CHAPTER 19 Mila de Moura Behar Pontremoli Salcedo1 and Kathleen M. Schmeler2 1Department of Gynecology and Obstetrics, Federal University of Health Sciences (UFCSPA)/Santa Casa de Porto Alegre, Porto Alegre, RS, Brazil 2Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA Cervical dysplasia or CIN is a premalignant condition of the cervix. It is caused by the human papillomavirus (HPV) and is usually detected by screening with cytology (Pap test) [1]. Women with low‐grade CIN have minimal potential of progression to malignancy. However, women with high‐grade CIN can develop invasive cervical cancer if left untreated. The goal of management of CIN is to prevent progression to invasive cancer while avoiding overtreatment of lesions that are likely to regress [2]. In order to address the issues of most relevance to your patient and to help in searching the literature for the evidence regarding cervical dysplasia and HPV issues, you structure your clinical questions as recommended in Chapter 1. You begin to address these questions by searching for evidence in the common electronic databases such as the Cochrane Library and MEDLINE looking specifically for systematic reviews and meta‐analyses. The Cochrane Library is particularly rich in high‐quality systematic review evidence on numerous aspects of cervical dysplasia. In fact, this group’s review productivity was the model for the development of the Cochrane Library. When a systematic review is identified, you also search for recent updates on the Cochrane Library and also search MEDLINE and EMBASE to identify randomized controlled trials that became available after the publication date of the systematic review. In addition, access to relevant, updated and evidence‐based clinical practice guidelines (CPGs) on cervical dysplasia are accessed to determine the consensus rating of areas lacking evidence. Search Strategy: There are three categories of CIN based on histological changes: CIN is graded based on the extent of abnormal cell proliferation of the basal layer of the cervical epithelium. CIN 1 is considered a low‐grade lesion, and CIN 2 and 3 are considered high‐grade lesions. In CIN 1, proliferation occurs up to the lower third of the epithelium. In CIN 2, proliferation occurs up to the upper two thirds; and in CIN 3, proliferation occurs in more than the upper two‐thirds of the epithelium. In CIS, the entire epithelium is abnormal [5–7]. CIN and cervical cancer are caused by HPV [8]. HPV is a small DNA virus that is sexually transmitted. The initial infection usually occurs during adolescence, and up to 80% of sexually active people become infected at least once during their lifetime. The large majority of HPV infections clear without treatment, however, in some patients the infection persists and can develop into CIN and possibly cancer [9]. HPV is central to the pathogenesis of cervical cancer, with the virus detected in the vast majority of the cases [10]. Furthermore, HPV has also been associated with other malignancies including cancer of the vulva, vagina, anus, oropharynx, and penis [9, 11, 12]. To date, more than 100 HPV subtypes have been identified [13]. Approximately 40 of these are associated with anogenital infections, and include both low‐risk and high‐risk types. The most common low‐risk types are HPV 6 and 11, which account for more than 90% of cases of anogenital condyloma or genital warts. HPV 16 and 18 are the most common high‐risk types and account for 70% of cervical cancer cases. Prophylactic vaccines are currently available to protect against HPV [14, 15]. In the United States, 3.5 million (7%) of the 50 million Pap tests performed each year are abnormal and require additional testing. Approximately 300 000 of these women (8.6% of women with abnormal Pap tests) are subsequently diagnosed with CIN 2 or 3 [16, 17]. The cost associated with the diagnosis and treatment of cervical dysplasia and genital warts in the United States is estimated to be $3 billion per year. Given the high rates of spontaneous regression, CIN 1 is usually managed expectantly. This is particularly true if the diagnosis of CIN 1 is preceded by low‐grade cervical cytology, i.e. atypical squamous cells of undetermined significance (ASCUS) or low‐grade squamous intraepithelial lesion (LSIL). These patients can undergo co‐testing with cytology and HPV testing at 12 months or repeat cytology alone at 12 month if patient is 21–24 years old [1, 3]. If the diagnosis of CIN 1 is preceded by cytology showing HSIL or atypical glandular cells (AGC), there is a higher chance of underlying CIN 2/3 or worse, and more aggressive management should be considered. In patients who have completed childbearing, an excisional procedure is recommended. In women who desire future fertility, close follow‐up with cytology and colposcopy at six months is performed [1, 3]. Given the lower rates of spontaneous regression and higher rates of progression, it is recommended that most women with CIN 2 or CIN 3 undergo treatment. Both ablative and excisional procedures are used, with similar efficacy rates (>90% cure) in properly selected patients [1–3, 18]. Ablative procedures are solely for the treatment of CIN and do not provide further diagnostic information. To qualify for ablative therapy, there should be no suspicion of glandular or invasive squamous disease. Specific criteria for ablative therapies include [1, 3]: The most common ablative procedures used in the United States are cryotherapy and laser ablation: Cryotherapy cools the ectocervix with a metal cryoprobe using a refrigerant gas, either carbon dioxide or nitrous oxide. The ectocervix is cooled to −20°C causing crystallization of intracellular water that destroys the lesion. A freeze‐thaw‐freeze‐thaw cycle is used where the cervix is frozen for three minutes, allowed to thaw and then frozen again for three minutes [19, 20]. Cryotherapy can be performed in the office setting. Laser ablation of CIN can be performed by physicians with specialized training. A carbon dioxide laser is directed at the cervical lesion under colposcopic guidance. Water in the tissue absorbs the laser energy, and the tissue is destroyed by vaporization. The lesion is typically ablated to a depth of 5 mm. Several safety procedures must be followed including the use of protective eyewear by all personnel in the procedure room, the use of a blackened or brushed speculum to avoid damage to surrounding tissues by misdirected laser beams, and using wet towels and cloth drapes to prevent fires. Excisional procedures have the advantage over ablative procedures of providing a pathologic specimen for further diagnostic information. The specific indications for an excisional procedure over an ablative procedure include: The standard procedures used in the United States include cold knife conization (CKC), laser conization, and loop electrosurgical excision procedure (LEEP), also called large loop excision of the transformation zone (LLETZ). In both procedures, the cervix is infiltrated with an anesthetic/vasoconstrictor solution and a cone shaped piece of the cervix inclusive of the transformation zone is removed [21]. This is often followed by an endocervical curettage (ECC) above the cone bed. There is no evidence that one technique is significantly more effective than the other with regards to treatment failures or procedure‐related morbidity [20].
Cervical dysplasia and HPV
Background
Clinical questions
General search strategy
Searching for evidence synthesis
Primary search strategy
Critical review of the literature
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