Updates in Pap Screening Part II: High Grade Lesions

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Here’s the RoshReview Question of the Week:

A 45-year-old woman presents to your office for follow-up. She has a history of postpartum tubal ligation. She had a colposcopy for high-grade squamous intraepithelial neoplasia. The procedure was performed at the office and revealed one white lesion after acetic acid application. Biopsy results reveal cervical intraepithelial neoplasia grade 1. The borders of this lesion were not entirely identified. Which of the following is the best next step in management?

We’re back this week with Part II on Pap smears! Let’s cover high grade lesions.

First, the easy part: any ASC-H result merits colposcopy, regardless of HPV status! The down-the-line management will vary by age. 

  • In patients aged 21-24, ASC-H and HSIL get treated the same - colposcopy.

  • In patients 25 and older, ASC-H goes to colposcopy, but HSIL can proceed immediately to excision, or perform colposcopy first prior to excision.

  • Why is there an option to go straight to excision?

    • The overall 5 year CIN2+ risk for HSIL above age 25 is 77%, and for CIN3+ its 49%. Given those high risks, it is acceptable to proceed directly to excision without colposcopy.

    • Most women with HSIL will have HPV+ testing. 

      • But even with negative HPV results, an HSIL test carries a 5-year risk of CIN3 of 25% and an invasive cancer risk of 7%. Thus, it’s still acceptable to proceed straight to excision in this scenario. 

        • One way to think about this is the number needed to treat, which is super impressive. For HSIL HPV+, the NNT is 1.7 – that is, 1.7 excisional procedures for every CIN3+ treated – a very low rate of overtreatment!

          • For HSIL HPV-, the NNT is still very low at 2.8.

So we do a colpo and get biopsies… now what?

Your biopsy result will be a histology result – so CIN1, CIN2, CIN3, AIS, or invasive cancer. Let’s review the non-invasive management strategies for post-colposcopic biopsy.

CIN1 - this depends on the preceding Pap cytology, and the patient’s age:

  • HSIL cytology: many strategies are acceptable:

    • Observation, which entails colposcopy and cytology in patients under 25, or HPV-based testing with colposcopy in patients 25 and older, at one year.

    • An excisional procedure (not recommended in patients under 25)

    • Or a pathology review to determine if there is a discrepancy in the previous interpretation of cytology or histology.  

    • With observation being most typical in younger patients:

      • Colposcopy and cytology/HPV testing should occur again in one year. 

        • If these are negative, age specific retesting should happen again in an additional year, followed by HPV-based testing every 3 years for at least 25 years.

        • If there’s any abnormality, then manage that using the ASCCP guideline for the specific abnormality; though specifically, if HSIL again, excision is recommended.

          • Unless the patient is still under age 25, then observation can be continued for up to 2 years prior to recommendation for excision. 

  • ASC-H cytology: observation is the most typical strategy:

    • Perform cytology if under 25, or HPV-based testing if > 25, in one year.

      • If negative, HPV-based testing can resume in 3 years from that.

      • If abnormal - you manage according to the ASCCP guideline.

        • Specifically, if progresses to HSIL – excision is recommended if over age 25.

        • If persistent ASC-H, can repeat again in 1 year, but excision is recommended if over age 25 and ASC-H persists for 2 years. 

        • For those under age 25, HSIL or ASC-H should persist for two years before excision is recommended.

  • Lower grade cytology (ASC-US or LSIL):

    • Repeat co-testing at 12 months and 24 months.

      • If normal, then can have repeat testing in 3 years before resuming normal age-appropriate intervals.

      • If there is an abnormality in this 2 year window, then management should be performed according to cytology – though if there’s progression to HSIL, colposcopy and/or excision is recommended using the same guidelines as we stated for ASC-H.

CIN 2 or 3 on colposcopic biopsy - this will warrant an excisional procedure, typically.

  • For CIN2, observation is considered acceptable in patients under 25, or those over 25 if there are concerns about future pregnancy that, for the patient, outweigh their concerns about cervical cancer.

    • If that’s the case, colposcopy and HPV-based testing should occur at 6 and 12 months. 

      • If two consecutive evaluations have less than ASC-H cytology and less than CIN2 histology, then testing can space to annually for 3 total years.

      • If the tests are abnormal, q6 month testing can continue for up to 2 years.

      • If CIN3 develops at any point, or the abnormalities persist for more than 2 years, excision becomes recommended.

  • For CIN3, observation is not advised – these should proceed to excision.

  • If you proceed with excision, the management is based on your excisional margins:

    • If margins are negative, then cotesting at 12 and 24 months is subsequently recommended, with repeat colposcopy needed for any abnormal result.

    • If margins are positive, then you have three choices:

      • Repeat cytology with endocervical curettage q4-6 months.

      • Repeat excision, if feasible.

      • Hysterectomy.

        • Notably, hysterectomy should only be considered if repeat excision is not feasible, or if high grade abnormalities are persistent after attempted repeat excision. 

Adenocarcinoma In Situ (AIS)

  • If AIS is identified, excision is needed to rule out invasive cancer.

    • If margins are positive, reexcision is recommended to try to achieve negative margins.

    • If margins are negative, hysterectomy is generally preferred after the excision.

      • The excision is mandatory! You can’t proceed straight to hysterectomy – because if invasive cervical cancer is advanced enough, then hysterectomy may not be the recommended treatment.

    • If margins are negative, and the patient desires fertility, then reevaluation with HPV-based testing every 6 months for 3 years, then annually for two years, is acceptable. 

      • Hysterectomy is recommended following childbearing, though! 

Other Uncommon Pap Results

Unsatisfactory Cytology

  • Super frustrating! Your Pap didn’t have enough to evaluate!

  • Recommendations:

    • Follow your HPV result if you got it!

      • If HPV positive (especially 16/18), colposcopy is warranted.

      • If HPV is negative in someone 25 years or older, or if no HPV result, or unknown HPV result, then repeat the Pap in 2-4 months.

        • If the Pap is again unsatisfactory, colposcopy is recommended – good idea to take a look and figure out what you’re missing if two in a row are not satisfactory.

Negative for Intraepithelial Lesion, but Absent transformation zone or endocervical cells

  • This is also usually an insufficient Pap that didn’t sample that transformation area from glandular to squamous cell. This is the area where most HPV-associated disease is located, so effectively this is an insufficient Pap.

    • If Age 21-24, routine screening can continue.

    • If age 25+, HPV screening can triage:

      • If negative, routine screening can continue.

      • If unknown, repeat cytology in 3 years is acceptable, or get HPV testing (preferred).

      • If positive, then you follow the HPV-positive management guideline – which as a reminder for 16/18 is colposcopy, and for other types of HPV in this case would be to repeat the HPV-based test in one year.

Atypical Glandular Cells (AGC) and Atypical Endometrial Cells (AEC)

  • For these pathologies, a number of tests are recommended:

    • If atypical glandular cells or other subcategories, 

      • Colposcopy with endocervical sampling is recommended. 

      • Endometrial sampling should also be performed if the patient is 35 or older, or under 35 with risk factors such as AUB, chronic anovulation, or obesity.

    • If atypical endometrial cells

      • Endometrial and endocervical sampling are recommended, and colposcopy can also be performed – 

        • and generally colposcopy should be performed, as if the other samplings are negative, colposcopy would then be warranted at that point. 

  • Management would then proceed on the basis of these findings.

    • If no CIN2+, AIS, or cancer, then cotesting is recommended at 1 and 2 years, and can be spaced to every 3 years after that if remains negative.

    • If CIN2+ is identified, or if the initial cytology was concerning for neoplasia, then excisional procedure is typically recommended.

Updates in Pap Screening and Management, Part I

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Here’s the RoshReview Question of the Week:

A 26-year-old woman presents to the office to review her Pap smear results. Her Pap smear showed atypical squamous cells of undetermined significance with positive human papillomavirus testing. Her previous Pap results are unknown. What is the best next step in management, given this result?

We talked about Pap screening last in July 2019 and managing an abnormal Pap in January 2020.

Shortly after, the ASCCP published its updated screening and management guidelines!

And they updated their awesome Pap management app – if you have $10 to spare, you’ll definitely get value out of it in residency and likely beyond.

What’s new with Pap screening?

  • Short answer – not a lot, but there is controversy!

    • In July 2020, the American Cancer Society published new recommended screening guidelines for individuals at average risk, with three major changes:

      • Recommendation of primary HPV testing every 5 years as the screening strategy, rather than co-testing.

      • Beginning Pap screening at age 25, rather than age 21.

      • Co-testing and/or cytology are acceptable per old guidelines, but ultimately the guidelines are meant to be transitory until facility/area has accessible primary HPV testing.

    • The USPSTF guidelines overall remain unchanged (for now!), but do include the option for primary HPV testing. Highlights:

      • Screening with cytology alone starting at age 21, q3 years.

      • Co-testing acceptable at age 25, and can space with cotesting to q5 years, HPV primary screening q5 years, or cytology alone q3 years. 

      • Ending screening after benign hysterectomy with no prior high risk dysplasia, or 25+ years after high-grade dysplasia, presuming adequate negative screening previously.

    • How does ASCCP feel?

      • July 2021 Statement

      • They note that evidence does exist that primary HPV screening is safe and effective as a cancer screening strategy, and in increasingly-immunized populations appears to be more effective than cytology-based screening.

        • One referenced study noted 5-fold higher detection rates in patients with CIN2+ based on HPV screening versus cytology beginning at age 21. 

      • However, uptake has been slow and implementation has been challenging, and thus they do endorse the USPSTF guidelines that suggest greater flexibility. 

        • They offer a more qualified statement of support for the ACS  guidelines in locations that can equitably and effectively implement primary HPV screening. 

      • They also recognize that HPV self-collection may help increase access and availability to patients, and hope to identify more evidence of comparative efficacy to provider-collected specimens. 

Comparison of USPSTF 2018 and ACS 2020 screening guidelines (ASCCP statement).

Managing Abnormal Pap Smears

  • In our last episode, we gave a framework that first separated Paps into “high grade” and “low grade,” age, and HPV status. We’ll apply that again and re-review the management.

  • Ultimately, the guidelines are framed around the question of what CIN3+ risk exists:

    • The first question: is the immediate risk greater than/equal to 4%?

      • If yes → how high is that risk? 

        • If 60+%, then expedited treatment is preferred

        • If 4-24%, then colposcopy is preferred

        • If in between, either is acceptable.

      • If immediate risk of CIN3+ is less than 4%:

        • What is the risk of CIN3+ within 5 years?

          • If > 0.55%, then return in 1 year for screening.

          • If between 0.15 and 0.54%, then return in 3 years.

          • If < 0.15%, then return in 5 years.

      • “Equal management for equal risk” is the underlying principle.

  • ASCCP also adjusts risk given the clinical situation, such as a routine screen; a patient who is rarely screened; management of results during post-colposcopy surveillance; or follow ups after excision/treatment. 

ASCCP

So let’s go through possible results on Pap smears at this point. 

We’ll presume that you are either performing co-testing, or HPV-primary screening with reflex to cytology.

We’ll also presume that the patients we mention here are undergoing “routine screening” – meaning that they’ve had prior screening, or it is their first screen in their lifetime if they are under age 30. 

Finally, given the additional nuances with screening, we strongly recommend reviewing management steps using the ASCCP app for guidance.

We will just review the first steps in management plans; follow ups get very much into the weeds and are individualized – a huge plus for patients, but much more challenging for memorization!

HPV Primary Screening Management

  • HPV 16/18+ – colposcopy (and obtain reflex cytology).

  • HPV other + – reflex cytology, then follow the appropriate cytology guidelines! 

Cytology/Cotesting Guidelines

Normal Cytology. 

The only potential abnormal in this category for someone 25 years or older is HPV positive. The risk of CIN 2 or greater in this population is approximately 2-6%. It increases if HPV is persistently positive over time, or is type 16/18.

  • If typed and result is HPV-16 or HPV-18, colposcopy is recommended.

  • If untyped or not 16/18, repeat cotesting in 1 year.

 Low Grade Cytology (ASC-US, LSIL)

  • Age 21-24, ASC-US and LSIL get treated the same, with the recommendation for repeat cytology in 12 months. 

    • This is because the clearance of HPV-caused ASC-US and LSIL is overall high in this group, and colposcopy may lead to overly aggressive management. 

    • As long as there’s no progression to high-grade, there is no indication for colposcopy.

  • In patients aged 25-29 and 30-64, the management of LSIL and ASC-US are similar.

    • Age 30-64, ideally HPV testing is always available by cotesting or primary screening!

    • The USPSTF guidelines in 25-29 year olds though do call for cytology q3 years as the primary screening strategy.

      • LSIL or ASC-US, HPV negative: overall low risk of malignant transformation.

        • Thus, with LSIL, can repeat cotesting in 1 year.

        • With ASCUS, repeat in 3 years.

      • LSIL, HPV unknown: get colposcopy given unknown HPV status.

      • ASC-US, HPV unknown: repeat cytology in 3 years if 25-29, and 1 year if 30-64

        • Ideally both would have co-testing on the repeat evaluation!

      • LSIL or ASC-US, HPV positive: colposcopy should be performed.

      • The 5-year CIN3+ risk for both HPV+ ASCUS and LSIL are very similar, approximately 7%.

  • Finally in patients aged 65+, Pap smears are likely only continuing at this point if there have been previous abnormalities, or a lack of screening. Thus, ASC-US or LSIL with negative HPV should be treated as abnormal, and thus merit repeat cytology in 1 year. All other abnormalities (i.e., HPV positive) in this age group should receive colposcopy!

Note that we didn’t talk excisional procedures at all; low grade lesions (ASC-US, LSIL) should generally proceed to colposcopy before considering excision. 

Part II will encompass high grade lesions, so stay tuned!