Cervical cancer exists in two forms—squamous cell carcinoma (SCC) and adenocarcinoma.1,2 SCC is preceded by cervical intraepithelial neoplasia (CIN) on the outer part of the cervix. Precancerous cervical lesions can be identified through colposcopy-directed biopsies and are graded based on severity of dysplasia, on a scale of 1-3, with 1 being the lowest dysplasia and 3 being the highest. CIN 2 and 3 are considered high grade while CIN 1 is considered low grade.
Although high grade CIN is more common than adenocarcinoma in situ (AIS), it is still relatively uncommon. A population-based study taking place over five states in the United States (US) and including over one million participants found that from 2008-2015, there were 6,587 cases of CIN 3 compared to 470 cases of AIS.3 On the other hand, high grade CIN is less common than CIN1.4
High grade CIN can progress to invasive SCC. A meta-analysis of data from 1973-2016 examining rates of regression, persistence, and progression of CIN 2 (n=3,160) found that approximately 50% (819/1470) of cases regressed within two years, 32% (334/1257) persisted, 18% (282/1445) progressed to CIN 3 or worse, and 0.5% developed into invasive cervical cancer.5 These values are more favorable among women younger than 30, with 60% (638/1069) regression, 23% (226/938) persistence, and 11% (163/1033) progression.
A retrospective cohort study of women diagnosed with CIN 3 between 1955 and 1976 (n=1,063) found that 6.6% of cases (approximately 53 cases per 100,000 person-years) progressed to cancer of the cervix or vagina (median follow-up 27.1 years).6 However, 26% (274/1063) received inadequate follow-up treatment. Among women who received inadequate treatment, 19.7% (54/274) had developed cancer by 30 years of follow-up, compared to 1.3% (4/299) among those who received adequate treatment.
High grade CIN is associated with human papillomavirus (HPV) infection. A 2013 retrospective cohort study (n=2,019) found that 91% of patients with high grade CIN were also HPV positive.7 A population-based study found that of 3,557 patients age 18-39 with CIN 3, 98% were positive for any HPV type, 81% were positive for just a single HPV type, and 17% were positive for multiple types.3
Diagnosis and Management
CIN is diagnosed from a colposcopic biopsy.1,2 A colposcopy is the examination of the cervix, vagina, and vulva with a colposcope, an instrument that provides light and magnification. Colposcopy is recommended in patients who are suspected of being high risk for development of cervical lesions, such as those who are HPV positive, or based on Pap smear results indicative of abnormal cells. Colposcopies can help verify the extent and type of pre-cancer or cancerous lesions present and help to guide biopsies of areas where abnormal cells are present. Once the sites of the abnormal cells have been identified, the physician can perform a biopsy by removing a small sample of abnormal tissue to be sent to a pathology laboratory for further analysis. This analysis can help classify dysplasia as normal, CIN grade 1-3, or invasive carcinoma.
American Society for Colposcopy and Cervical Pathology (ASCCP) clinical practice guidelines recommend that if colposcopic biopsy results return with high grade CIN, all nonpregnant patients 25 and older should be counseled on treatment.1 Patients with CIN2 lesions with concerns about effects of treatment of future pregnancy can be observed with serial colposcopy and HPV-testing.1 Treatment aims to destroy or remove pre-cancerous areas of the cervix. For nonpregnant patients of all ages with CIN 3, they warn that observation alone is unacceptable, and treatment is warranted. Excisional treatment (loop electrosurgical excision procedure [LEEP], cold knife conization [CKC], or laser cone biopsy) is preferred, although ablation (including cryotherapy, laser ablation, and thermoablation) is acceptable under certain circumstances (lesion does not extend into the canal and covers less than 75% of the surface area of the ectocervix). Hysterectomy is unacceptable as a sole treatment.
For patients with CIN 2, observation is acceptable for those who are concerned about the effects of treatment on future pregnancy outcomes.1 For patients younger than 25 with CIN 2, observation is recommended, although treatment is also acceptable. Observation includes colposcopy and HPV testing at six and 12 months. If the lesion persists, surveillance at 6-month intervals should be continued for an additional year. If the lesion persists after two years of observation, a diagnostic excisional procedure is recommended. Conversely, if two consecutive evaluations indicate disease regression, HPV testing can be done annually. If test results continue to return negative for three years, HPV testing can be moved to three-year intervals for at least 25 years.
Treatment is not recommended during pregnancy. For pregnant patients, surveillance colposcopy and diagnostic cytology or HPV testing is recommended every 12-24 weeks. Deferring colposcopy to after delivery is acceptable. Postpartum colposcopy is recommended no earlier than four weeks after delivery. If a lesion is detected, an excisional treatment procedure or full diagnostic evaluation is acceptable. If no lesion is detected, a full diagnostic evaluation is recommended, but treatment is not recommended.
LEEP
A LEEP is one of the diagnostic excisional procedures for the removal of high grade cervical dysplasia.1,2 A thin, loop-shaped wire attached to an electrosurgical generator is used to pass around and under the transformation zone, excising the abnormal portion of the cervix using thermal energy. The electrical current allows the loop tool to both cut and coagulate at the same time, and its use is followed by a ball electrode to complete the coagulation. The removed specimen is sent to a pathology laboratory for further analysis to help determine the extent of the lesion. In this way, LEEP is both a treatment and a diagnostic procedure.
The procedure is often done at the doctor’s office and is brief, usually taking less than 30 minutes.2 It begins very similarly to a colposcopy, in which the patient is placed in lithotomy position, a speculum is placed, and a colposcope may be used to better visualize the cervix. Local anesthetic and a vasoconstrictive solution are administered to minimize discomfort and bleeding. Application of local anesthetic is often associated with an initial burning sensation that fades as the anesthetic begins to work.
Cold Knife Conization
CKC is another diagnostic excisional procedure for the removal of high-grade cervical dysplasia.1,2 Using a scalpel, a circumferential incision is made to excise the portion of both the outer and inner cervix containing abnormal tissue. Local application of vasoconstrictive solution helps minimize blood loss during the procedure.8 If there is bleeding, the surgeon may use sutures or electrocautery for hemostasis. Additionally, a narrow piece rolled gauze dipped in ferric subsulfate solution known as Monsel’s solution or paste may be packed into the biopsy site to reduce perioperative blood loss and cramping. The removed specimen is sent to a pathology laboratory for further analysis.
CKC requires either regional or general anesthesia and is done in an operating room. A colposcopic exam may be done immediately preceding the procedure to help the surgeon decide on the size and shape of the cone biopsy. Patients usually go home on the same day of the procedure or the next morning.
Post-Procedure
Following a CKC or a LEEP, patients may experience some lower abdominal and pelvic pain and may have bloody vaginal discharge for 7-10 days followed by yellowish discharge for up to a month after a cervical excisional procedure.2 Fever, foul-smelling discharge, heavy vaginal bleeding (soaking through >1 pad in an hour or passing clots) are not expected and should prompt evaluation.
Patients should avoid intercourse, placing anything in the vagina, or immersing in water for 2-4 weeks. Patients are typically scheduled for a follow-up visit a few weeks after the procedure to ensure appropriate healing and to review histopathological results. The final pathology report is used to determine appropriate follow-up.
Other Procedures
Another less used cervical diagnostic procedure is laser conization, although it is not widely available due to the need for specific and expensive medical equipment.1,2 Laser conization is similar to CKC with the use of a highly focused laser to make a cone-shaped excision instead of a scalpel. Retractors are then used to manipulate the cone to allow deeper incision and complete the excision.
Ablative procedures such as cryotherapy, thermoablation, and laser ablation can also be used to treat cervical lesions, although their use is only appropriate under certain circumstances.1,2 ASCCP guidelines advise that ablative procedures are only an option if lesions do not extend into the canal and cover less than 75% of the surface area of the ectocervix.1
Cryotherapy involves destroying the abnormal tissue by freezing, using a metal probe that administers compressed refrigerant gas.1 Cryotherapy has the benefit of being able to be performed at all levels of the health system and by a wide variety of providers, including doctors, nurses, and midwives. It does not require the use of anesthesia.
Thermoablation destroys the abnormal tissue using heat at a minimum of 100°C for 20-30 seconds at a time.9 Similarly to cryotherapy, thermoablation has the advantage of being able to be performed in a variety of locations and by a variety of providers. Additionally, the equipment needed is simple, lightweight, and portable compared to the relatively bulky and heavy canisters of refrigerant gas needed for cryotherapy.
Laser ablation involves using a laser beam to destroy the abnormal tissue.1 However, laser treatments are not widely available due to the need for specific and expensive medical equipment.
Ablative treatment is less effective than excisional treatment. A 2022 systematic review with meta-analysis of 92 studies found that recurrence of high-grade lesions was 11.2% for laser ablation and 9.6% for cryotherapy compared to 5.3% for LEEP and 3.5% for CKC.10 However, ablative treatment is also more affordable and accessible, and in some parts of the world, may be the only treatment option available.2
Procedure Preference
The choice of treatment depends on the location, extent, and severity of the lesion, the cost, and resources available, and the expertise of the healthcare provider. It's unclear if LEEP or CKC is more efficacious, as studies have produced conflicting results, but both are considered appropriate and safe treatments for high-grade precancerous cervical lesions.1
Practically, both LEEP and CKC procedures are technically straightforward, although they both require a highly trained gynecologist and appropriate facilities. A LEEP can be done in the office setting while a CKC requires an operating room and general anesthesia and therefore more planning. The electric current used for a LEEP may cause thermal damage to tissue margins, which may compromise histological assessment of the dysplasia.2,11 LEEP also tend to have lower incidence of complications than CKC.
A 2022 systematic review with meta-analysis of 71 studies (n=19,240) indicated that CKC (n=3,865) had lower rates of any treatment failure (defined as abnormal histology or cytology) compared to LEEP (n=5644) (6.6% vs 10.2%, Odds Ratio [OR] 0.63, 95% Confidence Interval [CI] [0.50-0.81]).10 However, there was less of a difference in rates of high-grade treatment failure (CKC 3.5% vs LEEP 5.3%). While both procedures increased the risk of preterm birth in a subsequent gestation, LEEP (n=19,593) was associated with a milder increase in risk than CKC (n=2,598) (incidence 10.5% vs 16.3%, OR 1.65).
A 2016 meta-analysis of 20 studies (n=5,709) found no significant difference between rates of recurrence, positive margins, residual disease, and cervical stenosis when comparing LEEP and CKC procedures.12 However, CKC removed a larger volume of tissue on average, and therefore may be preferred for cases of more extensive disease.
Another 2016 meta-analysis of 167 studies found that recurrence rates were lower 12 months after CKC than LEEP (1.4% vs 5.3%; 228/17,616 vs 391/8269).13 Complications occurred more often after CKC than LEEP, including minor bleeding (2.5% vs 0.4%), major bleeding (0.9% vs 0.2%), and premature delivery (3.4% vs 1.9%). None of these differences were statistically significant. Nonetheless, the authors noted that evidence was very low quality, limiting the ability to compare studies directly.
References:
- Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis. Apr 2020;24(2):102-131. doi:10.1097/LGT.0000000000000525
- WHO Guidelines Approved by the Guidelines Review Committee. Comprehensive Cervical Cancer Control: A Guide to Essential Practice. World Health Organization; Copyright © World Health Organization 2014.; 2014.
- Cleveland AA, Gargano JW, Park IU, et al. Cervical adenocarcinoma in situ: Human papillomavirus types and incidence trends in five states, 2008-2015. Int J Cancer. Feb 1 2020;146(3):810-818. doi:10.1002/ijc.32340
- Benard VB, Castle PE, Jenison SA, et al. Population-Based Incidence Rates of Cervical Intraepithelial Neoplasia in the Human Papillomavirus Vaccine Era. JAMA Oncol. Jun 1 2017;3(6):833-837. doi:10.1001/jamaoncol.2016.3609
- Tainio K, Athanasiou A, Tikkinen KAO, et al. Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis. BMJ. Feb 27 2018;360:k499. doi:10.1136/bmj.k499
- McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. May 2008;9(5):425-34. doi:10.1016/S1470-2045(08)70103-7
- Katki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 3+ and cervical cancer among women with HPV-positive and HPV-negative high-grade Pap results. J Low Genit Tract Dis. Apr 2013;17(5 Suppl 1):S50-5. doi:10.1097/LGT.0b013e3182854282
- Martin-Hirsch PL, Kitchener H. Interventions for preventing blood loss during the treatment of cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2000;(2):CD001421. doi:10.1002/14651858.CD001421
- WHO Guidelines Approved by the Guidelines Review Committee. WHO guidelines for the use of thermal ablation for cervical pre-cancer lesions. World Health Organization© World Health Organization 2019.; 2019.
- Athanasiou A, Veroniki AA, Efthimiou O, et al. Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis. Lancet Oncol. Aug 2022;23(8):1097-1108. doi:10.1016/S1470-2045(22)00334-5
- Wang XI, Huang F, Zhang S. Loop Electrosurgical Excision Procedure vs. Cold Knife Cone in Treatment of Cervical Intraepithelial Neoplasia: Review of 447 Cases. Ann Clin Lab Sci. Nov 2017;47(6):663-667.
- Jiang YM, Chen CX, Li L. Meta-analysis of cold-knife conization versus loop electrosurgical excision procedure for cervical intraepithelial neoplasia. Onco Targets Ther. 2016;9:3907-15. doi:10.2147/OTT.S108832
- Santesso N, Mustafa RA, Wiercioch W, et al. Systematic reviews and meta-analyses of benefits and harms of cryotherapy, LEEP, and cold knife conization to treat cervical intraepithelial neoplasia. Int J Gynaecol Obstet. Mar 2016;132(3):266-71. doi:10.1016/j.ijgo.2015.07.026
