Cervical cancer exists in two forms—squamous cell carcinoma (SCC) and adenocarcinoma.1,2 While SCC is preceded by cervical intraepithelial neoplasia (CIN) on the outer part of the cervix, adenocarcinoma’s premalignant state is called adenocarcinoma in situ (AIS), which begin in the column of gland cells that line the cervical canal. AIS of the cervix can be found on Pap smear or colposcopy. It is a precursor to cervical adenocarcinoma – a tumor that originates in the glands of the cervix.
AIS is less common that its squamous counterpart, CIN grade 3 (CIN 3). 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, the average incidence of AIS was 5.7 per 100,000 women.3 Overall, there were 470 cases of AIS compared to 6,587 cases of CIN 3.
AIS is associated with human papillomavirus (HPV) infection, with the same study reporting 99% of cases being positive for any HPV type.3 The most common HPV types associated with AIS were type 16 (57% of cases) and type 18 (38% of cases), both of which are high-risk HPV types that are covered by the HPV vaccines. Only 3.2% of those with AIS had received at least one dose of the HPV vaccine. When broken out into age groups, there was a significant reduction in AIS incidence among 21–24-year-olds between 2008-2015, most likely attributable to higher rates of vaccination (5.0 cases per 100,000 women from 2008-2009, 7.0 from 2010-2011, and 1.3 from 2012-2015).
AIS is a relatively slowly developing form of pre-cancer. A 1999 population-based study (n=149,178) estimated that it takes an average of 13 years for AIS to progress to invasive adenocarcinoma if left untreated.4
Diagnosis and Management
AIS 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 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.
American Society for Colposcopy and Cervical Pathology (ASCCP) and Society of Gynecologic Oncology clinical practice guidelines recommend follow-up colposcopy for all patients regardless of pregnancy status, if: AIS is suspected based on cytology results of the Pap smear, the patient is positive for HPV 16 or 18, or two consecutive Pap smears return inconclusive findings.1,5 Endocervical sampling is recommended during colposcopy for non-pregnant patients, and endometrial sampling is recommended for those over 35 or older or younger than 35 with increased risk for endometrial neoplasia, including those with abnormal uterine bleeding, obesity, or chronic anovulation.
If colposcopy results confirm a diagnosis of AIS, a diagnostic excisional procedure such as a cold knife conization (CKC) or loop electrosurgical excision procedure (LEEP) is recommended for all patients regardless of pregnancy status, followed by a hysterectomy, the timing of which depends on the patient’s desire to preserve fertility. A diagnostic excisional procedure is recommended even when a hysterectomy is planned in order to rule out invasive adenocarcinoma, which may require further or different treatment.
Excisional procedures should remove an intact specimen, preferably at least 10 mm, for accurate interpretation of margins.1,5 The size of the specimen can be increased to 18-20 mm in patients who are not concerned with maintaining fertility. ASCCP guidelines make no recommendation between CKC or LEEP for AIS excision but note that the specimen should be excised intact.1 CKC was traditionally thought to be better than LEEP for AIS excision due to concern that cautery thermal damage in LEEP could obscure the diagnosis. However, a systematic review and meta-analysis of 18 studies from 2017 (n=1559) found no difference between the rates of recurrence or residual disease (9.1% vs 11.0%) between the two modalities.6 Disease recurrence was seen in 7.0% (10/142) of cases following LEEP vs 5.6% (10/177) of cases following cone. Residual rate of LEEP was 9.1 (17/186) and 11% (39/350) for CKC. In this meta-analysis, LEEP was significantly associated with greater likelihood of positive margins compared to CKC (44% [267/607] vs 29% [274/952]), with a relative Risk of 1.55 and 95% Confidence Interval [1.34-1.80]). These findings led the Society of Gynecologic Oncology to recommend the use of CKC over LEEP for treatment of AIS.5
If negative margins are not achieved on the first excision, a repeat excisional procedure is recommended if deemed safe and feasible.1,5 Once negative margins are achieved or repeat excisional procedures are no longer feasible, a simple hysterectomy is recommended. If negative margins could not be achieved, a simple or modified radical hysterectomy is acceptable. Hysterectomy is recommended even when negative margins are achieved due to the risk of recurrent AIS and development of invasive cancer, even with negative margins. A 2001 meta-analysis synthesized findings from 14 studies (n=157) and found that 54% of patients with positive margins had residual disease, but even among those who achieved negative margins, 26% of patients still had residual disease.7 They also found that among patients treated only with an excisional procedure and follow-up testing in order to maintain fertility (n=297), 9% suffered disease recurrence.
For patients who desire to preserve fertility, if the excisional procedure successfully removes the dysplastic tissue, guidelines recommend surveillance with Pap smears, HPV co-testing, and endocervical sampling every six months for three years, then annually until a simple hysterectomy can be performed.1,5 If co-testing and endocervical sampling are consistently negative during the first five years, foregoing a hysterectomy and instead continuing to test every three years indefinitely is considered acceptable. The risks and benefits of fertility-preserving treatment should be discussed with the patient.
Following hysterectomy, guidelines recommend continued long-term monitoring and testing, starting with HPV or co-testing six months after treatment and continuing annually. If any tests return positive, colposcopy and appropriate biopsies are recommended. Once three consecutive tests have returned negative results, testing can continue every three years for at least 25 years, even past the age of 65 as long as the patient is in reasonably good health.
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
- Plaxe SC, Saltzstein SL. Estimation of the duration of the preclinical phase of cervical adenocarcinoma suggests that there is ample opportunity for screening. Gynecol Oncol. Oct 1999;75(1):55-61. doi:10.1006/gyno.1999.5524
- Teoh D, Musa F, Salani R, Huh W, Jimenez E. Diagnosis and Management of Adenocarcinoma in Situ: A Society of Gynecologic Oncology Evidence-Based Review and Recommendations. Obstet Gynecol. Apr 2020;135(4):869-878. doi:10.1097/AOG.0000000000003761
- Jiang Y, Chen C, Li L. Comparison of Cold-Knife Conization versus Loop Electrosurgical Excision for Cervical Adenocarcinoma In Situ (ACIS): A Systematic Review and Meta-Analysis. PLoS One. 2017;12(1):e0170587. doi:10.1371/journal.pone.0170587
- Krivak TC, Rose GS, McBroom JW, Carlson JW, Winter WE, 3rd, Kost ER. Cervical adenocarcinoma in situ: a systematic review of therapeutic options and predictors of persistent or recurrent disease. Obstet Gynecol Surv. Sep 2001;56(9):567-75. doi:10.1097/00006254-200109000-00023
