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Cervical cancer screening

Normal colposcopic findings following LBC prediction of LSIL or HSIL

Clinical question

GUIDELINE UPDATES - This guideline was last updated 8/15/2018

UPCOMING GUIDELINES - This guideline was updated and comes into practice on 7/1/2022Download PDF

Evidence

Systematic reviews were conducted to answer the following questions:

  • For women with a positive oncogenic HPV test result (not in treatment follow-up) with negative or LSIL cytology and normal colposcopy, what is the safety and effectiveness of 12-month follow-up testing with a HPV test alone, compared with co-testing?
  • For women with a positive oncogenic HPV test result (not in treatment follow-up) with negative or LSIL cytology and normal colposcopy, which factors predict the presence of high-grade cervical neoplastic disease (CIN2, CIN3, cervical cancer, adenocarcinoma in situ (AIS) or cervical cancer mortality)?
  • For women with a positive oncogenic HPV test result and pHSIL/HSIL referral cytology but pLSIL/LSIL or less after cytologic review, and colposcopy is normal (negative), what is the safety and effectiveness of conservative management compared with excision of the TZ?
  • For women with a positive oncogenic HPV test result and pHSIL/HSIL referral cytology, confirmed pHSIL/HSIL after cytologic review, and colposcopy is normal (negative), what is the safety and effectiveness of cytological and colposcopic follow-up at 3–6 months, compared with excision of the TZ?

Outcomes for women with normal colposcopic findings following referral cytology prediction of LSIL

No randomised or pseudorandomised controlled trials were identified that compared HPV testing with co-testing (HPV and LBC) at 12-month follow-up for women with a positive oncogenic HPV (any type) test result, a cytology report of negative or LSIL and normal colposcopy, and which reported high grade-disease outcomes.

No studies were found that reported the risk of high-grade disease associated with follow-up cytology or HPV status.

Four studies reported the risks associated with referral cytology and/or HPV status for women reported as pLSIL/LSIL and normal (negative) colposcopic findings: two prospective cohort studies[1][2] (level II evidence) and two retrospective cohort studies[3][4] (level III-2 evidence) were identified. Follow-up ranged from 1 to 3 years. All four studies were considered at high risk of bias; none of the studies were specifically designed to answer the PICO question, so it was not clear as to whether women with different baseline cytology results or HPV status were similar in terms of important confounders such as smoking status. Furthermore, important study design aspects such as the potential blinded reading of subsequent colposcopies and histopathology (with respect to the baseline test status) were not described.

Two of the studies[3][4] examined the risks of cervical intraepithelial neoplasia (CIN) grade 3 or higher (CIN3+) associated with different baseline cytology results, and one study[2] examined the risks of CIN3+ associated with baseline HPV-positive ASC-US and LSIL (regardless of HPV status).Three studies[3][4][1] examined the risks of CIN2+ disease associated with different baseline cytology results, of which one study[1] examined the risks of CIN2+ associated with different baseline HPV status. Two studies[1][4] reported the risks associated with baseline cytology results in women who were HPV positive.

One of these studies[3] did not report HPV status. The remaining studies provided the following evidence:

  • In a cohort of women with a positive oncogenic HPV (any type) test result with normal colposcopy after referral cytology reported as ‘borderline dyskaryosis’ or ‘mild dyskaryosis’, rates of later detection of CIN3+ (median follow-up 27 months) were 3.5% and 2.1%, respectively.[4] This cohort may not be representative of women with a LBC prediction of pLSIL/LSIL identified after primary HPV testing in the renewed NCSP; the HPV test in this UK study used a higher cut-off than recommended, and the ‘borderline dyskaryosis’ group could have included women with pHSIL.
  • In a cohort of women with a referral cytology report of LSIL and normal colposcopy, the rate of CIN3+ after 1 year follow-up was 4.0%.[2] This cohort included women who tested HPV positive and women who tested HPV negative.
  • In a cohort of women with a positive oncogenic HPV (any type) test result with normal colposcopy after referral cytology reported as ‘borderline dyskaryosis’ or ‘mild dyskaryosis’, rates of later detection of CIN2+ (median follow-up 2.6 years) were 6.2% and 12.9%, respectively.[1]

The systematic reviews and their findings are described in detail in the Technical report.

As no studies were found that reported the risks of high-grade disease associated with follow-up cytology or HPV status, there was no directly relevant evidence on which to base an evidence-based recommendation. Detection of HPV, especially persistent HPV 16/18, is associated with an increased risk of high grade cervical lesions, and the HPV test is more sensitive than cytology (see Chapter 2. The rationale for primary HPV screening).

Outcomes for women with normal colposcopy following referral cytology prediction of HSIL

Systematic literature searches did not identify any studies directly addressing the management of women with HSIL cytology and a normal (negative) colposcopy. The search strategies and inclusion and exclusion criteria used are described in detail in the Technical report.

In the absence of any direct evidence from the systematic review, a general review of the literature was performed on the management of women with cytological prediction of pHSIL/HSIL and normal (negative) colposcopy was undertaken to inform relevant consensus-based recommendations.

No studies were found that reported outcomes for women followed up after referral cytology prediction of pHSIL/HSIL and normal colposcopic findings, and which reported the results of cytopathology review.

One cross-sectional cohort study[5] reported outcomes for women participating in conventional cytology (Pap test) screening with no history of a cytological abnormality, who had a cytological prediction of HSIL between 2000 and 2007. Of 340 women who underwent colposcopy, 17 had normal colposcopic findings. Biopsy was performed in nine of these women, including endocervical curettage in at least four women.[5] Ages of the women and results of cytopathology review (if performed) were not reported.

Of the 17 women with normal colposcopy (HPV status unknown), two (11.8%) were diagnosed with cervical adenocarcinoma and another two (11.8%) with AIS.[5] Findings for the other 13 women were not reported. No other cases of cervical adenocarcinoma or cervical adenocarcinoma in situ were identified among the 331 women with HSIL who underwent biopsy.[5] The degree to which these findings can be generalised to women in the renewed NCSP is limited, because HPV status and the findings of cytopathology review are not available.

Another retrospective cohort study[6] reported outcomes for a subgroup of 59 women (mean age 26.8 years) who underwent a loop electrosurgical excision procedure (LEEP) after a cytological prediction of HSIL and a colposcopically directed target biopsy finding of no abnormality detected (n = 34) or CIN1 (n = 25). On excisional biopsy, histologically confirmed CIN3 was diagnosed in 14 (41%) women with normal target biopsy and 16 (64%) women with CIN1 on target biopsy. The degree to which these findings can be generalised to women in the renewed NCSP is limited, because HPV status was unknown and the study did not report whether HSIL was reported at initial referral cytology or on cytopathology review. However, this study did demonstrate the failure of colposcopically directed biopsy to detect the high-grade lesion in 41% of cases, as high grade abnormality was subsequently confirmed in an excision biopsy.[6]

A summary of the literature considered can be found in the Technical report.

Overall, this body of evidence is insufficient to enable accurate prediction of risk in women with normal colposcopic findings despite a LBC report of HSIL.

In Australia, it is recommended that discordant findings between referral cytology and colposcopy warrant review of the cytology prior to further management decisions.

Current evidence does suggest that, in women with a normal colposcopy and HSIL on cytopathology review, the risk of CIN3 and/or invasive cervical cancer is high enough to warrant diagnostic excision of the TZ. In women with a normal colposcopy and pHSIL on cytopathology review, the risk of CIN3 and/or invasive cervical cancer is high enough to warrant diagnostic excision of the transformation zone in most cases, but in some situations a short period of observation may be appropriate (see Chapter 9. Management of histologically confirmed low-grade squamous abnormalities).

Recommendations

Flowchart 8.1. Normal colposcopy after LBC prediction of pLSIL/LSIL

Flowchart 8.2. Normal colposcopy after LBC prediction of possible HSIL


Flowchart 8.3. Normal colposcopy after LBC prediction of HSIL

Consensus-based recommendation

REC8.1: Normal colposcopy following LBC prediction of negative or pLSIL/LSIL
For women with a positive oncogenic HPV (any type) test result, a LBC report of negative or pLSIL/LSIL, and normal colposcopy, the HPV test should be repeated in 12 months:

  • If HPV is not detected at 12 months, the woman should return to routine 5-yearly HPV screening.
  • If the woman has a positive oncogenic HPV (not 16/18) test result at 12 months and a LBC report of negative or pLSIL/LSIL, the HPV test should be repeated in another 12 months.
    • If the woman has a positive oncogenic HPV ( any type) test at the 24 month HPV test, she should be referred directly for colposcopic assessment, which will be informed by the result of the reflex LBC.
  • If the woman has a positive oncogenic HPV (not 16/18) test result at 12 months and a LBC prediction of pHSIL/HSIL or any glandular abnormality, she should be referred for colposcopic assessment at the earliest opportunity, ideally within 8 weeks.
  • If the woman has a positive oncogenic HPV (16/18) test result at 12 months, she should be referred directly for colposcopic assessment at the earliest opportunity, ideally within 8 weeks, and the reflex LBC result will inform the colposcopy.
Practice point
REC8.2: Normal colposcopy following LBC prediction of HSIL: cytopathology review
Cytopathology review is recommended to confirm HSIL before proceeding to excisional treatment for women with a normal colposcopy after a positive oncogenic HPV (any type) test result and an initial LBC prediction of pHSIL/HSIL.
Practice point
REC8.3: Normal colposcopy following LBC prediction of HSIL: exclude VAIN
When colposcopic impression is discordant with a referral LBC prediction of HSIL, colposcopic examination of the vagina is indicated to exclude a vaginal intraepithelial neoplasia before diagnostic excisional treatment.
Consensus-based recommendation
REC8.4: Normal colposcopy following LBC prediction of HSIL: diagnostic excision of TZ
For women who have a positive oncogenic HPV (any type) test result, normal colposcopy, and a LBC prediction of HSIL on cytopathology review, diagnostic excision of the TZ should be performed.
Consensus-based recommendation
REC8.5: Normal colposcopy following LBC prediction of pHSIL: consider diagnostic excision of TZ
For women who have a positive oncogenic HPV (any type) test result, normal colposcopy, and a LBC prediction of pHSIL on cytopathology review, diagnostic excision of the TZ should be considered, though observation is an option.
Practice point

REC8.6: Normal colposcopy following LBC prediction of pHSIL: diagnostic excision or observation
Some women with a positive oncogenic HPV test result for whom diagnostic excision of the TZ is recommended due to a confirmed LBC prediction of pHSIL on cytopathology review, despite normal colposcopic findings, may be concerned about the possibility of having unnecessary treatment. The colposcopist may have similar concerns.
Women who opt to defer treatment, particularly younger women with concerns about fertility, can be offered observation:

  • A HPV test and colposcopy should be repeated at 6 months, and a diagnostic excisional procedure should be reconsidered based on the test results (HPV and reflex LBC, if performed) obtained at that time.
  • If oncogenic HPV is not detected, and the colposcopic impression is unchanged, the HPV test should be repeated in 12 months and if oncogenic HPV is not detected, the woman can return to routine 5-yearly screening.
Consensus-based recommendation
REC8.7: Downgrading of discordant results
For women who have a positive oncogenic HPV (any type) test result, normal colposcopy, and a subsequent LBC report of pLSIL/LSIL or less on cytopathology review, management should be according to the reviewed cytological report (i.e. repeat HPV test in 12 months).
Practice point
REC8.8: Colposcopist should manage discordant results
Women with discordant colposcopy and LBC results should have their management supervised by the colposcopist until both the colposcopist and the woman are satisfied with the proposed management plan.

Benefits and harms

If these recommendations, including review of cytology, are followed for women who have normal colposcopy in the presence of referral LBC predicting low-grade or high-grade grade lesions, they will benefit by avoiding over-investigation or unnecessary treatment.

See Chapter 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed National Cervical Screening Program (NCSP).

Health system implications of these recommendations

Clinical practice

It is not anticipated that there will be a significant change to clinical practice, apart from the addition of HPV testing to the recommended surveillance.

Resourcing

No material changes to the costs are anticipated.

Author(s):

References

  1. Cruickshank ME, Cotton SC, Sharp L, Smart L, Walker LG, Little J, et al. Management of women with low grade cytology: how reassuring is a normal colposcopy examination? BJOG 2015 Feb;122(3):380-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24947656.
  2. Lukic A, Sbenaglia G, Carico E, DI Properzio M, Giarnieri E, Frega A, et al. Prediction of clinical outcome using p16INK4a immunocytochemical expression in low-grade squamous intraepithelial lesions and high-risk HPV-positive atypical squamous cells of undetermined significance in patients with and without colposcopic evident cervical disease. Exp Ther Med 2011 Sep;2(5):853-858 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22977588.
  3. Smith MC, Keech SE, Perryman K, Soutter WP. A long-term study of women with normal colposcopy after referral with low-grade cytological abnormalities. BJOG 2006 Nov;113(11):1321-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17059394.
  4. Kelly RS, Walker P, Kitchener H, Moss SM. Incidence of cervical intraepithelial neoplasia grade 2 or worse in colposcopy-negative/human papillomavirus-positive women with low-grade cytological abnormalities. BJOG 2012 Jan;119(1):20-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21624034.
  5. Lerma Puertas E, Otal Salaverri C, Ríos Martín JJ, Sánchez Gómez A, Jiménez Caraballo A, González-Cámpora R. Human papillomavirus detection by PCR assay in a large series of high-grade squamous intraepithelial lesions with cytohistological correlation and follow-up. Acta Cytol 2011;55(5):426-32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21986169.
  6. Lanneau GS, Skaggs V, Moore K, Stowell S, Zuna R, Gold MA. A LEEP cervical conization is rarely indicated for a two-step discrepancy. J Low Genit Tract Dis 2007 Jul;11(3):134-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17596756.

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