19: Cervical dysplasia and HPV

CHAPTER 19
Cervical dysplasia and HPV


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


Background


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].


Clinical questions


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.



  1. What is the chance of developing cervical dysplasia if infected with the HPV?
  2. What are the risk factors for cervical dysplasia?
  3. How effective are the HPV vaccines in preventing cervical dysplasia and cancer?
  4. What is the risk of recurrence and progression to cancer with and without treatment for CIN 2 and 3?
  5. In women diagnosed with AIS (population), what is the risk of recurrence and progression to cancer (outcomes)?
  6. In patients who have undergone treatment for cervical dysplasia (population), what are the subsequent risks of preterm delivery and other adverse obstetrical outcomes (outcomes)?
  7. How is cervical dysplasia managed (intervention) in pregnant patients (population)?

General search strategy


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.


Searching for evidence synthesis


Primary search strategy



  • Cochrane Library: (cervical dysplasia odds ratio (OR) CIN) AND (topic)
  • MEDLINE: (cervical dysplasia OR CIN) AND MEDLINE AND (systematic review OR meta‐analysis OR meta‐analysis) AND adult AND (topic).
  • Consensus guidelines for the management and follow‐up of patients with cervical dysplasia are provided by:

    • American Society for Colposcopy and Cervical Pathology (ASCCP) Consensus Guidelines (www.asccp.org) [3]
    • National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Cervical Cancer Screening (www.nccn.org) [4]

Critical review of the literature



  1. In patients infected with HPV (population), what proportion of patients will develop cervical dysplasia (outcome)?

Search Strategy:



  • MEDLINE: (cervical dysplasia OR CIN) AND HPV.

There are three categories of CIN based on histological changes:



  • CIN 1 includes mild dysplasia and condyloma (anogenital warts).
  • CIN 2 includes moderate dysplasia.
  • CIN 3 includes severe dysplasia and carcinoma‐in‐situ (CIS).

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 [57].


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.



  • CIN 1 with Low‐Grade Cervical Cytology:

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].



  • CIN 1 with High‐Grade Cervical Cytology:

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].



  • How are CIN 2 & 3 Managed?

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 [13, 18].



  • Ablative Procedures:

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]:



  • Satisfactory colposcopy (visualization of entire cervical squamocolumnar junction)
  • Biopsy confirming presence of CIN; abnormal cytology alone is not sufficient
  • Negative endocervical curettage.

The most common ablative procedures used in the United States are cryotherapy and laser ablation:



  • Cryotherapy:

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:

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:

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:



  • Suspected microinvasion
  • Unsatisfactory colposcopy (the transformation zone is not fully visualized)
  • Lack of correlation between the cytology and colposcopy/biopsies
  • Suspected AIS
  • Unable to rule out invasive disease
  • Lesion extending into the endocervical canal
  • Endocervical curettage showing CIN or a glandular abnormality
  • Recurrence after an ablative or previous excisional procedure.

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].



  • Cold Knife Conization:

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Jul 19, 2020 | Posted by in GYNECOLOGY | Comments Off on 19: Cervical dysplasia and HPV
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