area: extent of the tumor: blue lymph node: sentinel lymph node.

[13] Rema P. Conservative Surgery for Early Cervical Cancer, Indian J Surg Oncol[internet].2016[cited 2020 Dec 15]7(3):336-340. Fig.7, LEEP excision specimen;p.338.

8. Research Methodology and Methods: Literature Review

The search was done in PubMed, and the most recent and relevant papers were selected in English language. All articles used in this work were published in the last 10 years.

The following keywords were used: “ cervical cancer”, “cervical cancer screening”. “cervical cancer staging”, “ fertility sparing surgery in cervical cancer”. “ cervical conisation”, “ trachelectomy”, “ fertility outcomes after trachelectomy”, ”HPV-related cancers”

Articles related to cervical cancer screening, staging, fertility-sparing management and their outcomes were selected.

Papers that were not in alignment with the objectives of this thesis were excluded.

After searching for the keywords in PubMed over 4000 articles were found. After reviewing 100 articles , 22 of them were used in this thesis based on the time of publication and topics most relevant to cover the aim and objectives of this work.

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9. Results and Discussion

9.1 Cervical cancer screening

The table shows most recent cervical cancer screening recommendations.

Table 2. Cervical Cancer screening

Age group 21-29 30-65

Screening recommendation Pap test every 3 years Pap test and HPV test (

co-test) every 5 years OR Pap smear every 3 years

[2]Brown A, Trimble C. New Technologies for Cervical Cancer Screening, Best Pract Res Clin Obstet Gynaecol [internet]. 2012 [cited 2020 Dec 10];26(2):233-242.

Proper CC screening programs are necessary in order to diagnose CC in early stage and to apply non-invasive methods of treatment which reduces the complications and allow women to preserve fertility which is really important nowadays where even young patients are diagnosed with CC.

It is not recommended to offer the Pap smear more often then in every 3 years to avoid false positive results and unnecessary treatment.

More frequent screening might be useful in case immunosuppressed patients, women exposed to diethylstilbestrol in the uterus , and for women previously diagnosed with CIN2, CIN3 or cancer.

Screening might be discontinued in women over 65 years with negative 3 previous cytology results or 2 negative cytologies together with negative HPV test results within the last 10 years.

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Table 3. The Swedish national cervical screening program

Age group 23-29 30-49 50-64

Screening

recommendation

Pap smear every 3 years as a primary screening Primary screening with HPV testing every 3 years Primary screening with HPV testing every 5 years ( every 7 years in some regions in Sweden)

[31]. Ernstson A, Urdell A, Forslund O, Borgfeldt C. Cervical cancer prevention among long-term screening non-attendees by vaginal self-collected samples for hr-HPV mRNA detection, Infect Agent Cancer [internet] 2020[cited 2020 Dec 31]15(10): 1-10

The table shows differences in cervical screening program in Sweden comparing to other countries. HPV testing as the primary screening method is recommended in Sweden since 2015.

Women with a negative HPV test result don’t need require further testing.

Women with a positive HPV test result should be offered a follow-up examination in a form of cytological examination and Aptima HPV mRNS testing.

The table shows a different method of screening against cervical cancer that might be considered in different countries for more effective screening.

Figure 2. Further steps in case of positive HPV test result

Women with positive HPV test and negative cytology

Repeat co –test in 12 months or perform HPV genotype specific testing for HPV 16 alone or HPV 16 and 18.

In case of negative results-> repeat the test in 12 months

In case of positive results-> colposcopy should be performed

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18 1.Tsikouras P, Zervoudis S, Manav B, Tomara E, Iatrakis G, Romanidis C, et al. Cervical cancer: screening, diagnosis and staging, JBUON [internet]. 2016 [cited 2020 Dec 10];21(2):320-325.

In case of positive Pap smear results, the next step is colposcopy during which the biopsy might be taken.

The evaluate the extent of the disease the pelvic CT or MRI scan is taken.

9.2 Fertility-sparing options depending on FIGO classification

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19 [17].Speiser D, Kohler C, Schneider A, Mangler M. Radical Vaginal Trachelectomy: A Fertility-Preserving Procedure in Early Cervical Cancer in Young Women, Dtsch Arztebl Int[internet]2013[cited 2020 Dec 18] 110(17):289-295.

The standard treatment for women with early-stage CC (IA1-IB1) remains radical hysterectomy with pelvic lymphadenectomy, however, this type of treatment does not allow women to conceive in the future. The alternative is radical trachelectomy and pelvic lymphadenectomy. Regular CC screening is important, because only the disease in early-stage might be treated with fertility-sparing methods. Surgeries including cervical conisation and RVT are considered. Less radical surgeries are appropriate not only for patients with a strong desire to preserve fertility, but also for all patients with low-risk early stage CC.

Radical fertility-sparing surgical management

Radical Trachelectomy is a removal of the cervix with the medial parametrium and upper 2 cm vaginal cuff, retaining the uterus and adnexa to allow future conception. Before the surgery, MRI is performed to asses tumor dimensions and depth of invasion. The procedure can be performed vaginally or through the abdomen. Radical Vaginal Trachelectomy (RVT) can be considered if the CC is in stage IA or IB1, size of the tumor is less then 2 cm and no pelvic lymph node metastasis are found.

Vaginal route with laparoscopic pelvic lymphadenectomy is usually performed, and results in higher pregnancy rates and live birth rates comparing to abdominal approach, however, in case of cervical anatomy distortion or regions with less-advanced laparoscopic skills, the abdominal approach is preferred for radical trachelectomy. The complications that are common after the procedure are irregular bleeding, dysmenorrheal, isthmic stenosis, and amenorrhea.

The oncological outcomes after radical trachelectomy are good, with the risk of recurrence <3.5%, which is comparable to radical hysterectomy.

Radical trachelectomy procedure starts with pelvic lymph node dissection, and if there are no metastatic tumors, the radical trachelectomy can be continued. During the procedure, the

parametria are resected at the level of radical hysterectomy type B. The cervix is transsected 1 cm above the margin of the tumor, while preserving at least 1 cm of cervical stroma caudally from the internal cervical os.

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20 For tumors more then 2cm, neoadjuvant chemotherapy might be offered before radical

trachelectomy, however it carries the risk of gonadal toxicity and ovarian failure.

Fig.4. Radical trachelectomy specimen showing cervix with tumor, vaginal cuff and parametrium.

[9].Rema P. Conservative Surgery for Early Cervical Cancer, Indian J Surg Oncol[internet].2016[cited 2020 Dec 15]7(3):336-340.

Non-radical surgical management

Cervical conisation is a FSS option for CC stage IA1. During the procedure, a cone-shaped portion of the cervix is removed with the base on the ecto cervix and apex 1 cm from the internal os in the endocervical canal.

The procedure might be either done by using scalpel, LASER or electrosurgical loops. The most popular method is electrosurgical excision called Loop Electro surgical Excision Procedure (LEEP).

Cold knife conisation requires general anesthesia. Local anesthesia might be used during LASER and LEEP conisation.

Loop electrodes are used during LEEP conisation, they are activated by electric current from an electrosurgical generator.

Electro surgical unit, colposcope and smoke evacuator are necessary equipment used in LEEP procedure.

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Fig 5. Colposcopic view of cervix with microinvasive cancer

Fig 6. LEEP electrodes- Loop electrodes for cutting, ball and needle electrodes for coagulation

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Fig 7.LEEP excision specimen

9.3 Obstetrical outcomes after fertility-sparing treatment of early-stage cervical cancer

Fig.8 Complications after Cervical Conisation

Cervical Conisation

Short-term complications

Long-term complications

Bleeding, vaginal burns, infections Cervical stenosis, deficient cervical mucous, cervical incompetence, premature rupture of membranes

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23 Minimally invasive surgeries led to reduced length of hospital stay, less blood loss, lower

analgesics requirements during the post operative period, a decreased rate of complications, and an early recovery of physiological functions.

Conisation procedure has higher recovery rate and results are comparable with hysterectomy, however there are some complications that might occure after this procedure. There are classified ad short –term and long-term complications.

Short-term complications include bleeding, vaginal burns and infection.

Cervical stenosis, deficient cervical mucous, cervical incompetence and premature rupture of membranes that might lead to pre-term labor are classified as long-term complications. Cervical conisation is an effective method in treating early-stage CC, however carries risk of complications like cervical stenosis and increased risk of obstetric complications.

Radical trachelectomy efficacy is hight and is compared to radical hysterectomy, however complications like cervical stenosis and cervical shortening, premature rupture of membranes might lead to increase rate if pre term deliveries.

Table 4. Obstetric outcomes after radical vaginal trachelectomy

Author [ref]

Cases Pregnancies Live births <32 weeks Term Milliken&

Shepherd[17]

790 320 24% 9% -

Plante [19] 256 256 40% 12% 65%

[20]. Gizzo S, Ancona E, Saccardi C, Patrelli T, Berretta R, Anis O,et al. Radical trachelectomy: The first step of fertility preservation in young women with cervical cancer( Review), Oncology Reports[internet]2013[cited 2020 Dec 20] 30(6): 2545-2554.

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Table 5. Obstetrical outcomes after radical vaginal trachelectomy

Author [ref] No. of patients FIGO stage (No) No. of pregnancies

Live births No. of delivery<32 weeks

Type and no. of pregnancy complications Shepherd and Milliken (9) 158 IB1(152) IIA(2) IA2(3) 88 44 10 PROM and chorioamnionitis-25. Stillbirths-1 Miscarriages-31 Ectopic pregnancy-1 Dargent et al (32) 47 IA1(5) IA2(13) IB(25) IA2(1) IIB(3) 25 13 0 Miscarriages-11 Sonoda et al.(35) 36 IA1(8) IA2(7) IB1(28) 11 11 Miscarriages-1 Cervical shortening-1 Plante et al.(28) 72 IA1(4) IA2(23) IB1(43) IIA(2) 50 36 3 Miscarriages-10 Therapeutic abortions-2 p-PROM-1 Diaz st al(31) 118 IB1(40) 9 4 0 Miscarriages-1 PROM-1 Burnett et al( 10)

21 IA2-IIA 3 2 1 PROM and

chorioamnionitis- 1,p-PROM-1,Fetal death-1 Bernardini et al (27) 80 IA(not reported) IB(not reported) 22 18 3 p-PROM-4 PROM-2 HELLP-1 Placenta previa-1

[20]. Gizzo S, Ancona E, Saccardi C, Patrelli T, Berretta R, Anis O,et al. Radical trachelectomy: The first step of fertility preservation in young women with cervical cancer( Review), Oncology Reports[internet]2013[cited 2020 Dec 20] 30(6): 2545-2554.

Table 6. Additional note to table nr 4

Author[ref.] Note

Sonoda et al (35) In vitro fertilization(IVF)-3

Intrauterine Insemination (IUI)-1 Voluntary interruptions-2

Bernardini et al (27) IVF-3

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25 Pregnancies after FSS are possible, majority of women will conceive spontaneously, some may require the help of Assisted Reproductive Technologies (ART), like IVF and IUI.

The results from different authors and their publications shows that the obstetrical complications after FSS, irrespectively from FIGO stage are common and the main concern is preterm labor and delivery. PROM is another common complication and increases the risk of chorioamnionitis. Cervical

Conisation aswell as Radical Trachelectomy might both be a reason for cervical stenosis, deficient cervical mucous, cervical incompetence and PROM. Miscarriages are more commonly observed after Radical Trachelectomy.

Routine genital tract infection screening, prophylactic antibiotics, bed rest and routine steroid administration might be offered during the pregnancies after FSS.

10.Conclusion

• Regular cervical cancer screening testing starting at age 21 may lead to early detection if the disease and as a result non-invasive methods of treatments might be applied,

• Cervical Conisation and Radical Vaginal Trachelectomy are the main treatment options in case of low risk, early stage cervical cancer for women with a strong desire for future pregnancy,

• The main concern with pregnancies following fertility sparing surgeries is the increase rate of premature labor and delivery, as well as miscarriages, caused by cervical incompetence, and ascending infections with premature rupture of membranes.

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26

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