Gynecologic Cryosurgery

Author: E L Kristiina Parviainen, MD, Assistant Professor, Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, University of Pittsburgh
Coauthor(s): Nancy D Gaba, MD,, Associate Dean for Graduate Medical Education, Director of Obstetrics and Gynecology Residency Program, Director of Division of General Gynecology and Associate Professor, Department of Obstetrics and Gynecology, George Washington University School of Medicine

Introduction

Cervical cytology by Papanicolaou test (Pap smear) is the basis for cervical cancer screening in the United States. The 2009 American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Cervical Cytology Screening recommends that screening be initiated at age 21, regardless of age of onset of sexual intercourse.1 Screening is recommended every 2 years until age 30. Thereafter, screening frequency may be decreased to every 3 years following 3 consecutive negative Papanicolaou test results for intraepithelial dysplasia and malignancy. Screening may be discontinued in low-risk women at age 65-70. The Bethesda System for reporting cervical and vaginal cytologic diagnoses was revised by the National Cancer Institute in 2001.2

The American Society for Colposcopy and Cervical Pathology (ASCCP) has developed guidelines for the management of women with cervical cytologic abnormalities. Evaluation following an abnormal finding on a Papanicolaou test may include repeat cytology, colposcopic examination with directed biopsies, endocervical curettage (ECC), and human papillomavirus (HPV) subtyping depending on the abnormal finding.

Biopsy-proven cervical intraepithelial neoplasia (CIN) in the absence of invasive cancer can be treated by destructive or excisional techniques. These techniques include local excision, cryosurgery, laser vaporization, loop electrode excision procedure (LEEP), cone biopsy, trachelectomy, and hysterectomy.

This article will review the role of cryosurgery in the treatment of preinvasive cervical neoplasia.

History of the Procedure

The modern recognition of cervical dysplasia as a premalignant disease of the uterine cervix dates back to the early 1940s, when Papanicolaou and Traut first described how exfoliated cells could be used to screen for cervical cancer and its precursors. The First International Congress of Exfoliative Cytology was convened in the 1960s, and the new age of screening for premalignant cervical disease began. Prior to this time, investigators such as Sir John Williams in the 1880s and T.S. Collen in 1900 recognized that premalignant disease often is found adjacent to invasive cancers of the cervix. Thus, the idea that invasive squamous cell cancers of the uterine cervix develop from precursor lesions was introduced.

Since the 1960s, many advances have been made in both diagnosis and management of premalignant diseases of the uterine cervix. Until the early 1970s, cervical cone biopsy and hysterectomy were the mainstays of treatment. Investigators such as Crisp3 and Townsend and Ostergard4  attempted to find methods of treatment that would obviate the need for extensive surgery and hospitalization. These investigators were the first to study the role of cryosurgery in managing selected patients with preinvasive cervical disease.

Problem

Because CIN is a premalignant condition, understanding the risk of progression to malignant disease is important in order to recommend treatment options. These recommendations depend on the abnormality and individual patient risk factors. Management of this spectrum of premalignant conditions may vary by provider and is summarized in an ACOG Practice Bulletin on Management of Cervical Cytology and Histology published in 2008.5 Rates of progression for biopsy-proven CIN are summarized in the Table.

Rates of Progression of CIN6

Open table in new window

[ CLOSE WINDOW ]
Table
CIN % Regression % Persistence % Progression
CIN 1 57 32 11
CIN 2 43 35 22
CIN 3 32 56 12
CIN % Regression % Persistence % Progression
CIN 1 57 32 11
CIN 2 43 35 22
CIN 3 32 56 12

More recently, investigators have reported even higher rates of spontaneous regression of CIN1 among young women and adolescents, with 90-100% regression over 24-36 month follow-up.7 ,8 ,9

Frequency

Worldwide, cervical cancer is the second leading cause of cancer death in women. In the United States, the American Cancer Society predicted 11,270 new cases of cervical cancer and 4,070 deaths due to cervical cancer in 2009.10

In the United States, cervical cancer incidence and mortality rates have declined dramatically with the use of Pap test screening and treatment of preinvasive disease.11 ,12 In a 2001 study, an encouraging 88.3% of women aged 18-44 years reported having had a Pap test in the past 3 years.13

The frequency of abnormal Papanicolaou test results and CIN varies by the population tested and the methodology of testing, and ranges from 1.5-6%.14 The frequency of dysplasia based on the Kaiser Pemanente Northwest database is 1.2 per 1,000 women for CIN 1 and 1.5 per 1,000 women for CIN 2/3.15

Etiology

Risk factors for preinvasive neoplastic lesions of the cervix include the following:

  • HPV infection (especially 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, which are known high-risk subtypes16 )
  • History of abnormal Pap test results or dysplasia
  • Cigarette smoking
  • Early age at first coitus
  • Multiple sexual partners
  • History of sexually transmitted diseases
  • Immunodeficiency, including HIV infection
  • Oral contraceptive use
  • Low socioeconomic status
  • Multiparity
  • African American, Hispanic, and Southeast Asian heritage

Pathophysiology

The concept of a continuum of squamous cell carcinoma precursors is the basis for the CIN classification for abnormal cervical histology results.17 Importantly, both CIS and dysplasia are known to consist of monoclonal cell lines with an aneuploid nuclear content.18

The CIN system differentiates mild (CIN 1), moderate (CIN 2), and severe dysplasia/CIS (CIN 3) based on the proportion of abnormal cells relative to the full epithelial thickness. The Bethesda System simplifies this to describe low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL), combining CIN 2 and CIN 3 into a single category due to similar risk of progression and prognosis.

The impact of HPV on cervical dysplasia and squamous cell carcinoma is an area of active clinical and research interest. HPV is an epitheliotropic double-stranded DNA virus. The HPV DNA is integrated into host chromosomes at specific loci. The E7 early protein binds to inactivate the retinoblastoma susceptibility gene, and the E6 early protein binds to p53. The affected epithelial cell then undergoes unregulated mitosis.19 HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58 are the types most frequently isolated from carcinomas and severe dysplasia.20 These HPV subtypes generally are not isolated from condyloma or CIN 1 lesions.21 On this basis, investigators use HPV genotyping as a method to determine treatment options for patients with abnormal Pap tests results and colposcopic findings.

Indications

Candidates for cryotherapy include patients with squamous CIN on biopsy who meet the following requirements:

  • Satisfactory colposcopic examination, with complete visualization of the transformation zone
  • Lesion identified and fully visualized
  • Biopsy consistent with cytology
  • Invasive carcinoma ruled out by biopsy
  • Negative ECC

Relevant Anatomy

The uterine cervix (from the Latin cervix , meaning neck) is the most distal portion of the uterus and extends into the upper vagina. The portio vaginalis is the location of the external os, the opening to the cervical canal and uterine cavity. The cervix consists of fibrous, muscular, and elastic tissue. It is lined by both columnar and squamous epithelium.

The squamocolumnar junction is found at the delineation between the stratified squamous epithelium and the columnar epithelium of the endocervix. Over time the columnar epithelium, which may be found on the ectocervix, is replaced by the metaplastic squamocolumnar junction. This junctional area is termed the transformation zone and is the site where most squamous neoplasia arises.

The purpose of cryosurgery is to destroy dysplastic cells that arise in this transformation zone by effecting cryonecrosis.

Contraindications

  • Unsatisfactory colposcopy
  • Lesion not fully visible or extending beyond the range of the cryotherapy probe
  • Colposcopically directed biopsy not consistent with cytology
  • ECC positive for CIN
  • Biopsy consistent with or suspicious for invasive carcinoma22
  • Glandular epithelial dysplasia or adenocarcinoma in situ

Workup

Diagnostic Procedures

  • Colposcopy of the vagina and cervix is performed with the application of acetic acid.
  • Cervical punch biopsies and ECC are used selectively to confirm histologically the diagnosis of CIN. This also permits identification of the size, shape, and location of the dysplastic lesion.

Histologic Findings

For a detailed discussion of the histologic findings of CIN, the reader is referred to a text of gynecologic pathology such as Blaustein's Pathology of the Female Genital Tract, Fifth Edition23 .

Treatment

Preoperative Details

No special preparation is required by the patient or physician prior to cryosurgery. The patient should be informed of the potential risks, benefits, failure rates, and alternatives to the procedure.

Prior to performing the procedure, the practitioner should confirm that the patient is not pregnant and is free of vaginal and cervical infections. The practitioner should review the Pap test, colposcopy, and ECC results to confirm that the patient is an appropriate candidate for cryosurgery. The lesion should not extend into the endocervical canal because this reduces the likelihood of success for the procedure.24 ,25

The equipment required to perform cervical cryosurgery is as follows:

  • Appropriately sized vaginal specula
  • Adequate light source
  • Refrigerant source - Liquid nitrous oxide
  • Cervical probes in a variety of sizes
  • Lubricant
  • Topical hemostatic agents

The following information may be provided to patients prior to their procedure.

Sample patient information sheet

Your doctor has determined that you have cervical dysplasia, which may be treated with cryosurgery. Cryosurgery is a procedure in which the abnormal cells on your cervix are destroyed by freezing. This procedure can be as much as 90% effective in eliminating the abnormal tissue. This procedure is performed in the office.

Prior to the procedure:

  • Notify your provider if you have (or will have) your period on the day of the procedure so it can be rescheduled when your period is over.
  • Notify your provider if you think that you might be pregnant. Cryosurgery usually is not performed during pregnancy because it might endanger the pregnancy.

Day of the procedure:

  • You may take a medication such as ibuprofen or acetaminophen 1-2 hours prior to your scheduled procedure.
  • No anesthetic is required for the procedure.
  • Your provider will perform the cryosurgery procedure in the office, which will require 15-20 minutes.
  • You may experience uterine cramping during and immediately after the procedure.

After the procedure:

  • You may return to work.
  • You may notice an abundant gray, white, or clear vaginal discharge for 2-4 weeks, which may have an odor. This is to be expected and is evidence of cells sloughing from the cervix.
  • Do not use tampons, douche, or have sexual intercourse for 4 weeks after treatment because this may result in infection or bleeding, which could delay the healing process.
  • You may take ibuprofen or acetaminophen for pain relief.
  • You may shower at any time after the treatment. Avoid tub baths until the vaginal discharge resolves.

Reasons to contact your provider:

  • Temperature above 38°C
  • Vaginal bleeding equal to or greater than a normal period
  • Pain not relieved by ibuprofen or acetaminophen

Intraoperative Details

Technique

In order to achieve hypothermia, liquid refrigerants are forced through a small hole at a pressure range of 750-900 pounds per square inch (psi).26 This produces a very low temperature at the surface of the probe due to the Joule-Thompson effect. The temperature at the probe tip can range from -65°C to -85°C. Cell death occurs secondary to crystallization of intracellular water at -20°C to -30°C.27 ,24 ,25 Proposed mechanisms for cell destruction include dehydration, crystallization, denaturation of membrane proteins, thermal shock, and vascular stasis.22

The refrigerant most commonly used at present is liquid nitrous oxide (N2 O). It is available commercially and is relatively inexpensive. A 2008 study found N2 O to be superior to carbon dioxide cryotherapy as indicated by greater mean depth of tissue necrosis with N2 O.28

The external temperature of the probe depends on the conductivity of the probe material. Silver and copper are the best materials for use in probe tips because high conductivity produces both a better freezing effect and more effective local cryonecrosis.22 Adequate cryonecrosis of the tissue depends on direct contact of the probe with the lesion. This is best achieved with a water-based lubricant coating an appropriately sized probe. Boonstra and others have shown that the size and shape of the probe can dramatically affect the depth of cryonecrosis.24 ,25 The cryotip should cover the entire lesion and transformation zone. The 19- and 25-mm mini-cone tips are recommended by Campion.

A double freeze technique in which the tissue is frozen for a period of several minutes, thawed completely, and then refrozen is preferred to single freeze.29 Creasman30 demonstrated that this method was significantly more efficacious than a single-freeze method. The freeze-thaw-freeze is divided as follows:

  • Freeze for 3 minutes
  • Thaw for 5 minutes
  • Freeze for 3 minutes

The freeze time required depends largely on the ice ball that is generated on the cervix. Campion in the 2005 edition of Practical Gynecologic Oncology recommends that the ice ball extend 7 mm laterally beyond the edge of the probe in order to achieve a 5-mm depth of destruction.27 This suggests that the operator need not watch the elapsed time, but rather monitor the width of the ice ball formed.

Procedure

  • The patient is carefully selected, as previously described.
  • She is premedicated with nonsteroidal anti-inflammatory drugs (NSAIDs).
  • A speculum is placed in the vagina to adequately expose the cervix and prevent contact of the probe tip with the vaginal walls and speculum.
  • Location and size of the lesion is confirmed by colposcopy or has previously been noted.
  • A water-soluble gel is applied to the tip of an appropriately sized probe, which is positioned over the lesion and transformation zone.
  • The flow of refrigerant is initiated, and the ice ball formation is observed carefully.
  • Thawing and refreezing then are carried out, if the operator prefers.

Postoperative Details

Postprocedure symptoms include the following:

  • Cramping: This can be minimized with pretreatment NSAIDs. Mucosal and paracervical block typically are not used.
  • Hydrorrhea: Most authors describe 2-4 weeks of profuse watery discharge, which may be greater in obese women. Debridement of the cervical eschar 48 hours after the cryosurgical procedure does not ameliorate this symptom.31
  • Bleeding: This symptom is rare.
  • Infection: This is a rare complication. Prophylactic antibiotics are not indicated.

Cellular repair

  • Crisp reports that 60% of patients were found to have normal histology findings on cervical biopsy at 6 weeks and 90% by 10 weeks.
  • Cervical cytology is difficult to interpret during the first 6 weeks due to the healing process, but then it returns to normal.
  • The squamocolumnar junction recedes deeper into the endocervical canal after cryosurgery.3

Follow-up

Acceptable strategies recommended by the ACOG Practice Bulletin on Management of Abnormal Cervical Cytology and Histology for follow-up after cryotherapy include (1) HPV testing at 6-12 months, (2) HPV & cytology at 6-month intervals, or (3) cytology alone at 6 month intervals.5 Factors that may affect screening frequency include size and grade of the lesion and patient compliance.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Women's Health Center . Also, see eMedicine's patient education articles Cervical Cancer and Pap Smear .

Complications

Potential impact on fertility, scarring complicating follow-up, and carcinoma developing postcryosurgery are the main concerns.

  • Fertility: Theoretical concerns about reduced fertility include the induction of cervical stenosis, a detrimental effect on cervical mucus, cervical incompetence, and tubal dysfunction secondary to ascending infection. No conclusive clinical evidence supports any of these concerns.32 ,33 ,34
  • Scarring complicating follow-up colposcopy: Of particular concern is the receding of the squamocolumnar junction into the endocervical canal.35 ,36 In a series of 204 patients, post-treatment colposcopy was adequate in 50% of patients after cryosurgery and 79% of patients after laser surgery.37 A more recent report of a small series of women treated with cryotherapy (n=82), LEEP (n=24), and no procedure (n=96), yielded likelihood odds ratios of 3.01 (0.78-11.58) for LEEP and 18.66 (6.99-49.81) for cryotherapy of inadequate follow-up colposcopic evaluation post procedure as compared with the no procedure group.38
  • Development of carcinoma postcryotherapy: In a series of invasive carcinoma diagnosed after cryotherapy, carcinoma was associated with the following findings: inappropriate evaluation prior to cryotherapy (57%), erroneous initial interpretation of ectocervical biopsies (20%), and erroneous initial interpretation of ECC specimens (67%).39 Appropriate preoperative evaluation is the key to minimizing the risk of postcryosurgery carcinoma.
  • Anaphylactoid reaction has been reported as a reaction to the cold exposure.40 Physicians performing cryosurgery should be aware of this potential risk and be familiar with its treatment.

Outcome and Prognosis

Cryosurgery can be an effective treatment for premalignant squamous lesions of the uterine cervix. Recurrence rates are low and depend, in part, on the size and grade of the lesion, as well as its location (ectocervix versus endocervix). Boonstra and colleagues examined hysterectomy specimens of women who received cryosurgery for CIN prior to hysterectomy. They reported that a success rate as high as 100% could be achieved using a large conical probe and an adequate freeze time based on the 64 patients they studied.25

Technical aspects that impact results include the method utilized, freeze and thaw time, size and extent of the ice ball that is formed, probe size and shape, and the refrigerant temperature.

Although many authors have investigated overall success rates, few have conducted large-scale prospective studies. Benedet and others reported on 1675 women with varying degrees of CIN and demonstrated an overall success rate of 94%.41 Further work by this same group in 1990 demonstrated an 88% success rate in 962 women in a higher-risk group in which more than half of the patients had severe dysplasia or CIS. Gordon and Duncan presented data from 1628 patients with severe dysplasia and found an initial 93% success rate. This study followed patients' cases for as long as 6 years after the procedure, and, in this group, the long-term success rate was 91%.42

Assessment of the subset of patients with severe dysplasia (CIN 3) treated with cryosurgery has yielded disparate results from different authors, with failure rate ranges of 7.1-38.8%. Bryson reported an 11-year study of patients with biopsy-proven severe dysplasia or CIS and found a 7.1% failure rate.43 Townsend and Ostergard followed the cases of 62 patients with severe dysplasia or CIS and found an 11.8% failure rate for those with severe dysplasia and 10% for those with CIS.4 In a follow-up study, Ostergard reported a 7.1% failure rate in 28 patients with severe dysplasia and an alarming 38.8% failure rate in 18 patients with the diagnosis of CIS.44 Failure rates for cryosurgical treatment have been reported to be consistently higher in patients with severe dysplasia and CIS than in patients with mild or moderate dysplasia.

Numerous investigators have compared the efficacy of cryosurgery and laser vaporization in the treatment of CIN. The two methods appear to be equally efficacious. Proponents of laser therapy stress the capacity to achieve precise destruction, and thereby more complete destruction, of the lesion by this method. Recurrence and persistence rates reported in the literature do not support this assertion. Laser equipment also is significantly more expensive than the cryoprobe apparatus, and patients report more pain during the laser vaporization. No proven benefit of laser therapy over cryosurgery exists.

A 2003 cost-effectiveness model on management of CIN 2/3 found cryotherapy, LEEP, and hysterectomy to be superior to observation, laser therapy, and cold knife cone.45 LEEP was more effective than cryotherapy but also more expensive at a cost of $31,347 per CIN cure and $1.8 million per cancer prevented. Hysterectomy was the most effective and most expensive. Cryotherapy should continue to have a role in the treatment of cervical intraepithelial dysplasia, with increasing focus on resource utilization in our health care system.

Mitchel et al compared cryosurgery, laser vaporization, and LEEP finding no difference in success or complication rates. However, persistence was reported to be greater in patients with larger lesions, history of prior treatment, older women (>30 y), and those with HPV 16 or 18.46 ,47 Another randomized trial comparing LEEP with cryotherapy did demonstrate higher cure rate following LEEP at 12-month follow-up for women with high-grade lesions, but concluded that cryotherapy has an "acceptable" cure rate and hence remains a good option for low-resource countries.48

The 2009 Cochrane review on surgery for CIN, concludes that while cryotherapy has equal efficacy to other modalities for the treatment of low-grade lesions, a trend toward greater residual disease following treatment of high-grade lesions with cryotherapy precludes recommending the use of cryotherapy for high-grade lesions.29

Future and Controversies

Despite the 85-95% success rate reported in most series, practitioners continue to be concerned about the potential for persistent disease and missed diagnosis of invasive carcinoma. Several investigators have reported a disparity between colposcopic biopsies and cone biopsy specimens.49 For this reason, LEEP, which provides tissue for pathologic diagnosis, has replaced cryosurgery in many cases in the ambulatory setting.

Several topical agents, including imiquimod, are currently being evaluated for efficacy in treatment of CIN. Future studies will no doubt determine their role in clinical practice.

Increasingly, physicians also are offering expectant management for patients with CIN 1 lesions and reserving therapy for CIN 2/CIN 3. Remember that eliminating HPV from the genital tract is not possible, and, therefore, women with a history of CIN remain at risk for recurrence.

Given the recent availability of the HPV vaccine, the prevalence and management of CIN may be dramatically altered in the decades to come.

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