Delayed CIN2 treatment does not increase cancer risk 

1. In this target trial emulation, delayed treatment of cervical intraepithelial neoplasia grade 2 (CIN 2) was associated with a substantially lower likelihood of potentially unnecessary excision than immediate treatment.

2. Delayed treatment was associated with similar risks of cervical cancer and progression to CIN 3+ compared with immediate treatment.

Evidence Rating Level: 2 (Good)

Study Rundown: Cervical abnormalities are classified as cervical intraepithelial neoplasia (CIN) grades 1-3 according to the extent of epithelial involvement. While CIN 3 is generally treated promptly because of its higher risk of progression to cancer, management of CIN 2 remains controversial. CIN 2 diagnoses are less reproducible, many lesions regress spontaneously, and only a small proportion progress to invasive disease, particularly among younger women. This study compared immediate treatment of CIN 2 (within 6 months of diagnosis) with delayed treatment (after 6 months, if at all) to assess their effects on treatment outcomes and subsequent risk of cervical cancer and CIN 3+. After three years, immediate treatment produced only a small increase in appropriate excisions, defined as procedures that identified CIN 3+ or followed a biopsy demonstrating CIN 3. However, this modest benefit came at the cost of a substantially higher number of potentially unnecessary excisions. Delayed treatment substantially reduced unnecessary procedures while yielding comparable rates of cervical cancer and CIN 3+ to immediate treatment. Subgroup analyses further showed that baseline cervical cancer risk strongly influenced outcomes: women at higher risk were considerably more likely to develop CIN 3+ than lower-risk women. Although immediate treatment was associated with a slight reduction in CIN 3+ risk across risk groups, this advantage was accompanied by a greater likelihood of overtreatment, particularly among lower-risk patients. Despite limitations, including its non-randomized design, the rarity of cancer outcomes, and relatively short follow-up, the findings suggest that carefully selected patients with CIN 2 may safely defer treatment, reducing unnecessary excisions without compromising cancer-related outcomes.

Click to read this study in AIM

Relevant Reading: Untreated cervical intraepithelial neoplasia grade 2 and subsequent risk of cervical cancer: population based cohort study

In-Depth [retrospective cohort]: This target trial emulation compared the benefits, harms, and risks of cancer and CIN 3+ among women with CIN 2 managed with immediate versus delayed treatment. Eligible participants had a first biopsy-confirmed CIN 2 diagnosis between January 1, 2017, and October 9, 2023, with no concurrent CIN 3, prior CIN 2+, hysterectomy, or destructive treatment suggestive of previous CIN 2+. Women who underwent hysterectomy or destructive treatment immediately following diagnosis were excluded. Excision outcomes were classified as appropriate (CIN 3+ detected on excision or excision following a CIN 3+ biopsy), intermediate (CIN 2 on excision or <CIN 2 with concurrent high-grade cytology), potentially unnecessary (<CIN 2 on excision without high-grade cytology), or no excision. Cancer and CIN 3+ outcomes were identified through pathology records during follow-up. The study included 12,012 women: 6,074 (50.6%) received immediate treatment and 5,938 (49.4%) underwent delayed treatment. Women in the immediate-treatment group were older (median age 38 vs. 29 years) and more likely to be HPV 16/18 positive (12.4% vs. 7.0%). Within three years, appropriate excision outcomes occurred in 7.6% of women receiving immediate treatment and 6.9% of those receiving delayed treatment. However, potentially unnecessary excisions were substantially more common with immediate treatment (36.2% vs. 7.8%). Three-year cancer risks were similar between groups: 0.39% with immediate treatment and 0.43% with delayed treatment. Likewise, CIN 3+ risks were comparable at 8.85% and 10.31%, respectively. Sensitivity analyses and subgroup analyses restricted to women aged 25-49 years produced similar findings. Women at high risk (HPV 16/18 positivity or high-grade cytology) had substantially higher risks of CIN 3+ than lower-risk women regardless of treatment strategy. Although immediate treatment was associated with a modestly lower CIN 3+ risk across risk groups, it markedly increased the likelihood of potentially unnecessary excision, particularly among lower-risk women (45.0% vs. 9.3%). Overall, delayed treatment was associated with similar cancer risk while substantially reducing unnecessary excisions.

Image: PD

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