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.

Managing Abnormal Pap Smears

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When you look at the American Society for Colposcopy and Cervical Pathology (ASCCP) guideline flowsheets, it can seem like an absolute maze, and remembering what to do when is challenging. The ASCCP guidelines are free to review in PDF form and are probably your most useful resource. They also have a very handy smartphone app to help for clinic or problems on the go, but obviously these aren’t available to you in an exam setting. The OBG Project has a ton of helpful articles on Pap smear management as well!

*** It’s also important to know we’re anticipating a change in these guidelines sometime in 2020 from the ASCCP, so stay tuned! ***

Today we’ll try to break it down so mentally, you can remember these algorithms for the exam. We find it helpful to evaluate abnormal Pap management systematically. 

Start by separating Pap cytology results into “low grade,” which are ASC-US and LSIL cytologies, and “high grade,” which are ASC-H and HSIL pathologies. Next, you need to remember the age cut offs: 21-24, 25-29, 30-64, and 65+. Finally, for those over age 30, HPV status will be the next important step in the algorithm.

Let’s break it down:

Normal Cytology. The only potential abnormal in this category 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.

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

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

    • If at 1 year, negative HPV and negative cytology, then cotesting in 3 years.

    • If at 1 year, positive HPV and/or abnormal cytology, then perform colposcopy.

      • This intuitively makes sense. If HPV is persistent, it is more likely to cause dysplasia that may be better evaluated with colposcopy. 

 Low Grade (ASC-US, LSIL)

  • In women aged 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 women aged 25-29:

    • LSIL go to colposcopy.

    • ASC-US in this group can have two options: Reflex HPV testing or Repeat Cytology in 12 months.

      • If reflex HPV is positive, management would proceed the same as LSIL with immediate colposcopy.

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

      • If reflex HPV is negative, then repeat cytology can be performed in 3 years, as HPV-negative ASC-US has very low risk of CIN2+. 

      • If HPV testing is not performed, repeat Pap in 12 months is recommended. A 2nd ASC-US result or worse would then warrant colposocopy.

  • In women aged 30-64, ideally HPV testing is always available! The management algorithm overall doesn’t change much.

    • 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, as you would for a 25-29 year old.

    • ASC-US, HPV unknown: repeat cytology, as you would for a 25-29 year old.

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

  • In women aged 65+, Pap smears are likely only continuing at this point if there have been previous abnormalities, or a lack of screening. 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 in our low grade, we didn’t talk excisional procedures at all; low grade lesions should generally proceed to colposcopy before considering exicsion. 

High Grade (ASC-H, HSIL).

Any ASC-H result merits colposcopy, regardless of HPV status!

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

    • If CIN2/3 Not Present: Repeat colpo and cytology q6 months for two years.

      • If no additional high grade abnormalities are noted, then the patient returns to normal screening.

      • If HSIL persists for 24 months, then excision is recommended.

    • If CIN2/3 Is Present: then management is challenging! The risk of excision is the risk of preterm delivery with future pregnancy.

      • With CKC, this can be up to 3.5x greater risk, and with LEEP this risk is approximately 2x greater. 

      • Thus, with CIN2/3, observation or treatment may be pursued after engaging in shared decision-making with your patient.

      • With CIN 2, observation with q6month cytology and colposcopy is preferred.

        • The likelihood of regression spontaneously in this population may be as high as 43%. 

        • If 2x cytology and colposcopy results are normal, the patient may have cotesting in 1 year.

          • If colposcopy or cytology persist as abnormal for 1 year, repeat biopsy is recommended, with treatment with excision recommended by 2 years if not resolved.

      • With CIN 3, treatment is preferred.

        • The likelihood of regression with true CIN3 is much lower, thus prompting recommendation for excision to prevent invasive cancer.

        • If strongly desired, observation may be pursued with the same algorithm as above.

  • In women aged 25-29, women aged 30-64, and women aged 65+ receiving screening, the management of ASC-H and HSIL is the same!

    • ASC-H goes to colposcopy.

    • HSIL results can proceed immediately to excision or perform colposcopy first.

      • Most women with HSIL will have HPV+ testing. Even with negative HPV results, an HSIL test carries a 5-year risk of CIN3 of near 30% and an invasive cancer risk of 7%. Thus, it’s prudent to proceed with further testing in this scenario. 

    • If CIN 2 or 3 is found on colposcopy as result of either of these, then excisional therapy is recommended. 

After colposcopy and biopsies…

We’ve detailed the management of this for 21-24 year olds above, so we’ll leave this group out, as their management varies. Very kindly, if you’ve made it to colposcopy for anyone aged 25 or older, the management is the same.

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

  • 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.

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

CIN 1 or Less on colposcopic biopsies

  • If the initial Pap was low grade (ASC-US or LSIL):

    • Repeat co-testing at 12 months.

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

      • If there is an abnormality, then colposcopy should be performed.

  • If the initial Pap was high grade (ASC-H or HSIL): 

    • recommend repeat cotesting at 12 and 24 months.

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

      • If there is an abnormality, then colposcopy should be performed.

      • If HSIL is noted, then an excision should be performed versus re-review of prior pathology.

What if the result is “AGC”? Atypical glandular cells can have two categories: “atypical endometrial cells” and then “other.”

  • If any “other” type of AGC, patient should be evaluated with colposcopy and consideration of endometrial sampling. 

    • In patients younger than 35, endometrial sampling may be considered based on risk factors for endometrial cancer. 

    • In patients older than 35, endometrial sampling should be done routinely.

  • If “Atypical endometrial cells,” then endometrial biopsy and endocervical curettage should be performed. Colposcopy should be deferred generally until the results of the endometrial testing is known, and performed if endometrial testing reveals no abnormality.

  • Excisional procedures should be considered if there is concern for neoplasia or adenocarcinoma in situ (AIS). 

    • If no CIN2+, AIS, or cancer, then repeat co-testing should be performed at 12 and 24 months.

What if I get an AIS result from an excisional procedure?

  • In this case, simple hysterectomy is the preferred management. 

  • If future fertility is desired, conservative management with excision may be pursued, though likely should be done alongside GYN oncology!