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!