- Author: E L Kristiina Parviainen, MD; Chief Editor: Michel E Rivlin, MD more...
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. 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.
The images below illustrate cell cervical carcinoma.
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 Crisp and Townsend and Ostergard 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.
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. Rates of progression for biopsy-proven CIN are summarized in the Table.
|CIN||% Regression||% Persistence||% Progression|
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]
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.
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.
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%. 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.
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 subtypes  )
History of abnormal Pap test results or dysplasia
Early age at first coitus
Multiple sexual partners
History of sexually transmitted diseases
Immunodeficiency, including HIV infection
Oral contraceptive use
Low socioeconomic status
African American, Hispanic, and Southeast Asian heritage
The concept of a continuum of squamous cell carcinoma precursors is the basis for the CIN classification for abnormal cervical histology results. Importantly, both CIS and dysplasia are known to consist of monoclonal cell lines with an aneuploid nuclear content.
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 image below illustrates both fine and coarse punctation in cervical lesions.
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. 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. These HPV subtypes generally are not isolated from condyloma or CIN 1 lesions. On this basis, investigators use HPV genotyping as a method to determine treatment options for patients with abnormal Pap tests results and colposcopic findings.
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
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.
See the list below:
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 carcinoma 
Glandular epithelial dysplasia or adenocarcinoma in situ
ACOG. ACOG Practice Bulletin number 109, December 2009. Cervical cytology screening. Obstet Gynecol. 2009 Dec. 114(6):1409-1420.
Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002. 287:2114-9.
Crisp WE, Smith MS, Asadourian LA. Cryosurgical treatment of premalignant disease of the uterine cervix. Am J Obstet Gynecol. 1970 Jul 1. 107(5):737-42. [Medline].
Townsend DE, Ostergard DR. Cryocauterization for preinvasive cervical neoplasia. J Reprod Med. 1971 Apr. 6(4):171-6. [Medline].
ACOG Practice Bulletin No. 99: management of abnormal cervical cytology and histology. Obstet Gynecol. 2008 Dec. 112(6):1419-44. [Medline].
Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993 Apr. 12(2):186-92. [Medline].
Schlecht NF, Platt RW, Duarte-Franco E, Costa MC, Sobrinho JP, Prado JC. Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst. 2003 Sep 3. 95(17):1336-43. [Medline].
Brown DR, Shew ML, Qadadri B, Neptune N, Vargas M, Tu W. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis. 2005 Jan 15. 191(2):182-92. [Medline].
Moscicki AB, Shiboski S, Hills NK, Powell KJ, Jay N, Hanson EN. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet. 2004 Nov 6-12. 364(9446):1678-83. [Medline].
American Cancer Society. Cancer facts and figures 2009. American Cancer Society. Available at http://www.cancer.org/download/STT/500809. Accessed: 4/30/2010.
Devesa SS. Descriptive epidemiology of cancer of the uterine cervix. Obstet Gynecol. 1984 May. 63(5):605-12.
Schoell WM, Janicek MF, Mirhashemi R. Epidemiology and biology of cervical cancer. Semin Surg Oncol. 1999 Apr-May. 16(3):203-11. [Medline].
Smith R. CA - A Cancer Journal for Clinicians. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2001. 51: 18-44.
Cirisano FD. Management of pre-invasive disease of the cervix. Semin Surg Oncol. 1999 Apr-May. 16(3):222-7. [Medline].
Insinga RP, Glass AG, Rush BB. Diagnoses and outcomes in cervical cancer screening: a population-based study. Am J Obstet Gynecol. 2004 Jul. 191(1):105-13. [Medline].
CDC National Cancer Institute Factsheet. Human papillomavirus and cancer; Questions and answers. CDC. Available at www.cancer.gov/cancertopics/factsheet/Risk/HPV. Accessed: 4/30/2010.
Richart RM. Natural history of cervical intraepithelial neoplasia. Clin Obstet Gynecol. 1968. 10:748-784.
Fu YS, Reagan JW, Richart RM. Definition of precursors. Gynecol Oncol. 1981 Oct. 12(2 Pt 2):S220-31. [Medline].
Hollingsworth RE, Lee WH. Tumor suppressor genes: new prospects for cancer research. J Natl Cancer Inst. 1991 Jan. 83(2):91-6.
Lorincz AT, Reid R, Jenson AB. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol. 1992 Mar. 79(3):328-37.
Willett GD, Kurman RJ, Reid R. Correlation of the histologic appearance of intraepithelial neoplasia of the cervix with human papillomavirus types. Emphasis on low grade lesions including so-called flat condyloma. Int J Gynecol Pathol. 1989. 8(1):18-25. [Medline].
Charles EH, Savage EW, Hacker N. Cryosurgical treatment of cervical intraepithelial neoplasia. Gynecol Oncol. 1981 Aug. 12(1):83-8. [Medline].
Precancerous Lesions of the Cervix. Kurman RJ. Blaustein's Pathology of the Female Genital Tract. 5th. New York: Springer-Verlag; 2002.
Boonstra H, Aalders JG, Koudstaal J. Minimum extension and appropriate topographic position of tissue destruction for treatment of cervical intraepithelial neoplasia. Obstet Gynecol. 1990 Feb. 75(2):227-31. [Medline].
Boonstra H, Koudstaal J, Oosterhuis JW. Analysis of cryolesions in the uterine cervix: application techniques, extension, and failures. Obstet Gynecol. 1990 Feb. 75(2):232-9. [Medline].
Figge DC, Creasman WT. Cryotherapy in the treatment of cervical intraepithelial neoplasia. Obstet Gynecol. 1983 Sep. 62(3):353-8. [Medline].
Campion Michael J. Preinvasive Disease. Jonathan S. Berek and Neville F. Hacker. Practical Gynecologic Oncology. 4th. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. 265-309.
Mariategui J, Santos C, Taxa L, Jeronimo J, Castle PE. Comparison of depth of necrosis achieved by CO2- and N2O-cryotherapy. Int J Gynaecol Obstet. 2008 Jan. 100(1):24-6. [Medline].
Martin-Hirsch pp, Paraskevaidis E, Kitchener HC. Surgery for intraepithelial neoplasia. The Cochrane Collaboration. 2009:[Full Text].
Creasman WT, Hinshaw WM, Clarke-Pearson DL. Cryosurgery in the management of cervical intraepithelial neoplasia. Obstet Gynecol. 1984 Feb. 63(2):145-9. [Medline].
Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the effectiveness of cryotherapy in the treatment of cervical intraepithelial neoplasia. Int J Gynaecol Obstet. 2013 Mar. 120(3):218-23. [Medline].
Harper DM, Mayeaux EJ Jr, Daaleman TP. The natural history of cervical cryosurgical healing. The minimal effect of debridement of the cervical eschar. J Fam Pract. 2000 Aug. 49(8):694-700. [Medline].
Weed JC Jr, Curry SL, Duncan ID. Fertility after cryosurgery of the cervix. Obstet Gynecol. 1978 Aug. 52(2):245-6. [Medline].
Hemmingsson E, Stendahl U, Stenson S. Cryosurgical treatment of cervical intraepithelial neoplasia with follow-up of five to eight years. Am J Obstet Gynecol. 1981 Jan 15. 139(2):144-7. [Medline].
Montz FJ. Impact of therapy for cervical intraepithelial neoplasia on fertility. Am J Obstet Gynecol. 1996 Oct. 175(4 Pt 2):1129-36. [Medline].
Ferenczy A. Comparison of cryo- and carbon dioxide laser therapy for cervical intraepithelial neoplasia. Obstet Gynecol. 1985 Dec. 66(6):793-8. [Medline].
Johnson VW, Homesley HD. Comparison of cryosurgery and carbon dioxide laser ablation for treatment of cervical intraepithelial neoplasia. Colposc Gynecol Laser Surg. 1984. 173-180.
Berget A, Andreasson B, Bock JE. Laser and cryo surgery for cervical intraepithelial neoplasia. A randomized trial with longterm follow-up. Acta Obstet Gynecol Scand. 1991. 70(3):231-5. [Medline].
Sparks RA, Scheid D, Loemker V, et al. Association of cervical cryotherapy with inadequate follow-up colposcopy. J Fam Pract. 2002 Jun. 51(6):526-9. [Medline].
Schmidt C, Pretorius RG, Bonin M. Invasive cervical cancer following cryotherapy for cervical intraepithelial neoplasia or human papillomavirus infection. Obstet Gynecol. 1992 Nov. 80(5):797-800. [Medline].
Ben-Arie A, Kogan S, Fink A. Anaphylactoid reaction after cryotherapy of the cervix. Obstet Gynecol. 1999 May. 93(5 Pt 2):841. [Medline].
Wojciech R. The importance of cryosurgery in gynecological practice. Ginekol Pol. 2011 Aug. 82(8):618-22. [Medline].
Benedet JL, Miller DM, Nickerson KG. The results of cryosurgical treatment of cervical intraepithelial neoplasia at one, five, and ten years. Am J Obstet Gynecol. 1987 Aug. 157(2):268-73. [Medline].
Gordon HK, Duncan ID. Effective destruction of cervical intraepithelial neoplasia (CIN) 3 at 100 degrees C using the Semm cold coagulator: 14 years experience. Br J Obstet Gynaecol. 1991 Jan. 98(1):14-20. [Medline].
Bryson SC, Lenehan P, Lickrish GM. The treatment of grade 3 cervical intraepithelial neoplasia with cryotherapy: an 11-year experience. Am J Obstet Gynecol. 1985 Jan 15. 151(2):201-6. [Medline].
Ostergard DR. Cryosurgical treatment of cervical intraepithelial neoplasia. Obstet Gynecol. 1980 Aug. 56(2):231-3. [Medline].
Kleinberg MJ, Straughn JM, Stringer JS, Partridge EE. A cost-effectiveness analysis of management strategies for cervical intraepithelial neoplasia grades 2 and 3. Am J Obstet Gynecol. 2003 May. 188(5):1186-8. [Medline].
Mitchell MF, Tortolero-Luna G, Cook E. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Obstet Gynecol. 1998 Nov. 92(5):737-44. [Medline].
Nuovo J, Melnikow J, Willan AR. Treatment outcomes for squamous intraepithelial lesions. Int J Gynaecol Obstet. 2000 Jan. 68(1):25-33. [Medline].
Chirenje ZM, Rusakaniko S, Akino V, Mlingo M. A randomised clinical trial of loop electrosurgical excision procedure (LEEP) versus cryotherapy in the treatment of cervical intraepithelial neoplasia. J Obstet Gynaecol. 2001 Nov. 21(6):617-21. [Medline].
Skehan M, Soutter WP, Lim K. Reliability of colposcopy and directed punch biopsy. Br J Obstet Gynaecol. 1990 Sep. 97(9):811-6. [Medline].
Andersen ES, Thorup K, Larsen G. The results of cryosurgery for cervical intraepithelial neoplasia. Gynecol Oncol. 1988 May. 30(1):21-5. [Medline].
Barron BA, Richart RN. A statistical model of the natural history of cervical carcinoma based on a prospective study of 557 cases. J. Nat Cancer Inst. 1968. 41:1343-53.
Benedet JL, Miller DM, Nickerson KG. Results of conservative management of cervical intraepithelial neoplasia. Obstet Gynecol. 1992 Jan. 79(1):105-10. [Medline].
Benedet JL, Nickerson KG, Anderson GH. Cryotherapy in the treatment of cervical intraepithelial neoplasia. Obstet Gynecol. 1981 Dec. 58(6):725-9. [Medline].
Berget A, Andreasson B, Bock JE. Outpatient treatment of cervical intra-epithelial neoplasia. The CO2 laser versus cryotherapy, a randomized trial. Acta Obstet Gynecol Scand. 1987. 66(6):531-6. [Medline].
Crisp WE. Cryosurgical treatment of neoplasia of the uterine cervix. Obstet Gynecol. 1972 Apr. 39(4):495-9. [Medline].
Dunton CJ. Cryotherapy: evidence-based interventions and informed consent. J Fam Pract. 2000 Aug. 49(8):707-8. [Medline].
Hatch KD, Shingleton HM, Austin JM Jr. Cryosurgery of cervical intraepithelial neoplasia. Obstet Gynecol. 1981 Jun. 57(6):692-8. [Medline].
Kalliala I, Anttila A, Pukkala E, Nieminen P. Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia: retrospective cohort study. BMJ. 2005 Nov 19. 331(7526):1183-5. [Medline].
Kalliala I, Nieminen P, Dyba T, Pukkala E, Anttila A. Cancer free survival after CIN treatment: comparisons of treatment methods and histology. Gynecol Oncol. 2007 Apr. 105(1):228-33. [Medline].
Kaufman RH, Irwin JF. The cryosurgical therapy of cervical intraepithelial neoplasia. III. Continuing follow-up. Am J Obstet Gynecol. 1978 Jun 15. 131(4):381-8. [Medline].
Kirwan PH, Smith IR, Naftalin NJ. A study of cryosurgery and the CO2 laser in treatment of carcinoma in situ (CIN III) of the uterine cervix. Gynecol Oncol. 1985 Oct. 22(2):195-200. [Medline].
Koutsky LA, Holmes KK, Critchlow CW. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med. 1992 Oct 29. 327(18):1272-8. [Medline].
Kwikkel HJ, Helmerhorst TJ, Bezemer PD. Laser or cryotherapy for cervical intraepithelial neoplasia: a randomized study to compare efficacy and side effects. Gynecol Oncol. 1985 Sep. 22(1):23-31. [Medline].
Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006 Feb 11. 367(9509):489-98. [Medline].
Martin-Hirsch PL, Paraskevaidis E, Kitchener H. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2000. (2):CD001318. [Medline].
Montz FJ. Management of high-grade cervical intraepithelial neoplasia and low- grade squamous intraepithelial lesion and potential complications. Clin Obstet Gynecol. 2000 Jun. 43(2):394-409. [Medline].
Munoz N, Bosch FX, de Sanjose S. The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. Int J Cancer. 1992 Nov 11. 52(5):743-9. [Medline].
National Cancer Institute. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA. 1989 Aug 18. 262(7):931-4. [Medline].
Persad VL, Pierotic MA, Guijon FB. Management of cervical neoplasia: a 13-year experience with cryotherapy and laser. J Low Genit Tract Dis. 2001 Oct. 5(4):199-203. [Medline].
Pinto AP, Crum CP. Natural history of cervical neoplasia: defining progression and its consequence. Clin Obstet Gynecol. 2000 Jun. 43(2):352-62. [Medline].
Popkin DR, Scali V, Ahmed MN. Cryosurgery for the treatment of cervical intraepithelial neoplasia. Am J Obstet Gynecol. 1978 Mar 1. 130(5):551-4. [Medline].
Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002 Apr 24. 287(16):2114-9. [Medline].
Soutter WP, Sasieni P, Panoskaltsis T. Long-term risk of invasive cervical cancer after treatment of squamous cervical intraepithelial neoplasia. Int J Cancer. 2006 Apr 15. 118(8):2048-55. [Medline].
Townsend DE, Richart RM. Cryotherapy and carbon dioxide laser management of cervical intraepithelial neoplasia: a controlled comparison. Obstet Gynecol. 1983 Jan. 61(1):75-8. [Medline].
Wright TC Jr. HPV DNA testing for cervical cancer screening. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006 Nov. 95 Suppl 1:S239-46. [Medline].
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007 Oct. 197(4):346-55. [Medline].
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol. 2007 Oct. 197(4):340-5. [Medline].
Wright VC, Davies EM. The conservative management of cervical intraepithelial neoplasia: the use of cryosurgery and the carbon dioxide laser. Br J Obstet Gynaecol. 1981 Jun. 88(6):663-8. [Medline].