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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.

Cover of WHO Guidelines for Treatment of Cervical Intraepithelial Neoplasia 2–3 and Adenocarcinoma in situ

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.

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Cervical intraepithelial neoplasia (CIN) is a premalignant lesion that is diagnosed by histology as CIN1, CIN2, or CIN3.2 If left untreated, CIN2 or CIN3 (collectively referred to as CIN2+) can progress to cervical cancer. It is estimated that approximately 1–2% of women have CIN2+ each year, with higher rates reported for women of HIV-positive status, at 10% (26). A diagnosis of CIN2+ is an histological diagnosis obtained from biopsies of the suspect lesions, either with or without colposcopy, for which treatment is recommended. Adenocarcinoma in situ (AIS) is a precursor lesion for cervical cancer that is diagnosed by cytology and can be treated. The majority of AIS are found in the transformation zone. AIS may be associated with CIN. There are three principal treatments available in low- and middle-income countries to treat CIN: cryotherapy, large loop excision of the transformation zone (LLETZ, or LEEP), and cold knife conization (CKC).

In 2006, the World Health Organization (WHO) published a guide to assist clinicians and programme managers to diagnose and treat CIN in order to prevent and control cervical cancer: Comprehensive cervical cancer control: a guide to essential practice (C4-GEP) (7). The C4-GEP provides background information about CIN, diagnosis, and treatments. However, in 2009, WHO committed to updating this guide to reflect new evidence available on HPV vaccination, cervical cancer screening methods, and treatments for cervical pre-cancer, and to make treatment recommendations. In 2011, WHO recommendations for the use of cryotherapy to treat CIN were developed and published (8, 9). Those recommendations covered the use of different techniques of cryotherapy, such as single- and double-freeze methods, and its use in specific populations, including pregnant women, and women of HIV-positive status. This guideline covers treatments for histologically confirmed CIN2+, including cryotherapy, LEEP, and CKC. Another guideline has been developed concurrently on strategies to screen and treat precancerous cervical lesions when there is no histological confirmation of CIN2+ (10).

Target audience

This document is intended primarily for policy-makers, managers, programme officers, and other professionals in the health sector who have responsibility of choosing strategies for cervical cancer prevention, at country, regional, and district levels. Individuals working in reproductive health care programmes, particularly programmes for prevention of sexually transmitted infections (STIs) including HIV/AIDS and for family planning, at the district and primary health care levels, should also consult this document to understand how recommendations are developed and why it is vitally important to select and implement evidence-based strategies to prevent cervical cancer.


This guideline builds upon the WHO guidelines: use of cryotherapy for cervical intraepithelial neoplasia published in 2011 (9), and provides recommendations for the use of cryotherapy versus LEEP versus CKC for the treatment of histologically confirmed CIN2+, and additional recommendations for the treatment of histologically confirmed AIS. This document also describes the WHO methodology that was used for the development of these guidelines based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach, and provides GRADE evidence profiles3 and evidence-to-recommendation tables4 for each recommendation (see: Supplemental material: GRADE evidence-to-recommendation tables and evidence profiles for each recommendation).



Diagnosis of CIN is established by histopathological examination of a cervical punch biopsy or excision specimen. A judgement of whether or not a cervical tissue specimen reveals CIN, and to what degree, is dependent on the histological features concerned with differentiation, maturation, and stratification of cells and nuclear abnormalities. The proportion of the thickness of the epithelium showing mature and differentiated cells is used for grading CIN. More severe degrees of CIN are likely to have a greater proportion of the thickness of epithelium composed of undifferentiated cells, with only a narrow layer of mature differentiated cells on the surface (1).


The GRADE evidence profiles summarize the evidence from the systematic reviews and the model, as well as the quality of the evidence.


The evidence-to-recommendation tables describe the process of going from the evidence to developing the recommendations, and explain the judgements and rationale for factors that are not part of the GRADE evidence profiles.

Copyright © World Health Organization 2014.

All rights reserved. Publications of the World Health Organization are available on the WHO website ( or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: tni.ohw@sredrokoob).

Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press through the WHO website (

Bookshelf ID: NBK206777


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