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 as 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
High grade CIN can progress to invasive SCC. A meta-analysis of 36 studies from 2018 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% (15/3160) developed into invasive cervical cancer.4 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).5 However, 5.1% of the 6.6% were found to have received inadequate follow-up treatment. The incidence of cancer was 19.7% among those who received inadequate follow-up compared to 2.0% 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.6 A population-based study found that of 3,557 patients 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 colposcopy-directed 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 have abnormal cells on their Pap smear. 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 colposcopy-directed biopsy results return with high grade CIN, all nonpregnant patients 25 and older should receive treatment.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. Excisional treatment (loop electrosurgical excision procedure (LEEP), cold knife conization, 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.
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
- 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
