Prevention of Cervical Cancer. Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) – Part 2 on Triage, Treatment and Follow-up

Abstract

Aims Annual opportunistic screening for cervical carcinoma has been done in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as this guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany.

Methods With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline.

Recommendations The second part of this short summary deals with the triage, treatment and follow-up care of cervical dysplasia. With regard to those women who do not participate in screening, the guideline authors recommend sending out repeat invitation letters or an HPV self-collection kit. Colposcopy should be carried out for further investigation if cytology findings are Pap II-p and HPV test results are positive or if the results of an HPV 16 or HPV 18 screening test are positive. A single abnormal Pap smear should be triaged and investigated using HPV testing or p16/Ki67 dual staining.

Key words

cervical cancer - cervical intraepithelial neoplasia (CIN) - cervical precancerous condition - HPV

I  Guideline Information

The Oncology Guidelines Program of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V., AWMF), the German Cancer Society (Deutsche Krebsgesellschaft e. V., DKG) and German Cancer Aid (Deutsche Krebshilfe, DKH).

Guidelines Program of the DGGG, the OEGGG and the SGGG.

For more information on the Guidelines Program, please refer to the end of this article.

Citation format

Prevention of Cervical Cancer – Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) – Part 2 on Triage, Treatment and Follow-up. Geburtsh Frauenheilk 2019; 79: 160–176

Guideline documents

The complete long version with a list of the conflicts of interest of all authors and a short version are available in German on the homepage of the AWMF under: https://www.awmf.org/leitlinien/detail/ll/015-027OL.html or www.leitlinienprogramm-onkologie.de

Guideline authors

The German Society of Gynecology and Obstetrics (DGGG, mandate holder: Prof. Dr. Peter Hillemanns, Hanover) was the lead medical society responsible for the compilation of this guideline. The guideline is issued by the Oncological Guidelines Program. Every participating medical society nominated a mandate holder, with the board of the respective society confirming the mandate in writing. [Table 1] lists the medical societies and other organizations which participated in developing the guideline together with their respective mandated representatives. Only mandate holders nominated by participating societies and organizations were eligible to take part in the voting process (consensus process) after they had disclosed and excluded any conflicts of interest. A patient representative was directly involved in the compilation of this guideline. Ms. Marion Gebhardt (Frauenselbsthilfe nach Krebs e. V. [Self-help for Women after Cancer]) was involved in developing the guideline right from the start, attended the consensus conferences and had the right to vote in the consensus conferences.

Table 1 Participating professional societies and other organizations.

Participating professional societies and other organizations	Mandate holder
*  AG-CPC, AZÄD, BVF and DGZ stepped down from participating in the compilation of the guideline on 12 May 2014. After a number of constructive discussions by the ad-hoc committee, BVF re-joined the guideline authors on 4 September 2017. **  These international medical societies participated in the consensus process but had no voting rights. ***  Although the ESGO nominated a mandate holder and a deputy, they did not participate in the compilation of this guideline.
German Society of Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie und Geburtshilfe], (DGGG)	Christian Dannecker
German Society for Epidemiology [Deutsche Gesellschaft für Epidemiologie], (DGEpi)	Stefanie Klug
German Society for Virology [Deutsche Gesellschaft für Virologie e. V.], (GfV)	Thomas Iftner
German Society of Pathology [Deutsche Gesellschaft für Pathologie e. V.], (DGP)	Thomas Löning Lars Horn (Deputy) Dietmar Schmidt (Deputy)
German STI Society [Deutsche STI-Gesellschaft e. V.], (DSTIG)	Hans Ikenberg
German Society for Cytology [Deutsche Gesellschaft für Zytologie], (DGZ)*	Heinrich Neumann (till 14.08.2013) Volker Schneider (till 12.05.2014)
German Society for Medical Informatics, Biometry and Epidemiology [Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e. V.], (GMDS)	Uwe Siebert Willi Sauerbrei (Deputy)
Gynecological Oncology Working Group of the DKG [Arbeitsgemeinschaft für gynäkologische Onkologie der DKG], (AGO)	Matthias Beckmann
Self-help for Women after Cancer [Frauenselbsthilfe nach Krebs e. V.]	Marion Gebhardt Heidemarie Haase (Deputy)
Professional Association of Gynecologists [Berufsverband der Frauenärzte e. V.], (BVF)*	Manfred Steiner Ulrich Freitag (Deputy)
Federal Association of Senior Physicians in Gynecology and Obstetrics [Arbeitsgemeinschaft Leitender Ärztinnen und Ärzte in der Frauenheilkunde und Geburtshilfe e. V.], (BLFG)	Michael Friedrich
Professional Association of German Physicians Working in Cytology [Berufsverband zytologisch tätiger Ärzte in Deutschland e. V.], (AZÄD)*	Klaus Neis Bodo Jordan (Deputy)
Cervical Pathology and Colposcopy Working Group of the DGGG [Arbeitsgemeinschaft Zervixpathologie und Kolposkopie der DGGG]*	Wolfgang Kühn Michael Menton (Deputy)
Prevention and Integrative Oncology Working Group of the DKG, Section B [Arbeitsgemeinschaft Prävention und integrative Onkologie (PRIO), DKG Sektion B]	Karsten Münstedt
HPV Management Forum of the Paul Ehrlich Society for Chemotherapy [HPV-Management-Forum (Paul-Ehrlich-Gesellschaft für Chemotherapie PEG e. V.)]	Achim Schneider Andreas Kaufmann (Deputy)
Colposcopy Study Group [Studiengruppe Kolposkopie e. V.]	K. Ulrich Petry
Working Group on Infections and Immunology of the DGGG [Arbeitsgemeinschaft für Infektionen und Infektionsimmunologie der DGGG], (AGII)	Axel P. A. Schäfer
German Cancer Research Center, (DKFZ)	Magnus von Knebel-Doeberitz (till 25.06.2013) Michael Pawlita
International organizations
Gynecological Oncology and Breast Health Working Group of the SGGG [Arbeitsgemeinschaft für gynäkologische Onkologie und Brustgesundheit (AGO) der SGGG]**	Mathias Fehr
Gynecological Oncology Working Group of the OEGGG [Arbeitsgemeinschaft für gynäkologische Onkologie (AGO) der OEGGG]**	Christoph Grimm Olaf Reich (Deputy)
European Society of Gynaecological Oncology, (ESGO)***	Rainer Kimmig Martin Heubner (Deputy)

II  Guideline Application

Purpose and objectives

The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer. The S3 guideline provides important information and support for the planned organized screening for cervical cancer in Germany.

The old German-language S2k guideline “Prevention, Diagnosis and Therapy of HPV Infections and Preinvasive Lesions of the Female Genitalia” was consulted, and the new guideline focused on those aspects which deal with the cervix. Guideline recommendations on primary prevention were taken from the updated German-language S3 guideline “082/002 Vaccination to Prevent HPV-associated Neoplasias” and supplemented with additional information about the impact of HPV vaccination on screening. The German-language S3 guideline “032/033OL Cervical Cancer: Diagnosis, Treatment and Follow-up” published in 2014 covers all aspects of invasive cervical cancer.

Targeted areas of patient care

This S3 guideline on the prevention of cervical cancer presents various aspects of the prevention of cervical cancer and the diagnosis, treatment and follow-up of cervical cancer including high-grade preinvasive lesions. The main priorities of the guideline were analyzing existing data in order to optimize screening strategies for cervical cancer by determining the optimal test procedures, organizations, investigative algorithms and treatments, and considering how best to encourage women who previously refused to attend screening to participate in the program. In addition, the guideline considered the impact of HPV vaccination on screening strategies for cervical cancer.

Target patient group

This S3 guideline is aimed at all women aged 20 and above.

Target user groups/target audience

The recommendations of the guideline are addressed to all physicians and professionals involved in screening for cervical cancer, particularly gynecologists, pathologists and cytologists as well as all healthcare professionals working in dysplasia outpatient clinics and centers.

Other target groups include:

• scientific medical societies and professional associations which are involved in screening for cervical cancer,

• womenʼs advocacy groups (womenʼs health organizations, patient and self-help organizations),

• quality assurance organizations and similar projects on national and federal state levels,

• healthcare policy institutions and decision-makers at national and federal state levels,

• payers,

• the general public to inform them about what constitutes good medical practice.

Adoption and period of validity

This guideline is valid from 31 December 2017 through to 31 December 2020. Because of the contents of the guideline, this period of validity is only an estimate. The guideline may need to be updated if new scientific evidence appears or the methodology used in the guideline is developed further. Moreover, the key statements and recommendations of the guideline should be subjected to regular editorial checks, and the contents of the guideline should be regularly reviewed.

III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2) and highest (S3) class. The lowest class is defined as a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches. This guideline is classified as: S3.

Grading of evidence

The GRADE (GRADE = Grading of Recommendations Assessment, Development and Evaluation) system developed by the GRADE Working Group [1] (www.gradeworkinggroup.org) was used to evaluate the quality of evidence of the studies identified and used for this guideline ([Table 2]).

Table 2 Grading of the quality of evidence based on the GRADE system.

GRADE	Beschreibung	Symbol
High quality	“We are very confident that the true effect lies close to that of the estimate of the effect.”	⊕⊕⊕⊕
Moderate quality	“We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.”	⊕⊕⊕⊖
Low quality	“Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.”	⊕⊕⊖⊖
Very low quality	“We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.”	⊕⊖⊖⊖

Grading of recommendations

The methodology of the Oncology Guidelines Program requires guideline authors to assign a level of recommendation to each recommendation which indicates the strength of the recommendation. The strength of each recommendation is agreed upon in a formal consensus process which requires structured consensus conferences [2]. (Details are available in the German-language Guideline Report.) As part of this process, the mandate holders with voting rights formally voted on the recommendations in this guideline.

This guideline includes information on the grading of the evidence of the underlying studies used for all evidence-based Statements and Recommendations and additionally shows the strength of each recommendation (level of recommendation). In accordance with the AWMF Guidance Manual [2], this guideline differentiates between three strengths or levels of recommendation, and the respective level of recommendation is reflected by the syntax used in the recommendation ([Table 3]).

Table 3 Level of recommendation.

Level of recommendation	Description	Syntax
A	Strong recommendation	must
B	Recommendation	should
0	Open recommendation	may

The decision criteria used to determine the level of recommendation are explained in the German-language Guideline Report for this guideline.

Statements

Statements are expositions or explanations of specific facts, circumstances, or problems, with no direct recommendations for action. Statements are adopted after a formal consensus process using the same approach as that used when formulating recommendations and can be based either on study results or expert opinions ([Table 4]).

Table 4 Level of consensus.

Level of consensus	Extent of agreement in percent
Strong consensus	> 95% of participants entitled to vote agree
Consensus	> 75 – 95% of participants entitled to vote agree
Majority agreement	> 50 – 75% of participants entitled to vote agree
No consensus	< 50% of participants entitled to vote agree

Expert consensus (EC)

Statements/Recommendations which were issued based on the expert consensus of the guideline authors are identified as being based on expert consensus. No symbols or letters are used to grade the level of expert consensus; the respective level of consensus is demonstrated by the syntax used (must/should/may) in accordance with the differentiation described in [Table 3].

IV  Guideline

1  Differential diagnosis and evaluation algorithm

No.	Recommendations/Statements	GRADE	Sources
10.1.	If a cytological finding is classified as group IIa, the treating gynecologist should be informed that abnormal findings were detected previously (in the last 2 years) and that the patient should continue to be monitored. Additional work-ups to obtain a differential diagnosis are only indicated if they are necessary in the current constellation to avoid overtreatment.	EC

1.1  Indication for coloscopy depends on probability of CIN 3

No.	Recommendations/Statements	GRADE	Sources
10.2.	A colposcopic work-up should be done if the post-test probability for an average cumulative risk of CIN 3+ is 10% or more.	EC

1.2  What is the best diagnostic work-up strategy to investigate abnormal cytology

1.2.1  Atypical squamous or glandular cells (Pap II-p, II-g)

No.	Recommendations/Statements	GRADE	Sources
10.3.	If the findings obtained during organized cytological screening are classified as group II-p ~ ASC-US and II-g ~ AGUS, HR-HPV testing should be done after 6 months. If the HR-HPV test is positive, a colposcopic work-up should be done within 3 months. If the HPV test is negative, the patient should be followed up by HPV testing and cytology after 12 months.	⊕⊕⊕⊖ B	[3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]
10.4.	If the findings obtained during organized cytological screening are classified as group II-p ~ ASC-US and II-g ~ AGUS, p16/Ki-67 testing may be carried out after 6 months. If the results of dual staining with p16/Ki-67 are positive, a colposcopic work-up should be performed within 3 months. If the results of dual staining with p16/Ki-67 are negative, the patient should be followed up with HPV testing and cytology after 12 months.	⊕⊖⊖⊖ 0	[43], [54], [55], [56]

1.2.2  Cytological suspicion of low-grade dysplasia (Pap IIID1)

No.	Recommendations/Statements	GRADE	Sources
10.5.	If the findings obtained during organized cytological screening are classified as group IIID1~ LSIL, a diagnostic work-up based on HR-HPV testing should be carried out after 6 months. If the HR-HPV test is positive, a colposcopic work-up should be done within 3 months. If the HPV test is negative, the patient should be followed up with HPV testing and cytology after 12 months.	⊕⊕⊕⊖ B	[4], [5], [8], [10], [13], [17], [23], [26], [27], [28], [29], [31], [32], [35], [39], [41], [42], [43], [45], [46], [47], [48], [49], [51], [52], [53], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68]
10.6.	If the findings obtained during organized cytological screening are classified as group IIID1~ LSIL, a diagnostic work-up based on p16/Ki-67 testing should be done after 6 months. If the results of this dual staining with p16/Ki-67 are positive, the patient should be investigated further by colposcopy within 3 months. If the results of dual staining with p16/Ki-67 are negative, the patient should be followed up with HPV testing and cytology after 12 months.	⊕⊖⊖⊖ 0	[43], [55], [56], [68], [69]

1.2.3  Unclear cytological findings classified as Pap III-p, III-g, III-x

No.	Recommendations/Statements	GRADE	Sources
10.7.	a) If the findings obtained during organized cytological screening are classified as group III-p, III-x, III-e or III-g, a diagnostic work-up based on either HR-HPV testing or p16/Ki-67 immunocytochemistry may be carried out within 3 months. If the HR-HPV test or the results of dual staining with p16/Ki-67 are positive, a colposcopic work-up should be done within 3 months. If the diagnostic tests are negative, the patient should be followed up with HPV testing and cytology after 12 months. b) If the findings obtained during organized cytological screening are classified as group III-x, III-e and III-g, an endometrium-specific work-up should be done to exclude endometrial neoplasia (vaginal ultrasound, hysteroscopy, fractionated curettage, etc.).	EC

1.2.4  Moderate and high-grade cytological abnormalities (Pap IIID2, Pap IVa, Pap IVb, Pap V)

No.	Recommendations/Statements	GRADE	Sources
10.8.	If the findings obtained during organized cytological screening are classified as group IIID2, IV a – p, IV a – g, IV b – p, IV b – g, V-p, V-g, V-e or V-x, diagnostic colposcopy must be carried out.	EC

1.3  What are the best diagnostic work-up strategies for patients with a positive HPV test at screening and aged > 30 years?

No.	Recommendations/Statements	GRADE	Sources
10.9.	If the results of an HPV test done as part of routine screening are positive, a diagnostic work-up using cytology should be carried out.	⊕⊕⊖⊖ B	[70], [71], [72], [73], [74], [75], [76], [77], [78], [79]
10.10.	If the results of an HPV test done as part of routine screening are positive, a diagnostic work-up using p16/Ki-67 testing may be carried out.	⊕⊖⊖⊖ 0	[72], [73]
10.11.	If the results of an HPV-16/18 test carried out as part of HPV-based screening are positive, a diagnostic work-up using colposcopy should be carried out.	⊕⊖⊖⊖ B	[77], [79]
10.12.	If the results of a routine screening HPV test are positive and the results of diagnostic cytology or the results of combined HPV and Pap screening are classified as group II-p or above, a diagnostic work-up using colposcopy should be carried out.	EC

2  Colposcopy

2.1  Use of diagnostic colposcopy

No.	Recommendations/Statements	GRADE	Sources
*  Post-test probability
11.1.	Colposcopy must not be used for screening.	EC
11.2.	If there is a high suspicion of CIN 3+ or ACIS/adenocarcinoma (risk ≥ 10%*), diagnostic colposcopy must be carried out to histologically confirm squamous and glandular atypia/neoplasia, to determine the surgical strategy.	EC
11.3.	If the transformation zone is classified as Type 1 or Type 2 at diagnostic colposcopy, colposcopy-guided biopsies should be obtained from the highest-grade lesion(s); if the transformation zone is classified as Type 3, endocervical curettage should be carried out.	EC

2.2  Quality criteria for diagnostic colposcopy or dysplasia clinics

No.	Recommendations/Statements	GRADE	Sources
11.4.	Diagnostic colposcopy procedures must be carried out by a dysplasia clinic or dysplasia unit certified in accordance with the requirements of the DKG/DGGG/AGO/AG-CPC/EFC.	EC

3  Healthcare structures

No.	Recommendations/Statements	GRADE	Sources
12.1.	Around 50% of women in Germany participate annually in cancer screening (Krebsfrüherkennungsuntersuchung, KFU) which has been recommended in Germany since 1971 and screens participants for cervical cancer. Around 70% of women participate in screening at least once every 3 years.	EC
12.2.	In Germany, rates of participation in cervical cancer screening (KFU) are lower for women with a low socio-economic status and/or for women of advanced age.	EC
12.3.	Organized screening with population-based invitations to attend screening and more stringent quality controls may result in more effective and more balanced screening in terms of the socio-economic status and the age of participants.	EC

4  Strategy for non-participation in screening

4.1  Letters of invitation

No.	Recommendations/Statements	GRADE	Sources
13.1.	The repeated sending of letters of invitation to attend screening as part of an organized screening program results in an only marginal increase in participation rates among those women who have not previously participated in regular screening.	⊕⊕⊖⊖	[80], [81], [82], [83], [84]

4.2  HPV self-collection

No.	Recommendations/Statements	GRADE	Sources
13.2.	The participation rates of women who did not participate in cancer screening despite receiving a letter of invitation can be doubled with HPV self-collection.	⊕⊕⊕⊖ B	[85], [86], [87], [88], [89], [90], [91], [92], [93], [94]
13.3.	Self-sampling should therefore be offered to these women (nonresponders).	⊕⊕⊕⊖ B	[85], [86], [87], [88], [89], [90], [91], [92], [93], [94]
13.4.	HPV self-collection for screening must be reserved for those women who do not otherwise participate in cancer screening.	⊕⊕⊕⊖ A	[89], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127]

5  Treatment

5.1  Appropriate treatment methods for squamous and glandular cervical intraepithelial neoplasia

No.	Recommendations/Statements	GRADE	Sources
14.1.	Loop excision and laser excision are the methods of choice to treat squamous and glandular cervical intraepithelial neoplasia.	⊕⊖⊖⊖ A	[128], [129], [130]
14.2.	Cold-knife conization may be used as an alternative to treat glandular intraepithelial neoplasia.	⊕⊖⊖⊖ 0	[128]
14.3.	After histological confirmation using punch biopsy, laser vaporization must only be used to treat CIN 1, CIN 2 or CIN 3 if all of the following conditions are met: the whole transformation zone can be visualized (T-Zone Type 1), there are no indications of any changes in the glandular epithelium, there are no indications of any invasive process, there are no discrepancies between cytological, colposcopic and histological assessments of the biology of any changes, the patient is not older than 50 years.	EC

5.2  Treatment under colposcopic control

No.	Recommendations/Statements	GRADE	Sources
14.4.	Treatment, whether it consists of excision or ablative procedures, must be carried out under colposcopic control.	EC

5.3  Management of CIN

5.3.1  Monitoring, testing or treatment for CIN 1

No.	Recommendations/Statements	GRADE	Sources
*  Colposcopy with a positive predictive value for CIN 2 or CIN 3 of at least 65% is recommended if the patient is managed with expectant monitoring or undergoes purely ablative treatment [130].
14.5.	If CIN 1 is confirmed histologically, the initial approach must be to wait and see and re-evaluate the patient after 6 months*.	EC
14.6.	If CIN 1 is accompanied by Pap smear results classified as group IVa or higher and the lesion cannot be adequately evaluated and extends into the endocervix, the endocervical canal must be evaluated by histopathology.	EC

5.3.2  Monitoring or treatment for CIN 2

No.	Recommendations/Statements	GRADE	Sources
*  Colposcopy with a positive predictive value for CIN 2 or CIN 3 of at least 65% is recommended if the patient is managed with expectant monitoring or undergoes purely ablative treatment [130].
14.7.	If a histologically confirmed CIN 2 lesion can be evaluated in its entirety and the transitional area between squamous and columnar epithelium can be entirely visualized, the initial approach is to wait and see and re-examine the patient after 6 months*.	EC
14.8.	If the transitional area between squamous and columnar epithelium cannot be entirely visualized in a patient with a histologically confirmed CIN 2 lesion and/or at least one Pap smear was classified as IVa, the endocervical canal must be evaluated by histopathology.	EC

5.3.3  Treatment for CIN 3

No.	Recommendations/Statements	GRADE	Sources
14.9.	A lesion confirmed histopathologically as CIN 3 must be resected.	EC

5.3.4  Treatment recommendations for adolescents

No.	Recommendations/Statements	GRADE	Sources
*  Colposcopy with a positive predictive value for CIN 2 or CIN 3 of at least 65% is recommended if the patient is managed with expectant monitoring or undergoes purely ablative treatment [130].
14.10.	A conservative strategy must be used for women up to the age of 24 with histopathologically confirmed CIN 2 and can be used for women up to the age of 24 with histopathologically confirmed CIN 3, provided the lesion can be evaluated colposcopically in its entirety, and it does not contain any atypical glandular components, and an invasive process can be excluded with a high degree of certainty. Treatment should be carried out if the CIN 2 persists for more than 24 months or the CIN 3 persists for more than 12 months or the lesion expands into the endocervix. Treatment must be tissue-sparing.*	EC
14.11.	Women up to the age of 24 with CIN 3 who are managed conservatively should be monitored by a certified dysplasia clinic (s. Chapter 2 Colposcopy).	EC

5.3.5  Excision procedures vs. hysterectomy for cervical adenocarcinoma in situ (ACIS)

No.	Recommendations/Statements	GRADE	Sources
14.12.	The definitive histopathological diagnosis of ACIS (with the differential diagnosis excluding invasive adenocarcinoma) must be obtained by excision. Hysterectomy should be the definitive treatment for ACIS if the patient plans to have no more children. If the patient wishes to have children, R0 resection must be carried out and the patient must be followed up using colposcopy, cytology and HPV testing.	EC

5.3.6  R0 resection and approach for R1 resection

No.	Recommendations/Statements	GRADE	Sources
14.13.	The goal must be to achieve R0 resection of a CIN 3.	EC
14.14.	If the resection status after surgical excision of a CIN 3 is R1 and there is no suspicion of invasive cancer, the patient must attend a follow-up appointment after 6 months with cytology and HPV testing. If the findings at follow-up show that CIN 3 has persisted, the patient must be re-operated.	EC

6  Pregnancy

No.	Recommendations/Statements	GRADE	Sources
15.1.	The indications for colposcopy (and biopsy, if required) during pregnancy are the same as those for non-pregnant women.	EC
15.2.	During pregnancy, the investigation of abnormal cervical cancer screening results should be done by a DKG/AG-CPC-certified dysplasia clinic.	EC
15.3.	Endocervical curettage must not be performed during pregnancy. An endocervical smear extending deep into the endocervical canal should not be done during pregnancy.	EC
15.4.	If the results of the investigation (obtained by cytology, colposcopy and histologically if necessary) exclude high-grade dysplasia and carcinoma, no further colposcopy and/or cytological investigations are required during pregnancy.	EC

6.1  Approach for CIN 2/CIN 3 and ACIS in pregnancy

No.	Recommendations/Statements	GRADE	Sources
15.5.	Pregnant women with CIN 2/CIN 3 or ACIS must not be treated surgically if invasive cancer can be excluded with a high degree of certainty.	EC
15.6.	Pregnant women with CIN 2/CIN 3 or ACIS must be monitored regularly by colposcopy. The pregnant patient must be evaluated by colposcopy every three months.	EC
15.7.	Excision to obtain histological confirmation is indicated in pregnant women if it is not possible to exclude invasive carcinoma by cytology, colposcopy and biopsy with any high degree of certainty.	EC

6.2  Birth procedure when CIN 2/3 is present

No.	Recommendations/Statements	GRADE	Sources
15.8.	The presence of CIN 2/CIN 3 must have no impact on the decision about the birth procedure.	EC

6.3  Obstetric complications after treatment for CIN

No.	Recommendations/Statements	GRADE	Sources
15.9.	Excision procedures performed during pregnancy are associated with significant obstetric risks such as preterm birth. Previous excision procedures are also associated with higher risk in subsequent pregnancies.	EC
15.10.	As cold-knife conization is associated with the highest obstetric risk, it must not be carried out in women who still wish to have children.	EC

7  Follow-up care

7.1  Follow-up with HPV testing and cytology after treatment for CIN

No.	Recommendations/Statements	GRADE	Sources
16.1.	Follow-up after treatment for CIN/ACIS must consist of examinations combining HPV testing and cytology.	⊕⊕⊖⊖ A	[131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146]
16.2.	Differential colposcopy should be performed if the findings at follow-up are abnormal (at least 1 of the test results is positive).	⊕⊕⊖⊖ B	[131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146]

7.1.1  Time and duration of follow-up

No.	Recommendations/Statements	GRADE	Sources
16.3.	Follow-up examinations combining HPV testing and cytology should be performed at 6, 12 and 24 months after completing treatment. The patient must continue to participate in regular screening, even if the findings at follow-up are unremarkable.	EC

7.2  Importance of biomarkers during follow-up after treatment for CIN

7.2.1  Resection margin as a predictor for recurrence of treated CIN

No.	Recommendations/Statements	GRADE	Sources
16.4.	Follow-up after treatment for CIN/ACIS must consist of examinations combining HPV testing and cytology.	⊕⊖⊖⊖	[134], [135], [136], [147], [148], [149], [150], [151], [152]

7.2.2  Other biomarkers as predictors for recurrence of treated CIN 2/3 lesion

No.	Recommendations/Statements	GRADE	Sources
16.5.	Biomarkers (5-type HPV mRNA, HPV type-specific persistence) must not be used to follow up patients treated for CIN 2/3 lesions.	⊕⊖⊖⊖ A	[134], [137], [151], [153], [154], [155], [156], [157]

8  Complementary, alternative and integrative medicine

8.1  Alternative medical diagnostic methods

No.	Recommendations/Statements	GRADE	Sources
17.1.	Alternative medical diagnostic methods must not be used to detect cervical dysplasia or establish a predisposition for cervical dysplasia.	EC

8.2  Alternative medical treatment

No.	Recommendations/Statements	GRADE	Sources
17.2.	Alternative medical treatments of dysplasia should be rejected.	EC

8.3  Complementary medical treatment

No.	Recommendations/Statements	GRADE	Sources
17.3.	It is not possible to make any recommendations about complementary medical treatments because of the lack of meaningful studies.	EC

9  Patient education and information, dealing with psychological stress

9.1  Patient education and information given to women participating in cervical cancer screening

No.	Recommendations/Statements	GRADE	Sources
18.1.	Information given to the women who participate in screening for cervical cancer must cover the following aspects: an explanation of the disease, the natural progression of infection with HPV and associated cell changes, the different HPV types, the risk factors for cervical cancer, the impact on the patientʼs partner(s), a description of the screening method, information about the benefits and harm of screening methods, information on the quality of the screening methods.	EC

9.2  Educating patients about their diagnosis, treatment options and follow-up care

No.	Recommendations/Statements	GRADE	Sources
18.2.	The information given to women with findings at screening which require further investigation must include the following: the findings the differential diagnosis the treatment options the treatment goals the duration of the different treatments and how they are carried out the necessity of regular follow-up appointments	EC

10  Cost-effectiveness

No.	Recommendations/Statements	GRADE	Sources
19.1.	HPV-based screening performed every 3 years has a relatively favorable cost-effectiveness ratio. Compared to annual cytology-based screening, HPV-based screening has a similar expected benefit and a lower expected harm (e.g. surgical interventions, colposcopies, psychological stress caused by abnormal findings and follow-up examinations).	⊕⊖⊖⊖	[cf. Guideline Report and Evidence Report]
19.2.	In Germany, HPV-based screening carried out at intervals of every 3 – 5 years is considered to be cost-effective. HPV-based screening carried out at intervals of every 2 years has a less favorable cost-effectiveness ratio. Annual screening significantly increases costs without generating a significant additional benefit.	⊕⊖⊖⊖	[158]

• References/Literatur

• 1 Balshem H, Helfand M, Schunemann HJ. et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64: 401-406
• 2 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) – Ständige Kommission Leitlinien. AWMF-Regelwerk „Leitlinien“. 2012. Online: http://www.awmf.org/leitlinien/awmf-regelwerk.html last access: 10.11.2015
• 3 Manos MM, Kinney WK, Hurley LB. et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 1999; 281: 1605-1610
• 4 Bergeron C, Jeannel D, Poveda J. et al. Human papillomavirus testing in women with mild cytologic atypia. Obstet Gynecol 2000; 95 (6 Pt 1): 821-827
• 5 Lytwyn A, Sellors JW, Mahony JB. et al. Comparison of human papillomavirus DNA testing and repeat Papanicolaou test in women with low-grade cervical cytologic abnormalities: a randomized trial. HPV Effectiveness in Lowgrade Paps (HELP) Study No. 1 Group. CMAJ 2000; 163: 701-707
• 6 Shlay JC, Dunn T, Byers T. et al. Prediction of cervical intraepithelial neoplasia grade 2-3 using risk assessment and human papillomavirus testing in women with atypia on papanicolaou smears. Obstet Gynecol 2000; 96: 410-416
• 7 Morin C, Bairati I, Bouchard C. et al. Managing atypical squamous cells of undetermined significance in Papanicolaou smears. J Reprod Med 2001; 46: 799-805
• 8 Rebello G, Hallam N, Smart G. et al. Human papillomavirus testing and the management of women with mildly abnormal cervical smears: an observational study. BMJ 2001; 322: 893-894
• 9 Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: Baseline results from a randomized trial. J Natl Cancer Inst 2001; 93: 293-299
• 10 Kulasingam SL, Hughes JP, Kiviat NB. et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA 2002; 288: 1749-1757
• 11 Pretorius RG, Belinson JL, Burchette RJ. et al. Regardless of skill, performing more biopsies increases the sensitivity of colposcopy. J Low Genit Tract Dis 2011; 15: 180-188
• 12 Cuzick J, Szarewski A, Cubie H. et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 2003; 362: 1871-1876
• 13 Guyot A, Karim S, Kyi MS. et al. Evaluation of adjunctive HPV testing by Hybrid Capture II in women with minor cytological abnormalities for the diagnosis of CIN2/3 and cost comparison with colposcopy. BMC Infect Dis 2003; 3: 23
• 14 Lonky NM, Felix JC, Naidu YM. et al. Triage of atypical squamous cells of undetermined significance with hybrid capture II: colposcopy and histologic human papillomavirus correlation. Obstet Gynecol 2003; 101: 481-489
• 15 Ordi J, Puig-Tintore LM, Torne A. et al. [Contribution of high risk human papillomavirus testing to the management of premalignant and malignant lesions of the uterine cervix]. Med Clin (Barc) 2003; 121: 441-445
• 16 Wensveen C, Kagie M, Veldhuizen R. et al. Detection of cervical intraepithelial neoplasia in women with atypical squamous or glandular cells of undetermined significance cytology: a prospective study. Acta Obstet Gynecol Scand 2003; 82: 883-889
• 17 Andersson S, Dillner L, Elfgren K. et al. A comparison of the human papillomavirus test and Papanicolaou smear as a second screening method for women with minor cytological abnormalities. Acta Obstet Gynecol Scand 2005; 84: 996-1000
• 18 Dalla Palma P, Pojer A, Girlando S. HPV triage of women with atypical squamous cells of undetermined significance: a 3-year experience in an Italian organized programme. Cytopathology 2005; 16: 22-26
• 19 Davis-Devine S, Day SJ, Freund GG. Test performance comparison of inform HPV and hybrid capture 2 high-risk HPV DNA tests using the SurePath liquid-based Pap test as the collection method. Am J Clin Pathol 2005; 124: 24-30
• 20 Giovannelli L, Capra G, Lama A. et al. Atypical squamous cells of undetermined significance-favour reactive compared to atypical squamous cells of undetermined significance-favour dysplasia: association with cervical intraepithelial lesions and human papillomavirus infection. J Clin Virol 2005; 33: 281-286
• 21 Nieh S, Chen SF, Chu TY. et al. Is p 16(INK4A) expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies. Gynecol Oncol 2005; 97: 35-40
• 22 Bergeron C, Cas F, Fagnani F. et al. [Assessment of human papillomavirus testing on liquid-based Cyto-screen system for women with atypical squamous cells of undetermined significance. Effect of age]. Gynecol Obstet Fertil 2006; 34: 312-316
• 23 Holladay EB, Logan S, Arnold J. et al. A comparison of the clinical utility of p 16(INK4a) immunolocalization with the presence of human papillomavirus by hybrid capture 2 for the detection of cervical dysplasia/neoplasia. Cancer 2006; 108: 451-461
• 24 Kelly D, Kincaid E, Fansler Z. et al. Detection of cervical high-grade squamous intraepithelial lesions from cytologic samples using a novel immunocytochemical assay (ProEx C). Cancer 2006; 108: 494-500
• 25 Kiatpongsan S, Niruthisard S, Mutirangura A. et al. Role of human papillomavirus DNA testing in management of women with atypical squamous cells of undetermined significance. Int J Gynecol Cancer 2006; 16: 262-265
• 26 Monsonego J, Pintos J, Semaille C. et al. Human papillomavirus testing improves the accuracy of colposcopy in detection of cervical intraepithelial neoplasia. Int J Gynecol Cancer 2006; 16: 591-598
• 27 Ronco G, Cuzick J, Segnan N. et al. HPV triage for low grade (L-SIL) cytology is appropriate for women over 35 in mass cervical cancer screening using liquid based cytology. Eur J Cancer 2007; 43: 476-480
• 28 De Francesco MA, Gargiulo F, Schreiber C. et al. Comparison of the AMPLICOR human papillomavirus test and the hybrid capture 2 assay for detection of high-risk human papillomavirus in women with abnormal PAP smear. J Virol Methods 2008; 147: 10-17
• 29 Monsonego J, Pollini G, Evrard MJ. et al. Detection of human papillomavirus genotypes among high-risk women: a comparison of hybrid capture and linear array tests. Sex Transm Dis 2008; 35: 521-527
• 30 Siddiqui MT, Hornaman K, Cohen C. et al. ProEx C immunocytochemistry and high-risk human papillomavirus DNA testing in papanicolaou tests with atypical squamous cell (ASC-US) cytology: correlation study with histologic biopsy. Arch Pathol Lab Med 2008; 132: 1648-1652
• 31 Szarewski A, Ambroisine L, Cadman L. et al. Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears. Cancer Epidemiol Biomarkers Prev 2008; 17: 3033-3042
• 32 Cattani P, Zannoni GF, Ricci C. et al. Clinical performance of human papillomavirus E6 and E7 mRNA testing for high-grade lesions of the cervix. J Clin Microbiol 2009; 47: 3895-3901
• 33 Silverloo I, Andrae B, Wilander E. Value of high-risk HPV-DNA testing in the triage of ASCUS. Acta Obstet Gynecol Scand 2009; 88: 1006-1010
• 34 Del Mistro A, Frayle-Salamanca H, Trevisan R. et al. Triage of women with atypical squamous cells of undetermined significance (ASC-US): results of an Italian multicentric study. Gynecol Oncol 2010; 117: 77-81
• 35 Denton KJ, Bergeron C, Klement P. et al. The sensitivity and specificity of p 16(INK4a) cytology vs. HPV testing for detecting high-grade cervical disease in the triage of ASC-US and LSIL pap cytology results. Am J Clin Pathol 2010; 134: 12-21
• 36 Halfon P, Benmoura D, Agostini A. et al. Stepwise algorithm combining HPV high-risk DNA-based assays and RNA-based assay for high grade CIN in women with abnormal smears referred to colposcopy. Cancer Biomark 2010; 7: 133-139
• 37 Alameda F, Pijuan L, Lloveras B. et al. The value of p 16 in ASCUS cases: a retrospective study using frozen cytologic material. Diagn Cytopathol 2011; 39: 110-114
• 38 Belinson JL, Wu R, Belinson SE. et al. A population-based clinical trial comparing endocervical high-risk HPV testing using hybrid capture 2 and Cervista from the SHENCCAST II Study. Am J Clin Pathol 2011; 135: 790-795
• 39 Clad A, Reuschenbach M, Weinschenk J. et al. Performance of the Aptima high-risk human papillomavirus mRNA assay in a referral population in comparison with Hybrid Capture 2 and cytology. J Clin Microbiol 2011; 49: 1071-1076
• 40 Dufresne S, Sauthier P, Mayrand MH. et al. Human papillomavirus (HPV) DNA triage of women with atypical squamous cells of undetermined significance with Amplicor HPV and Hybrid Capture 2 assays for detection of high-grade lesions of the uterine cervix. J Clin Microbiol 2011; 49: 48-53
• 41 Monsonego J, Hudgens MG, Zerat L. et al. Evaluation of oncogenic human papillomavirus RNA and DNA tests with liquid-based cytology in primary cervical cancer screening: the FASE study. Int J Cancer 2011; 129: 691-701
• 42 Ratnam S, Coutlee F, Fontaine D. et al. Aptima HPV E6/E7 mRNA test is as sensitive as Hybrid Capture 2 Assay but more specific at detecting cervical precancer and cancer. J Clin Microbiol 2011; 49: 557-564
• 43 Schmidt D, Bergeron C, Denton KJ. et al. p 16/ki-67 dual-stain cytology in the triage of ASCUS and LSIL papanicolaou cytology: results from the European equivocal or mildly abnormal Papanicolaou cytology study. Cancer Cytopathol 2011; 119: 158-166
• 44 Stoler MH, Wright jr. TC, Sharma A. et al. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol 2011; 135: 468-475
• 45 Szarewski A, Mesher D, Cadman L. et al. Comparison of seven tests for high-grade cervical intraepithelial neoplasia in women with abnormal smears: the Predictors 2 study. J Clin Microbiol 2012; 50: 1867-1873
• 46 Alaghehbandan R, Fontaine D, Bentley J. et al. Performance of ProEx C and PreTect HPV-Proofer E6/E7 mRNA tests in comparison with the hybrid capture 2 HPV DNA test for triaging ASCUS and LSIL cytology. Diagn Cytopathol 2013; 41: 767-775
• 47 Oliveira A, Verdasca N, Pista A. Use of the NucliSENS EasyQ HPV assay in the management of cervical intraepithelial neoplasia. J Med Virol 2013; 85: 1235-1241
• 48 Denise Zielinski G, Snijders PJF, Rozendaal L. et al. High-risk HPV testing in women with borderline and mild dyskaryosis: long-term follow-up data and clinical relevance. J Pathol 2001; 195: 300-306
• 49 Chen HS, Su TH, Yang YC. et al. Human Papillomavirus Testing (Hybrid Capture Ii) to Detect High-Grade Cervical intraepithelial Neoplasia in Women with Mildly Abnormal Papanicolaou Results. Taiwanese Journal of Obstetrics and Gynecology 2005; 44: 252-257
• 50 Cuschieri KS, Graham C, Moore C. et al. Human Papillomavirus testing for the management of low-grade cervical abnormalities in the UK–Influence of age and testing strategy. J Clin Virol 2007; 38: 14-18
• 51 You K, Liang X, Qin F. et al. High-risk human papillomavirus DNA testing and high-grade cervical intraepithelial lesions. Aust N Z J Obstet Gynaecol 2007; 47: 141-144
• 52 Huang S, Erickson B, Tang N. et al. Clinical performance of Abbott RealTime High Risk HPV test for detection of high-grade cervical intraepithelial neoplasia in women with abnormal cytology. J Clin Virol 2009; 45 (Suppl. 01) S19-S23
• 53 Lee JK, Kim MK, Song SH. et al. Comparison of Human Papillomavirus Detection and Typing by Hybrid Capture 2, Linear Array, DNA Chip, and Cycle Sequencing in Cervical Swab Samples. Int J Gynecol Cancer 2009; 19: 266-272
• 54 Edgerton N, Cohen C, Siddiqui MT. Evaluation of CINtec PLUS^® testing as an adjunctive test in ASC-US diagnosed SurePath^® preparations. Diagn Cytopathol 2013; 41: 35-40
• 55 Wentzensen N, Schwartz L, Zuna RE. et al. Performance of p 16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res 2012; 18: 4154-4162
• 56 Loghavi S, Walts AE, Bose S. CINtec^® PLUS dual immunostain: a triage tool for cervical pap smears with atypical squamous cells of undetermined significance and low grade squamous intraepithelial lesion. Diagn Cytopathol 2013; 41: 582-587
• 57 Lee NW, Kim D, Park JT. et al. Is the human papillomavirus test in combination with the Papanicolaou test useful for management of patients with diagnoses of atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions?. Arch Pathol Lab Med 2001; 125: 1453-1457
• 58 Pretorius RG, Peterson P, Novak S. et al. Comparison of two signal-amplification DNA tests for high-risk HPV as an aid to colposcopy. J Reprod Med 2002; 47: 290-296
• 59 Sherman ME, Schiffman M, Cox JT. et al. Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst 2002; 94: 102-107
• 60 Meyer JL, Hanlon DW, Andersen BT. et al. Evaluation of p 16INK4a expression in ThinPrep cervical specimens with the CINtec p 16INK4a assay: correlation with biopsy follow-up results. Cancer 2007; 111: 83-92
• 61 Castle PE, Fetterman B, Thomas Cox J. et al. The age-specific relationships of abnormal cytology and human papillomavirus DNA results to the risk of cervical precancer and cancer. Obstet Gynecol 2010; 116: 76-84
• 62 Halford JA, Batty T, Boost T. et al. Comparison of the sensitivity of conventional cytology and the ThinPrep Imaging System for 1,083 biopsy confirmed high-grade squamous lesions. Diagn Cytopathol 2010; 38: 318-326
• 63 Voss JS, Kipp BR, Campion MB. et al. Assessment of fluorescence in situ hybridization and hybrid capture 2 analyses of cervical cytology specimens diagnosed as low grade squamous intraepithelial lesion for the detection of high grade cervical intraepithelial neoplasia. Anal Quant Cytol Histol 2010; 32: 121-130
• 64 Wu R, Belinson SE, Du H. et al. Human papillomavirus messenger RNA assay for cervical cancer screening: the Shenzhen Cervical Cancer Screening Trial I. Int J Gynecol Cancer 2010; 20: 1411-1414
• 65 Heider A, Austin RM, Zhao C. HPV test results stratify risk for histopathologic follow-up findings of high-grade cervical intra-epithelial neoplasia in women with low-grade squamous intra-epithelial lesion Pap results. Acta Cytol 2011; 55: 48-53
• 66 Levi AW, Harigopal M, Hui P. et al. Use of high-risk human papillomavirus testing in patients with low-grade squamous intraepithelial lesions. Cancer Cytopathol 2011; 119: 228-234
• 67 Tsoumpou I, Valasoulis G, Founta C. et al. High-risk human papillomavirus DNA test and p 16(INK4a) in the triage of LSIL: a prospective diagnostic study. Gynecol Oncol 2011; 121: 49-53
• 68 Ziemke P, Marquardt K. [Immunocytochemistry of p 16(INK4a) and Ki-67 as adjunctive method for routine gynecological cytology of mild and moderate dysplasia]. Pathologe 2013; 34: 323-328
• 69 Waldstrom M, Christensen RK, Ornskov D. Evaluation of p 16(INK4a)/Ki-67 dual stain in comparison with an mRNA human papillomavirus test on liquid-based cytology samples with low-grade squamous intraepithelial lesion. Cancer Cytopathol 2013; 121: 136-145
• 70 Ronco G, Segnan N, Giorgi-Rossi P. et al. Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst 2006; 98: 765-774
• 71 Ronco G, Giorgi-Rossi P, Carozzi F. et al. Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial. Lancet Oncol 2006; 7: 547-555
• 72 Carozzi F, Confortini M, Palma PD. et al. Use of p 16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2008; 9: 937-945
• 73 Carozzi F, Gillio-Tos A, Confortini M. et al. Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p 16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2013; 14: 168-176
• 74 Kitchener HC, Almonte M, Gilham C. et al. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol Assess (Rockv) 2009; 13: 1-150 iii–iv
• 75 Naucler P, Ryd W, Törnberg S. et al. Efficacy of HPV DNA Testing With Cytology Triage and/or Repeat HPV DNA Testing in Primary Cervical Cancer Screening. J Natl Cancer Inst 2009; 101: 88-99
• 76 Rijkaart DC, Berkhof J, Rozendaal L. et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: Final results of the POBASCAM randomised controlled trial. Lancet Oncol 2012; 13: 78-88
• 77 Dijkstra MG, van Niekerk D, Rijkaart DC. et al. Primary hrHPV DNA Testing in Cervical Cancer Screening: How to Manage Screen-Positive Women? A POBASCAM Trial Substudy. Cancer Epidemiol Biomarkers Prev 2014; 23: 55-63
• 78 Leinonen MK, Anttila A, Malila N. et al. Type- and age-specific distribution of human papillomavirus in women attending cervical cancer screening in Finland. Br J Cancer 2013; 109: 2941-2950
• 79 Castle PE, Stoler MH, Wright jr. TC. et al. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 2011; 12: 880-890
• 80 Black ME, Yamada J, Mann V. A systematic literature review of the effectiveness of community-based strategies to increase cervical cancer screening. Can J Public Health 2002; 93: 386-393
• 81 Camilloni L, Ferroni E, Cendales BJ. et al. Methods to increase participation in organised screening programs: a systematic review. BMC Public Health 2013; 13: 464
• 82 Ferroni E, Camilloni L, Jimenez B. et al. How to increase uptake in oncologic screening: a systematic review of studies comparing population-based screening programs and spontaneous access. Prev Med 2012; 55: 587-596
• 83 Tseng DS, Cox E, Plane MB. et al. Efficacy of patient letter reminders on cervical cancer screening: a meta-analysis. J Gen Intern Med 2001; 16: 563-568
• 84 Stone EG, Morton SC, Hulscher ME. et al. Interventions that increase use of adult immunization and cancer screening services: A meta-analysis. Ann Intern Med 2002; 136: 641-651
• 85 Bais AG, van Kemenade FJ, Berkhof J. et al. Human papillomavirus testing on self-sampled cervicovaginal brushes: An effective alternative to protect nonresponders in cervical screening programs. Int J Cancer 2007; 120: 1505-1510
• 86 Gök M, Heideman DA, van Kemenade FJ. et al. HPV testing on self collected cervicovaginal lavage specimens as screening method for women who do not attend cervical screening: cohort study. BMJ 2010; 340: c1040
• 87 Castle PE, Rausa A, Walls T. et al. Comparative community outreach to increase cervical cancer screening in the Mississippi Delta. Prev Med 2011; 52: 452-455
• 88 Giorgi-Rossi P, Marsili LM, Camilloni L. et al. The effect of self-sampled HPV testing on participation to cervical cancer screening in Italy: a randomised controlled trial (ISRCTN96071600). Br J Cancer 2011; 104: 248-254
• 89 Lazcano-Ponce E, Lorincz AT, Cruz-Valdez A. et al. Self-collection of vaginal specimens for human papillomavirus testing in cervical cancer prevention (MARCH): A community-based randomised controlled trial. Lancet 2011; 378: 1868-1873
• 90 Szarewski A, Cadman L, Mesher D. et al. HPV self-sampling as an alternative strategy in non-attenders for cervical screening – a randomised controlled trial. Br J Cancer 2011; 104: 915-920
• 91 Virtanen A, Nieminen P, Luostarinen T. et al. Self-sample HPV tests as an intervention for nonattendees of cervical cancer screening in Finland: a randomized trial. Cancer Epidemiol Biomarkers Prev 2011; 20: 1960-1969
• 92 Gok M, van Kemenade FJ, Heideman DA. et al. Experience with high-risk human papillomavirus testing on vaginal brush-based self-samples of non-attendees of the cervical screening program. Int J Cancer 2012; 130: 1228-1235
• 93 Darlin L, Borgfeldt C, Forslund O. et al. Comparison of use of vaginal HPV self-sampling and offering flexible appointments as strategies to reach long-term non-attending women in organized cervical screening. J Clin Virol 2013; 58: 155-160
• 94 Sancho-Garnier H, Tamalet C, Halfon P. et al. HPV self-sampling or the Pap-smear: A randomized study among cervical screening nonattenders from lower socioeconomic groups in France. Int J Cancer 2013; 133: 2681-2687
• 95 Morrison EAB, Goldberg GL, Hagan RJ. et al. Self-administered home cervicovaginal lavage: A novel tool for the clinical-epidemiologic investigation of genital human papillomavirus infections. Am J Obstet Gynecol 1992; 167: 104-107
• 96 Hillemanns P, Kimmig R, Hüttemann U. et al. Screening for cervical neoplasia by self-assessment for human papillomavirus DNA. Lancet 1999; 354: 1970
• 97 Sellors JW, Lorincz AT, Mahony JB. et al. Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions. CMAJ 2000; 163: 513-518
• 98 Wright jr. TC, Denny L, Kuhn L. et al. HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA 2000; 283: 81-86
• 99 Belinson J, Qiao YL, Pretorius R. et al. Shanxi province cervical cancer screening study: A cross-sectional comparative trial of multiple techniques to detect cervical neoplasia. Gynecol Oncol 2001; 83: 439-444
• 100 Lorenzato FR, Singer A, Ho L. et al. Human papillomavirus detection for cervical cancer prevention with polymerase chain reaction in self-collected samples. Am J Obstet Gynecol 2002; 186: 962-968
• 101 Nobbenhuis MAE, Helmerhorst TJM, Van den Brule AJC. et al. Primary screening for high risk HPV by home obtained cervicovaginal lavage is an alternative screening tool for unscreened women. J Clin Pathol 2002; 55: 435-439
• 102 Garcia F, Barker B, Santos C. et al. Cross-sectional study of patient- and physician-collected cervical cytology and human papillomavirus. Obstet Gynecol 2003; 102: 266-272
• 103 Salmerón J, Lazcano-Ponce E, Lorincz A. et al. Comparison of HPV-based assays with Papanicolaou smears for cervical cancer screening in Morelos State, Mexico. Cancer Causes Control 2003; 14: 505-512
• 104 Brink AATP, Meijer CJLM, Wiegerinck MAHM. et al. High concordance of results of testing for human papillomavirus in cervicovaginal samples collected by two methods, with comparison of a novel self-sampling device to a conventional endocervical brush. J Clin Microbiol 2006; 44: 2518-2523
• 105 Daponte A, Pournaras S, Mademtzis I. et al. Evaluation of HPV 16 PCR detection in self- compared with clinician-collected samples in women referred for colposcopy. Gynecol Oncol 2006; 103: 463-466
• 106 Girianelli VR, Thuler LCS, Szklo M. et al. Comparison of human papillomavirus DNA tests, liquid-based cytology and conventional cytology for the early detection of cervix uteri cancer. Eur J Cancer Prev 2006; 15: 504-510
• 107 Holanda jr. F, Castelo A, Veras TM. et al. Primary screening for cervical cancer through self sampling. Int J Gynaecol Obstet 2006; 95: 179-184
• 108 Seo SS, Song YS, Kim JW. et al. Good correlation of HPV DNA test between self-collected vaginal and clinician-collected cervical samples by the oligonucleotide microarray. Gynecol Oncol 2006; 102: 67-73
• 109 Szarewski A, Cadman L, Mallett S. et al. Human papillomavirus testing by self-sampling: Assessment of accuracy in an unsupervised clinical setting. J Med Screen 2007; 14: 34-42
• 110 Qiao YL, Sellors JW, Eder PS. et al. A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China. Lancet Oncol 2008; 9: 929-936
• 111 Bhatla N, Dar L, Patro AR. et al. Can human papillomavirus DNA testing of self-collected vaginal samples compare with physician-collected cervical samples and cytology for cervical cancer screening in developing countries?. Cancer Epidemiol 2009; 33: 446-450
• 112 Balasubramanian A, Kulasingam SL, Baer A. et al. Accuracy and cost-effectiveness of cervical cancer screening by high-risk human papillomavirus DNA testing of self-collected vaginal samples. J Low Genit Tract Dis 2010; 14: 185-195
• 113 Gustavsson I, Sanner K, Lindell M. et al. Type-specific detection of high-risk human papillomavirus (HPV) in self-sampled cervicovaginal cells applied to FTA elute cartridge. J Clin Virol 2011; 51: 251-254
• 114 Taylor S, Wang C, Wright TC. et al. A comparison of human papillomavirus testing of clinician-collected and self-collected samples during follow-up after screen-and-treat. Int J Cancer 2011; 129: 879-886
• 115 Twu NF, Yen MS, Lau HY. et al. Type-specific human papillomavirus DNA testing with the genotyping array: A comparison of cervical and vaginal sampling. Eur J Obstet Gynecol Reprod Biol 2011; 156: 96-100
• 116 Wikström I, Lindell M, Sanner K. et al. Self-sampling and HPV testing or ordinary Pap-smear in women not regularly attending screening: A randomised study. Br J Cancer 2011; 105: 337-339
• 117 Belinson JL, Du H, Yang B. et al. Improved sensitivity of vaginal self-collection and high-risk human papillomavirus testing. Int J Cancer 2012; 130: 1855-1860
• 118 Dijkstra MG, Heideman DAM, van Kemenade FJ. et al. Brush-based self-sampling in combination with GP5+/6+-PCR-based hrHPV testing: High concordance with physician-taken cervical scrapes for HPV genotyping and detection of high-grade CIN. J Clin Virol 2012; 54: 147-151
• 119 Longatto-Filho A, Naud P, Derchain SFM. et al. Performance characteristics of Pap test, VIA, VILI, HR-HPV testing, cervicography, and colposcopy in diagnosis of significant cervical pathology. Virchows Archiv 2012; 460: 577-585
• 120 Van Baars R, Bosgraaf RP, Ter Harmsel BWA. et al. Dry storage and transport of a cervicovaginal self-sample by use of the Evalyn Brush, providing reliable human papillomavirus detection combined with comfort for women. J Clin Microbiol 2012; 50: 3937-3943
• 121 Zhao FH, Lewkowitz AK, Chen F. et al. Pooled analysis of a self-sampling HPV DNA test as a cervical cancer primary screening method. J Natl Cancer Inst 2012; 104: 178-188
• 122 Darlin L, Borgfeldt C, Forslund O. et al. Vaginal self-sampling without preservative for human papillomavirus testing shows good sensitivity. J Clin Virol 2013; 56: 52-56
• 123 Geraets DT, van Baars R, Alonso I. et al. Clinical evaluation of high-risk HPV detection on self-samples using the indicating FTA-elute solid-carrier cartridge. J Clin Virol 2013; 57: 125-129
• 124 Guan Y, Gravitt PE, Howard R. et al. Agreement for HPV genotyping detection between self-collected specimens on a FTA cartridge and clinician-collected specimens. J Virol Methods 2013; 189: 167-171
• 125 Jentschke M, Lange V, Soergel P. et al. Enzyme-linked immunosorbent assay for p 16INK4a – A new triage test for the detection of cervical intraepithelial neoplasia?. Acta Obstet Gynecol Scand 2013; 92: 160-164
• 126 Jentschke M, Soergel P, Hillemanns P. Evaluation of a multiplex real time PCR assay for the detection of human papillomavirus infections on self-collected cervicovaginal lavage samples. J Virol Methods 2013; 193: 131-134
• 127 Nieves L, Enerson CL, Belinson S. et al. Primary cervical cancer screening and triage using an mRNA human papillomavirus assay and visual inspection. Int J Gynecol Cancer 2013; 23: 513-518
• 128 World Health Organization. WHO Guidelines for Treatment of cervical intraepithelial Neoplasia 2 – 3 and Adenocarcinoma in situ: Cryotherapy, large Loop Excision of the Transformation Zone, and Cold Knife Conization. Geneva: World Health Organization; 2014
• 129 Massad LS, Einstein MH, Huh WK. et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013; 17 (5 Suppl. 1): S1-S27
• 130 Luesley D, Leeson S. Colposcopy and programme management Guidelines for the NHS Cervical Screening Programme. 2010; 2: [NHSCSP Publication No 20]. Online: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/436873/nhscsp20.pdf last access: 15.01.2016
• 131 Alonso I, Torné A, Puig-Tintoré LM. et al. Pre- and post-conization high-risk HPV testing predicts residual/recurrent disease in patients treated for CIN 2–3. Gynecol Oncol 2006; 103: 631-636
• 132 Melnikow J, McGahan C, Sawaya GF. et al. Cervical Intraepithelial Neoplasia Outcomes After Treatment: Long-term Follow-up From the British Columbia Cohort Study. J Natl Cancer Inst 2009; 101: 721-728
• 133 Strander B, Hällgren J, Sparén P. Effect of ageing on cervical or vaginal cancer in Swedish women previously treated for cervical intraepithelial neoplasia grade 3: population based cohort study of long term incidence and mortality. BMJ 2014; 348: f7361
• 134 Tropé A, Jonassen CM, Sjøborg KD. et al. Role of high-risk human papillomavirus (HPV) mRNA testing in the prediction of residual disease after conisation for high-grade cervical intraepithelial neoplasia. Gynecol Oncol 2011; 123: 257-262
• 135 Ryu A, Nam K, Kwak J. et al. Early human papillomavirus testing predicts residual/recurrent disease after LEEP. J Gynecol Oncol 2012; 23: 217-225
• 136 Verguts J, Bronselaer B, Donders G. et al. Prediction of recurrence after treatment for high-grade cervical intraepithelial neoplasia: the role of human papillomavirus testing and age at conisation. BJOG 2006; 113: 1303-1307
• 137 Kang WD, Oh MJ, Kim SM. et al. Significance of human papillomavirus genotyping with high-grade cervical intraepithelial neoplasia treated by a loop electrosurgical excision procedure. Am J Obstet Gynecol 2010; 203: 72.e1-72.e6
• 138 Cecchini S, Carozzi F, Confortini M. et al. Persistent human papilloma virus infection as an indicator of risk of recurrence of high-grade cervical intraepithelial neoplasia treated by the loop electrosurgical excision procedure. Tumori 2004; 90: 225-228
• 139 Ang C, Mukhopadhyay A, Burnley C. et al. Histological recurrence and depth of loop treatment of the cervix in women of reproductive age: incomplete excision versus adverse pregnancy outcome. BJOG 2011; 118: 685-692
• 140 Flannelly G, Bolger B, Fawzi H. et al. Follow up after LLETZ: could schedules be modified according to risk of recurrence?. BJOG 2001; 108: 1025-1030
• 141 Prato B, Ghelardi A, Gadducci A. et al. Correlation of recurrence rates and times with posttreatment human papillomavirus status in patients treated with loop electrosurgical excision procedure conization for cervical squamous intraepithelial lesions. Int J Gynecol Cancer 2008; 18: 90-94
• 142 Castle PE, Schiffman M, Herrero R. et al. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis 2005; 191: 1808-1816
• 143 Aerssens A, Claeys P, Garcia A. et al. Natural history and clearance of HPV after treatment of precancerous cervical lesions. Histopathology 2008; 52: 381-386
• 144 Sarian LO, Derchain SF, Pitta Dda R. et al. Factors associated with HPV persistence after treatment for high-grade cervical intra-epithelial neoplasia with large loop excision of the transformation zone (LLETZ). J Clin Virol 2004; 31: 270-274
• 145 Strander B, Andersson-Ellström A, Milsom I. et al. Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study. BMJ 2007; 335: 1077
• 146 Jeong NH, Lee NW, Kim HJ. et al. High-risk human papillomavirus testing for monitoring patients treated for high-grade cervical intraepithelial neoplasia. J Obstet Gynaecol Res 2009; 35: 706-711
• 147 Chua KL, Hjerpe A. Human papillomavirus analysis as a prognostic marker following conization of the cervix uteri. Gynecol Oncol 1997; 66: 108-113
• 148 Houfflin Debarge V, Collinet P, Vinatier D. et al. Value of human papillomavirus testing after conization by loop electrosurgical excision for high-grade squamous intraepithelial lesions. Gynecol Oncol 2003; 90: 587-592
• 149 Chao A, Lin CT, Hsueh S. et al. Usefulness of human papillomavirus testing in the follow-up of patients with high-grade cervical intraepithelial neoplasia after conization. Am J Obstet Gynecol 2004; 190: 1046-1051
• 150 Fambrini M, Penna C, Pieralli A. et al. PCR detection rates of high risk human papillomavirus DNA in paired self-collected urine and cervical scrapes after laser CO2 conization for high-grade cervical intraepithelial neoplasia. Gynecol Oncol 2008; 109: 59-64
• 151 Aerssens A, Claeys P, Beerens E. et al. Prediction of recurrent disease by cytology and HPV testing after treatment of cervical intraepithelial neoplasia. Cytopathology 2009; 20: 27-35
• 152 Torné A, Fusté P, Rodriguez-Carunchio L. et al. Intraoperative post-conisation human papillomavirus testing for early detection of treatment failure in patients with cervical intraepithelial neoplasia: a pilot study. BJOG 2013; 120: 392-399
• 153 Persson M, Brismar Wendel S, Ljungblad L. et al. High-risk human papillomavirus E6/E7 mRNA and L1 DNA as markers of residual/recurrent cervical intraepithelial neoplasia. Oncol Rep 2012; 28: 346-352
• 154 Tinelli A, Guido M, Zizza A. et al. The mRNA-HPV test utilization in the follow up of HPV related cervical lesions. Curr Pharm Des 2013; 19: 1458-1465
• 155 Kreimer AR, Guido RS, Solomon D. et al. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia grade 2 or 3 disease. Cancer Epidemiol Biomarkers Prev 2006; 15: 908-914
• 156 Brismar S, Johansson B, Borjesson M. et al. Follow-up after treatment of cervical intraepithelial neoplasia by human papillomavirus genotyping. Am J Obstet Gynecol 2009; 201: 17.e1-17.e8
• 157 Heymans J, Benoy IH, Poppe W. et al. Type-specific HPV geno-typing improves detection of recurrent high-grade cervical neoplasia after conisation. International journal of cancer. Int J Cancer 2011; 129: 903-909
• 158 Sroczynski G, Siebert U. Evidence Report: Decision Analysis to evaluate Benefits, Harms and Cost-effectiveness of different cervical Cancer Screening Strategies to inform the S3 clinical Guideline “Prevention of Cervical Cancer” in the Context of the German Health Care System. Hall i.T., Austria: UMIT – University for Health Sciences, Medical Informatics and Technology; 2015