Updates in Pap Screening Part II: High Grade Lesions

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?

• Colposcopy and human papillomavirus-based testing in 1 year

• Cryotherapy

• Laser ablation therapy

• Loop electrosurgical excision procedure

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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.

Cervical Cancer

Today we welcome Erin Lips, MD to the podcast. She’s a current 2nd year GYN Oncology fellow at Brown University / Women and Infants of RI!

Cervical cancer is almost a completely preventable disease, yet it represents the 4th most common female malignancy worldwide. The burden of cancer and cancer-related deaths is disproportionately weighted toward populations without access to adequate screening or adequate treatments: 

• 90% of cancer deaths occur in low and middle income countries:

  • Mortality in these countries is 18x higher than in developed countries.

  • In 2012, in high income countries, cervical CA was 11th most common female cancer and 9th most common cause of cancer mortality 

  • In LMICs by comparison, it was the 2nd most common cancer and the 3rd most common cause of cancer death.

  • In Africa and Latin America, cervical cancer is the leading cause of cancer specific mortality in women. 

• SEER estimates 13,800 new cases in the US for the year 2020 and 4290 deaths. 

  • In the US, median age of diagnosis is 47-50 years, and half are diagnosed under 35. 

  • Within the US, racial, socioeconomic, and geographic disparities exist in cervical cancer.

    • Black and Hispanic patients have the highest rates.

    • There is also geographic differences in incidence between states.

    • Multifactorial, but overall due to poor access and barriers to routine care.  

• In high income countries, incidence and mortality have decreased by more than half over last 30 years due to formalized screening programs, involving Pap and HPV testing.

Cervical Cancer Risk Factors:

• Chronic high risk HPV infection causes almost all cases of cervical cancer!

• Early age of sexual debut

• Higher number of sexual partners or high risk sexual partner

• Immunosuppression (organ transplant or HIV)

• h/o STIs

• h/o HPV-related vulvar or vaginal dysplasia

• Non-attendance for screening

• Tobacco is a major risk factor, doubling risk of dysplasia and cancer even after adjusting for HPV status. 

  • Smoking cessation associated with 2-fold risk reduction!

Primary Prevention: the HPV vaccine

• 90% efficacy in preventing HPV 16 and 18 (the 2 types most highly associated with high grade dysplasia). In 2018. a nine-valent vaccine was introduced that covered additional high-risk serotypes.

• Australia was the first country to establish an HPV vaccine program in 2007

  • >70% vaccine coverage in boys and girls aged 12-13 yrs. 

  • 38% reduction in high grade dysplasia in young women within 3 years!

• In countries where at least 50% of females are vaccinated, HPV 16 and 18 infections decreased by almost 70%.

  • In the USA, HPV coverage by 2014 was <50% in girls under age 17

Secondary Prevention: Papanicolau smear 

• Primary HPV testing will likely take over, but we are still holding on to our cotesting strategy and most institutions can’t let go of cytology yet!

• Check out the Pap smear episode for more: Episode 1; Episode 2

Clinical presentation:

• Early stages: 

  • Often asymptomatic 

  • Post-coital or abnormal vaginal bleeding, malodorous discharge

  • Diagnosed after routine screening or pelvic exam

• Advanced disease: limb edema, flank pain, sciatica

• Fistula: passage of urine or stool through the vagina suggests invasion into bladder or rectum c/w vesicovaginal or rectovaginal fistula 

Diagnosis:

• Based on histopathological assessment of a cervical biopsy

  • 80% Squamous, 20% Adenocarcinoma

• Usually when cervical cancer is diagnosed in the US, next step is to stage:

  • A cold-knife cone excisional procedure will often be performed first - with smaller tumors, this is to ensure disease is not more advanced. This may be the point of first diagnosis after identifying dysplasia on Pap/colposcopy.

  • If cancer is diagnosed, in the US:

    • PET/CT scan

    • proceed to the OR for an exam under anesthesia (EUA), cystoscopy, and proctoscopy. 

    • Assess for parametrial invasion on EUA. 

    • Depending on the stage and plan, patient may or may not warrant lymph node dissection. Radiation oncology could be consulted to examine as well for radiation planning.

Staging:

This is a popular topic to be tested on CREOGs and board exams! However, it’s important to know that there is a new FIGO staging system we are now using.

• Traditionally, staged clinically based on exam and use of limited imaging because this cancer is so prevalent in LMICs, and PET scan or surgical staging is not always accessible in these areas. 

  • For instance: in the old staging system, you would choose the stage based on exam. If the patient then ended up having pathologically proven lymph nodes, you might still say “this is a stage IB with positive para-aortic lymph nodes” instead of upstaging to at stage III (like you do in endometrial cancer).

• In 2018, FIGO introduced a new staging system which does incorporate radiologic and lymph node positivity into the staging system, and now resembles endometrial cancer staging that way. You can see them side-by-side below:

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FIGO 2018 Staging

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FIGO 2009 Staging

First Line therapies 

• Rule of thumb is that the ideal approach to these patients is to have the intention of doing either curative surgery or curative radiation, but not both. 

• Surgery and radiation are equally effective but morbidity of doing both is significant and increases risk for lifelong complications. SInce these patients are often young and many have young children, this is a very important piece to consider.

SURGERY:

• Cutoff for surgical candidacy is early. 

• Candidates are patients with a small tumor confined to the cervix (<4cm in size), with no spread to parametria, lymph nodes, or anything else. 

  • IA1 and no lymphovascular space invasion (LVSI): simple hysterectomy, 

  • IA1 with LVSI and IA2: Radical hysterectomy, pelvic lymph nodes

  • IB1, IB2, IIA1 (i.e., tumor <4cm or confined to upper vagina with no parametrial involvement): Radical hysterectomy, pelvic lymph nodes

  • IB3 (AKA tumor >4cm) and beyond: Chemosensitizing radiation. 

  • Distant metastases: Just chemotherapy (no radiation).

• During surgery, if any lymph nodes are enlarged, those should be removed and sent immediately to path → if positive, abort the hysterectomy, sample PALN, and plan for chemoradiation instead.

• After hysterectomy, assess for SEDLIS or PETERS criteria to determine whether patient needs post-op radiation

  • SEDLIS: HIR criteria (tumor size, depth of invasion, and LVSI)

  • PETERS: High risk criteria (positive margins, parametria, or lymph nodes)

What to do about ovaries?

• Usually leave in situ unless patient is post-menopausal

  • Risk of mets to ovaries is very low, and you’re usually only doing surgery if you think it’s very early stage anyway. 

LACC trial 2018: 

• Widely disseminated change of “standard of care” to abdominal rad hyst (not MIS)

• Large Phase III randomized clinical trial comparing outcomes of MIS vs open radical hysterectomy.

• Trial terminated early due to higher recurrence rates and more deaths in the MIS group

  • At 4.5 years, 96.5% of pts who had open surgery had no recurrences, but only 86.0% who had MIS had no recurrences 

  • At 3 years: 99.0% of pts who had open surgery were still alive, while only 93.8% who had MIS were still alive (HR 6.0)

Fertility Sparing Surgical Options:

• IA1 no LVSI: Cone with neg margins

• IA1 with LVSI, IA2: Cone and LND OR Radical trachelectomy and LND

• IB1, select IB2: Radical trachelectomy and LND (traditional cutoff is <2cm tumor size for trachelectomy)

RADIATION:

• If pre-operatively it is known the patient is not a candidate for surgery, want to keep the uterus and cervix in situ to allow for the optimal radiation treatment to be administered.

• PET/CT will usually help delineate spread to lymph nodes. However, if no PALNs lit up, can go to OR to sample. This helps with mapping of RT fields.

• Standard RT is co-administered with chemotherapy, which we call “chemoradiation” or “chemosensitizing radiation.” 

  • Weekly small doses of Cisplatin during course of RT, 5-6 cycles

  • RT is combination of EBRT (whole pelvic) and internal brachytherapy

    • EBRT is 45Gy, divided into 25 fractions. 

      • This means daily, 5 days a week, for 5 weeks

    • Brachytherapy is another 40 Gy, divided up into fractions. 

      • administered via one of several methods: tandem and ovoids, tandem and ring, tandem and sleeve, etc. 

      • LDR (Low dose rate) vs HDR (high dose rate)

      • Interstitial - for cases of obliterated anatomy- radiation source loaded into needles, which are placed into the tumor and remain in place for prescribed period of time for treatment.

  • Very important to stay on schedule, as timing of RT is crucial for optimal cell kill and efficacy. 

CHEMO for METASTATIC DISEASE:

• Typically Cisplatin/Paclitaxel/Bevacizumab

Cervical cancer in pregnancy: 

• Though breast cancer is most common cancer diagnosed in pregnancy, cervix is the most common GYN malignancy in pregnancy - might actually diagnose earlier because of increased care, so usually stage I.

• If gestation is still pre-viable and the patient desires termination, then usually a gravid hysterectomy or radical hysterectomy and lymph node dissection is performed.

• If >24 weeks or if the patient desires continuation of pregnancy, then patient has the option for neoadjuvant chemotherapy until delivery. Deliver via C-section and then can perform a cesarean radical hysterectomy if appropriate mode of treatment OR postpartum RT if non-operative management is indicated.

  • Vaginal delivery is contraindicated in known diagnosis of cervical cancer!

Managing Abnormal Pap Smears

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! 

Cervical Cancer Screening and Prevention

Today we discuss one of the basic screening tools of the OB-GYN office: the Pap smear. Named for Georgios (George) Papanikolau, credited for its creation around 1923, it is a test that has singlehandedly changed the face of cancer screening. With its widespread use, the incidence of cervical cancer in the US has dropped from 14.8 / 100k women in 1975, to 6.7 / 100k women in 2011. The converse also demonstrates the importance of this routine test: 50% of those diagnosed with cervical cancer have never had Pap screening, and 10% have not had screening within the preceding 5 years.

We also now know and can test for the presence of oncogenic strains of human papilloma virus, or HPV. Types 16 and 18 account for over 70% of cervical cancer worldwide, and 12 other strains account for the remaining majority of cases. Ongoing trials are looking at whether HPV screening may ultimately supplant cytology as the preferred 1st test, but HPV screening has added another excellent tool to help OB-GYNs discuss risk and prevent cancer in their patients.

Follow along with ACOG PB 168!

So what are the screening guidelines?
In the immunocompetent patient, they are as follows:

• < 21 years: Screening should not be performed, even in the presence of behavior-related risk factors.

  • Only 0.1% of cervical cancer cases occur before age 20.

  • Women younger than 21 with no immunocompromising conditions generally clear HPV infection between 8-24 months after exposure. 

  • This population should have discussion about safe sex practices to avoid exposure to STIs including HPV, and strong consideration for HPV vaccination.

• 21 - 29 years: Screening should be performed using cytology alone every 3 years.

  • Annual screening is discouraged in this group, as it exposes patients to a much more significant number of unnecessary procedures for minimal improvement in outcomes. 

  • HPV co-testing is not recommended in this group; however, HPV reflex testing in the event of an ASC-US Pap smear may be considered to determine need for colposcopy.

• 30 - 65 years: Screening should be performed with cytology alone every 3 years, or cytology with HPV co-testing every 5 years. 

  • In this population, with a negative cytology and negative HPV test, the risk of developing CIN 2 or 3 in the next 4-6 years is extremely low, based on large database studies (approximately 0.08% risk over 5 years). The risk is higher, but also quite low, with cytology alone (0.26% over 5 years). This is the rationale for the screening interval being extended.

  • RCTs have demonstrated in this population that cotesting has a number of distinct advantages:

    • Cotesting has a higher detection rate of high-grade dysplasia in first round of screening, and decreases risk of CIN3 or cancer in subsequent screening.

    • Cotesting likely has a better pickup rate for cervical adenocarcinomas (vs. squamous cell) than cytology alone.

• > 65 years, or post-benign hysterectomy: Screening should be discontinued, provided that:

  • There has been no history of CIN2, CIN3, or AIS in the preceding 20 years, and:

  • There are adequate negative prior results:

    • 3 consecutive negative cytology results within last 10 years, or

    • 2 consecutive negative cotest results within the last 10 years, with the most recent test performed within the past 5 years.

  • Women in this age group do get cervical cancer; however, the majority of these cases occur in women who are not screened, or in those who are underscreened.

  • The changes of menopause may also cause false positive Pap tests in this group, leading to likely unnecessary additional and invasive testing and procedures.

Behavioral risks, such as cigarette smoking, new or multiple sexual partners, or early sexual debut, may increase risk of HPV acquisition or persistence, but do not alter screening recommendations.

However, two particular conditions do merit changes to screening:

• In utero diethylstilbestrol (DES) exposure:

• DES was an estrogen that was manufactured and prescribed in the US during the 1930s until 1971. It was thought that the medication helped with premature birth or history of miscarriage, though by the 1950s it had been demonstrated to be ineffective.

• ACOG states that annual cytology is reasonable in women exposed to DES in utero, as cohort studies have demonstrated a much higher incidence of clear cell adenocarcinoma of the vagina in women born to mothers who took DES or similar medications. DES has also been associated with other health problems in both men and women.

• You can find a list of DES and related medications online at the CDC, and there is an interactive tool for patients to use to determine if they may be at risk.

• HIV or immunocompromising conditions:

  • Women infected with HIV or with other immunocompromising conditions are less readily able to clear HPV infections. Thus, the recommendations in this population differ:

• Screening should begin within 1 year of sexual activity, and no later than age 21.

• In women less than 30, If the first screen is negative, it should be repeated in 12 months. If three consecutive annual screens are normal, screening may be spaced to regular intervals (i.e., q3 year cytology). HPV cotesting is not recommended.

• In women older than 30, three annual tests should be normal, before moving to cytology alone or co-testing. Screening intervals should be every 3 years in this population, regardless of the method chosen. 

• Screening should continue for the lifetime of the woman, and not stop at age 65.

What about HPV vaccination?

HPV vaccination has been an incredible advance for primary prevention of cancer. Currently available include a bivalent vaccine, a quadrivalent vaccine, and a 9-valent vaccine. All of these cover HPV types 16 and 18. The 9-valent vaccine covers up to 50% additional cases of cervical cancer versus the bivalent vaccine. The 9-valent vaccine should be given to boys and girls ages 9-26. 

• For those receiving their first dose before age 15, only two doses given 6 months apart are needed. 

• For those receiving it after age 15, 3 doses given at 0, 1-2, and 6 months apart are recommended. 

HPV vaccination is not recommended during pregnancy, but also hCG screening is not necessary prior to initiating the dose. If pregnancy interrupts the schedule, it should be resumed postpartum without need for redosing. Studies are ongoing to determine the safety of HPV vaccination during pregnancy. 

In June 2019, the CDC’s advisory council on immunization practices (ACIP) updated its HPV vaccination recommendations, to extend recommendation for vaccination for all persons up through age 45, after the FDA approved this in October 2018. While this hasn’t made it into official ACOG practice guidance yet, it’s safe to say that this is forthcoming!

Further Reading from the OBG Project:

USPSTF Releases Final Cervical Cancer Screening Guidelines – Including ‘HPV Only’ Option
Screening for Cervical Cancer in the Woman at Average Risk
What is the Most Efficient Method for Cervical Cancer Screening?
Cervical Cytology and HPV Screening in the HIV Positive Woman
Cervical Cancer Screening Strategies and Cost-Effectiveness: Which is the Best?