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.

BRCA for the OB/GYN

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Here’s the RoshReview Question of the Week:

A 37-year-old woman presents to your office for health care maintenance. She reports that her maternal cousin was diagnosed with advanced-stage breast cancer at the age of 35. Genetic testing was performed, and her relative tested positive for breast cancer susceptibility gene 1. Which of the following is associated with this condition?

Check your answer at the links above!

Follow along with ACOG PB 182

What are we talking about, exactly?

  • Certain germline mutations predispose patients to heritably higher risk of breast and ovarian cancer

  • In particular, you have probably heard of BRCA1 and BRCA2

    • Others you may or may not have heard of include: 

      • Lynch syndrome genes (MSH2, MLH1, MSH6, PMS2), 

      • PTEN, 

      • TP53 (Li-Fraumeni syndrome), and 

      • STK11 (Peutz-Jehger Syndrome), just to name a few!

  • However, we’ll spend today’s podcast focusing on BRCA specifically.

What exactly are the BRCA risks?

  • Estimates of carrier frequency range from 1/300 to 1/800 for either genes.

  • BRCA1 is found on Chr 17

  • BRCA2 is found on Chr 13

  • Both are tumor suppressor genes that function in DNA repair process.

    • The inherited mutation is non-functional or defective allele in some way, but patients usually have a second, functional copy.

    • If the second allele becomes nonfunctional due to somatic mutation, cancer can develop – 

      • Two-hit hypothesis of tumor suppressor genes.

  • Risk of breast cancer in person without BRCA by age 70: ~12% (1/8)

    • Risk in patient by age 70 with BRCA1/2: 45-85%

      • Also more likely to be “triple negative” breast cancer for hormone and HER2 receptor

  • Risk of ovarian / fallopian tube / primary peritoneal cancer:

    • BRCA1: 39-46% by age 70

    • BRCA2: 10-27% by age 70

    • Both associated with high grade, serous or endometrioid phenotype

  • BRCA1/2 also associated with prostate, pancreatic, uterine cancers as well as melanoma

Who should I send for genetic counseling?

  • If your patient has a new cancer, genetics recommended:

    • New ovarian epithelial cancers (including fallopian tube or primary peritoneal)

    • Breast cancer at age 45 or less;

    • Breast cancer, and have a close relative with breast cancer at age 50 or less, or a relative with ovarian cancers at any age; or with limited/unknown family history

    • Breast cancer with two or more relatives affected by breast cancer at any age

    • Breast cancer and two or more close relatives with pancreatic cancer or aggressive prostate cancer

    • Two breast cancer primaries, with the first diagnosed under age 50

    • Triple negative breast cancer at under age 60

    • Breast cancer and Ashkenazi Jewish ancestry at any age

    • Pnacreatic cancer and have 2+ close relatives with breast, ovarian, pancreatic, or aggressive prostate cancer

  • If your patient does not have a new cancer, genetics recommended based on the history of:

    • A first-degree or several close relatives that meet the above criteria

    • A close relative carrying a known BRCA1 or BRCA2 mutation

    • A close relative with male breast cancer

  • If you’re not sure but the history seems high risk, a referral to cancer genetics to discuss is always worthwhile – the histories above should definitely prompt your referral though! 

  • And as you’re taking family history - it bears special mention that both maternal and paternal histories are important!

    • Especially given association with male breast CA, prostate CA, melanoma – be sure to get both sides!

  • Genetics may recommend performing BRCA mutation testing, which can have a variety of possible outcomes:

    • True positive: pathogenic BRCA variant identified

    • True negative: no pathogenic variant identified in someone who has known BRCA variant in family

    • Uninformative negative: no pathogenic variant identified, but uninformative because of:

      • a) other family members not tested

      • b) family carries a variant, but it was not detected because of test limitations

      • c) family carries a high risk mutation in another gene

      • d) there is no high risk mutation

    • Variant of uncertain significance (VUS): abnormality detected in BRCA gene, but unknown whether the variant is associated with increased cancer risk

  • Patients should be informed about the possible outcomes before undergoing genetic testing so they are aware of potential limitations and importance of family testing.

    • Unintended consequences of testing can include anxiety/stress and family dynamic issues regarding need for disclosure.

  • Multigene panel testing also exists to look for mutations beyond BRCA and can be suggested by genetic counselors if indicated. 

How do I counsel and care for the patient with BRCA1 or BRCA2 mutation?

Screening

  • Breast:  broken out by age:

    • Age 25-29: clinical breast exam every 6-12 months and annual screen (preferably by MRI with contrast)

      • Avoid ionizing radiation at this younger age as this may increase risk of cancer

    • Age 30+: Annual breast mammography and MRI, generally alternating every 6 months, as well as continuing CBE q6-12 months

  • Ovarian:

    • TVUS and CA-125 monitoring routinely is not recommended

      • However, could be considered for short term surveillance around age 30-35 until patient undergoes risk-reducing BSO.

Medical

  • Breast:

    • Tamoxifen and raloxifene can be considered (SERMs)

      • Can be considered in patients age 35 or older and not planning on pregnancy, or on prophylactic mastectomy

      • Tamoxifen is used in pre-menopausal and post-menopausal women, and may reduce breast cancer risk by 62% in BRCA2 carriers, but has not been found to reduce risk of cancer in BRCA1 carriers (likely due to higher triple-negative rates in this pop)

      • Raloxifene has been found to be effective in reducing invasive breast cancer in postmenopausal women at increased risk, though not evaluated specifically in BRCA mutation carriers

        • Tamoxifen may have a more significant risk reduction based on one head-to-head trial

      • Recall side effects of SERMs: vasomotor symptoms, vaginal symptoms (dryness, itching, dyspareunia), and increased risk of VTE!

      • Tamoxifen: also associated with concern for endometrial hyperplasia. While generally preferred in pre-menopausal patients, consider this in patietns with risk factors for endometrial hyperplasia!

      • Raloxifene: other significant side effect is leg cramps! Does not act on endometrium so may be considered in patients with significant risk factors. 

    • Aromatase inhibitors

      • Two trials have shown reduction in breast cancer risk in at-risk postmenopausal individuals; could be considered as alternative if contraindication to SERM

      • Not used in premenopausal women because it would end up actually stimulating ovarian function (i.e., ovulation induction)

  • Ovarian:

    • OCPs are reasonable to use for cancer prophylaxis until BSO:

      • Reduction of ovarian cancer risk estimated at 33-80% for BRCA1, 58-63% for BRCA2

      • No increased risk of breast cancer in those with BRCA mutations using OCPs

Surgical

  • Breast: bilateral mastectomy

    • Can be offered to any patient with BRCA mutation; reduces risk by 85-100%, depending on procedure type

    • However, this is big surgery - should be referred to breast surgeon to discuss risks of surgery in short term (surgical issues like hematomas, flap issues, infection) and long-term (pain, numbness, swelling, breast hardnes)

      • 70+% of patients report satisfaction with choice to undergo mastectomy at a follow up of 14.5 years

  • Ovarian: bilateral salpingoophorectomy

    • Most effective option for risk reduction; should be considered by age 35-40 for BRCA1 patients, 40-45 for BRCA2 patients

      • This can be individualized based on patient’s family history and plans for childbearing

      • Also worth discussion of fertility-preservation with oocyte or embryo cryoperservation

    • Salpingectomy alone is not recommended at this time; however, the PB notes that salpingectomy followed by future oophorectomy could be reasonable to consider for some patients desiring this.

    • How to perform a risk-reducing BSO:

      • Perform a survey on entry - visualize peritoneal surfaces for any obvious disease and perform pelvic washings

        • Inspect diaphragm, liver, omentum, bowel, paracolic gutters, appendix, ovaries, falliopian tubes, uterus, bladder serosa, and cul-de-sac; biopsy any abnormal areas

      • All tissue from ovaries and fallopian tubes need to be removed!

        • Ligate IP 2cm proximal to the end of identifiable ovarian tissue

          • Beware of your ureter!

        • If hysterectomy not performed, tubes should be divided at insertion to cornua, and ovary removed from utero-ovarian ligament as close to uterus as possible.

      • Frozen pathology not necessary, as most malignancies identified from this procedure are occult

        • Your pathologist needs to know that the patient is BRCA-carrier though! This will prompt them to perform complete, serial sectioning of the tissue with microscopic screening (rather than representative sections typically performed with other benign BSO)

    • Hysterectomy can be considered simultaneously:

      • Advantages: simplifies hormone therapy (estrogen alone, vs E-P if retained); removal of cornual aspect of fallopian tube; reduce endometrial cancer risk if genetically-predisposed or taking tamoxifen

      • Disadvantages: bigger surgery, longer recovery, higher risk of complications from surgery

    • After BSO:

      • Patients who are premenopausal will need HRT to mitigate effects of early menopause and help with cardiovascular health and bone protection

        • Recall that HRT in the WHI increased risk of breast cancer in the estrogen-progesterone arm, but not in the estrogen-alone arm.

        • Given the higher rates of triple-negative breast cancer in BRCA population – HRT would not alter that course. Data suggests that HRT does not seem to reduce the protective effects of risk-reducing surgery overall.

      • In post-menopausal patients, this is controversial – other options are generally preferred to HRT for VMS management.

      • Local estrogen therapy for vaginal symptoms (genitourinary syndrome of menopause) is safe and effective in BRCA population – please use it! 

      • Ongoing surveillance after BSO is not necessary - so no need to collect CA125 or perform surveillance imaging. Patients should report any concerning symptoms.

Vulvar Intraepithelial Neoplasia (VIN)

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Here’s the RoshReview Question of the Week!

A 41-year-old woman, G2P2, presents to your office for postcoital bleeding. She has a history of laparoscopic hysterectomy for persistent cervical intraepithelial neoplasia 3. A vaginoscopy is performed and shows multiple lesions in the upper third of the vagina. One lesion located within a suture recess near the vaginal cuff is not able to be visualized in its entirety. Biopsy reveals a high-grade squamous epithelial lesion. Her social history is significant for smoking. Which of the following is the best therapy?

Check your answer at the links above and check out RoshReview’s CREOG question bank!

Follow along with ACOG CO 675!

What is Vulvar Squamous Intraepithelial Lesions (SIL) and why do we care? - previously called VIN 

  • VIN is increasingly common - esp in women in their 40s 

    • VIN has increased more than 4x from 1973 to 2000! 

    • VIN should be considered a premalignant condition

  • How do we classify?

    • Has changed a lot over time, but most recently we have used:

      • LSIL of the vulva - used for low grade changes that come from HPV infections (usually present as genital warts) 

      • HSIL of the vulva - used for high grade changes that comes from HPV infections (precancerous lesions) - used to be called “usual type” 

        • VIN, warty type 

        • VIN, basaloid type 

        • VIN, mixed (warty or basaloid) type 

      • Differentiated type - from things like lichen sclerosus 

    • The International Society for the Study of Vulvovaginal Disease ISSVD recommends these terms to unify the nomenclature of HPV-associated squamous lesions of the lower genital tract - all of these are based on histopathologic findings:

ACOG CO 675

How do we diagnose VIN? 

  • Unfortunately, no good screening strategies

    • Detection usually limited to visual inspection 

    • What does it look like?

      • Can vary. Most will be raised, but some can be flat 

      • Discoloration of the skin - white, gray, red, brown, or even black 

    •  Should biopsy to make definitive diagnosis if not sure of diagnosis of something else (ie. LS) 

      • Biopsy should be performed in postmenopausal women with apparent genital warts and in women of all ages with genital warts where topical therapies have failed 

      • Colpo can also be useful - just remember that you need to soak the vulva in acetic acid with a gauze pad for several minutes 

What do we do to treat? 

  • Treat all vulvar HSIL (VIN usual type) 

    • Surgery 

      • Wide local excision should be done if there is suspected to be cancer 

      • Can be occult invasion even if initial biopsy is vulvar HSIL 

      • Should include gross margin of 0.5-1 cm around tissue with visible disease 

      • May be altered to avoid injury to critical structures like clitoris, urethra, anus, or other structures 

      • However, if lesions in critical areas, should be referred to specialist to avoid impaired psychosexual function (ie. if extensive around the perineum, reaching back to anus or around the clitoris 

      • If clear margins in excised tissue, much lower risk of recurrence 

    • Laser Ablation Therapy 

      • Should be done if occult invasion is not a concern

      • Can be used for single, multifocal, or confluent lesions, although risk of recurrence may be higher than with excision 

      • Colpo can help delineate lesions of margins 

      • As with excision, 0.5-1cm margin to be treated 

      • Remember than unlike genital warts, the entire thickness of the epithelium must be treated

    • Medical Therapy 

      • Topical imiquimod 5% 

      • Regimens that have been published include 3x/week to affected area for 12-20 weeks 

      • Colpo assessment at 4-6 weeks 

      • Residual lesions require surgical treatment 

  • Surveillance

    • Recurrence rate is as high as 9-50% with all treatment regimens

      • Higher with positive margins

      • Lower in surgically treated patients 

    •  Follow up has been limited in most studies 

    • However, women with Vulvar HSIL are at high risk of recurrence during their life time 

    • If complete response to therapy and no new lesions at follow-up visits, scheduled 6 and 12 months after initial treatment should be monitored by visual inspection 

Evidence-Based GYN Surgery

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Check out: https://www.ajog.org/article/S0002-9378(18)30583-0/fulltext

Remember the evidence-based C-section? Turns out, there is also good evidence for gyn surgery practices!

Preoperative - Includes things that are part of the ERAS protocol

  1. Patient Education 

    • Two randomized control trials 

    • There was some potential association between preoperative patient education and improved outcomes (low level evidence) —> perhaps some decrease in length of stay and pain.

  2. Bowel Prep

    • Minimally invasive gyn surgery:

      • Strong evidence that oral mechanical bowel prep should not be used.

    • In those with high risk of colorectal resection:

      • Based on colorectal surgery evidence, oral mechanical bowel prep alone is not effective 

      • Use of one of the following regimens can be considered: (moderate level evidence) 

        • Oral bowel prep AND oral antibiotic 

        • Oral antibiotic alone

  3. Surgical site infection bundles - high level of evidence

  4. Glucose management 

    • Goal of <180 mg/dL (high level of evidence) 

  5. Diet

    • Reduce fasting - may ingest solids until 6 hours prior to anesthesia induction and clear liquids until 2 hours prior to induction 

      • High level of evidence 

    • Carbohydrate loading - routine carbohydrate loading is recommended (moderate level of evidence) 

      • May ingest 2-3 hours up to induction of anesthesia - can include things like apple juice, ensure clear, etc. 

  6. Pre-anesthesia medication 

    • Pain:

      • Combination of acetaminophen, COX-2 inhibitor (celecoxib, for example), and/or gabapentin - level of evidence is high!

    • Nausea:

      • Scopolamine, midazolam, or gabapentin (high level of evidence) 

  7. VTE prophylaxis - moderate evidence 

    • Overall low rates of VTE in general, but preoperative intermittent pneumatic compression alone for patients undergoing MIS or laparotomy for benign disease

    • Weak evidence from observational studies supports adding preoperative pharmacologic prophylaxis for patients undergoing laparotomy for gynecologic malignancies  

Intra-operative 

  1. Drains 

    • Routine NG tube - associated with patient discomfort and no known benefit (high level of evidence) - from the ERAS Society 

    • Routine peritoneal drains - not recommended routinely in gyn or onc surgery including cases with lymphadenectomy or bowel surgery

      • 2017 Cochrane Database showed drainage was not associated with reduced rates of lymphocyst formation. However, use of surgical drains increased rates of symptomatic lymphocyst formation when the pelvic peritoneum was left open 

      • Overall, moderate evidence  

  2. Antibiotic prophylaxis

    • Given within 1 hour prior to incision per CDC and ACOG; redose prophylactic antibiotics for long procedures (ie. Ancef 3-4 hours after incision)

      • Level of evidence is high

  3. Skin prep

    1. Ideally use 2% chlorhexidine and 70% isopropyl alcohol solution (high level of evidence) 

  4. Blood transfusion (for hemoglobin 6-10) and fluids to maintain intraoperative euvolemia

  5. Maintain normothermia 

  6. Pain management - liposomal bupivicaine for laparotomy cases (moderate)  

Postoperative

  1. Early mobilization - moderate level of evidence 

    • Has been shown to be beneficial and to avoid prolonged bedrest; basically meaning out off bed and mobilizing within 24 hours of surgery 

      • Reduces PEs and VTEs, also may protect against muscle atrophy and deconditioning 

  2. Early alimentation 

    • Postoperative feeding - within 24 hours of surgery (can be as early as 4 hours after surgery with or without bowel resection) 

    • Two systematic reviews and 1 meta-analysis - early feeding is safe, well-tolerated and results in earlier return of bowel function and shorter LOS 

  3. Early urinary bladder catheter removal (mod level evidence) 

    • Catheter use for < 24 hours, but appropriate to consider fall risk and necessity of urine output monitoring 

    • Uncomplicated surgeries: consider removal at 6 hours to balance rate of infection vs retention 

    • Complicated: morning after may be more appropriate (ie. urogyn or gyn onc cases) 

  4. Prevention of ileus and accelerate return of bowel function

    • Use of postop laxatives (recommended for gyn surg, low level of evidence) 

    • Chewing gum (high level of evidence) 

    • Alvimopan (novel peripheral u-opioid antagonist) - may not be beneficial in benign gyn 

      • However, may decrease ileus in ovarian cancer surgery and can be considered for use in patients undergoing bowel resection  

  5. Early IV fluid discontinuation 

    • Discontinue maintenance IV fluids within 12-24 hours following surgery, especially with early PO intake (low level of evidence) 

      • Urine output as low as 20 mL/hour

        • Can be normal post op stress response 

        • Intervention not required 

  6. Postoperative VTE: 

    • Mechanical prophylaxis for duration of hospitalization in all gyn surg patients 

    • Mechanical and/or pharmacologic prophy for gyn onc surgical patients (high level of evidence) 

      • Additionally, for oncology cases with laparotomy, should extend VTE prophylaxis for 4 weeks following surgery 



Cervical Cancer

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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:

FIGO 2018 Staging

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!