Soft Markers for Aneuploidy

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Here’s this week’s RoshReview Question of the Week!

A 38-year-old G1P0 woman at 20 weeks gestation presents to the clinic for her anatomy ultrasound examination. She underwent a first-trimester screen, which showed a borderline nuchal translucency of 3.1 mm. Which one of the following isolated ultrasound findings confers the greatest risk for trisomy 21?

Check out the links above to see if you answered correctly. Also, you can enter for a chance to win a Rosh Review Qualifying Exam (“written boards”) QBank!

Check out the SMFM Consult Series 57 for excellent companion reading!

What are the ultrasound soft markers, and why do we care? 

  • In the era of cell-free DNA, you might ask: what is the utility of soft markers? Aren’t they poor predictors of aneuploidy?

    • Originally introduced to improve the detection of Down syndrome over that of just age-based or serum-based screening 

    • While it is true that each isolated soft marker may be poor predictors, if we see multiple soft markers, that does improve sensitivity  

    • There may also be some misunderstanding of soft markers seen on ultrasound, and so the purpose here is to review some of these soft markers in the setting of cfDNA and discuss next steps 

  • Remember: patient’s baseline risk should not limit screening options, and cfDNA should be offered to all per ACOG and SMFM 

What are the first steps when you see a soft marker?

  • Make sure that the soft marker is truly isolated - look for other soft markers, fetal growth restriction, or other anomalies 

    • If you feel that your office is not equipped to do this, can refer to MFM to have a level II ultrasound performed - this is of course a discussion with the patient, and not all patients will want further evaluation 

  • Look at the patient’s history: 

    • What is their baseline risk? (age, family history, history of aneuploidy) 

    • What are their previous aneuploidy screening results? Did they have any? 

  • Ok, so I see one of the soft markers, what do I do next?

    • First of all, have they had cfDNA?

      • Most of the time, there is not much to do after that (again: ISOLATED soft marker) 

      • This is because with cfDNA, the posttest probability of a common aneuploidy (ie. Trisomy 21) of negative cfDNA is very low - it is lowered by 300x for trisomy 21

        • Per the consult series, the residual risk of a 35-yo woman, whose age related risk of Down syndrome is 1/356 is reduced to <1/50,000 after a negative cfDNA result  

    • But what if they didn’t have cfDNA? 

      • If they have had negative serum screening, also ok, no need to do further testing at this time 

        • The detection rate of serum screening test for Down is still high, about 81%-99% depending on the test 

      • If no screening at all, counsel about noninvasive aneuploidy testing - not all patients will want screening 

    • Remember: there isn’t an established cut off residual risk when there is recommendation to do diagnostic testing 

      • Many labs will establish a cutoff of 1:250 or 1:300 

    • SMFM does not recommend diagnostic testing for aneuploidy only for evaluation of isolated soft marker following negative serum or cfDNA screening result 

The Soft Markers (all photo credit to Radiopedia)

Tubal Ectopic Pregnancy Management

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Here’s the RoshReview Question of the Week!

A 24-year-old G2P1 woman presents to the emergency department with right-sided pelvic pain and vaginal spotting. She has been trying to conceive and her last menstrual period was 8 weeks ago. The patient reports her left fallopian tube was removed 3 years ago due to hydrosalpinx. Her beta-human chorionic gonadotropin is 6,700 mIU/mL. On ultrasound, there is no intrauterine pregnancy identified. Fetal heart tones are detected in the right fallopian tube. There is a minimal amount of free fluid noted in the posterior cul-de-sac. What is the most indicated intervention at this time?

Check to see if you got it right at the links above!

While we have reviewed the workup of the early unlocated pregnancy and diagnosis of ectopic pregnancy previously with Dr. Cleary, and talked about the unusual problem of cesarean ectopic pregnancy before on the show, somehow we missed the management of the regular tubal ectopic! 

ACOG PB 191 is a great resource for all things ectopic pregnancy and important companion reading for the podcast today.

Background Info

  • Ectopic pregnancy represents about 2% of reported pregnancies, but this is likely an undercall as not all ectopic pregnancies are reported.

  • Ruptured ectopic accounts for a significant cause of maternal morbidity and mortality - 2.7% of maternal deaths in 2011-2013 were attributable to ruptured ectopics. 

  • Fallopian tube is the most common location for an ectopic (90%), but as we’ve talked about before, these can be anywhere – abdomen (1%), cervix (1%), ovary (1-3%), and cesarean scar (1-3%). 

    • Can also co-occur with an intrauterine pregnancy – heterotopic pregnancy.

      • Naturally conceived: 1 in 4,000 to 1 in 30,000

      • IVF: as high as 1 in 100

Risk Factors for Ectopic Pregnancy

  • 50% of those who receive a diagnosis don’t have any known risk factor. 

  • Risk factors that can be present include:

    • Prior ectopic - recurrence risk is about 10% after 1 prior, 25% after 2 prior

    • Prior fallopian tube surgery / damage

    • History of PID or ascending pelvic infection

    • ART - tubal infertility, multiple embryo transfer, infertility in general

    • Cigarette smoking

    • AMA > 35yo

  • Contraception and ectopic risk:

    • Those using IUDs are at lower risk overall of ectopic because IUDs are highly effective at preventing pregnancy in general.

      • However, in those who do become pregnant with an IUD in place, up to 53% of these pregnancies are ectopic.

    • OCP use, emergency contraceptive failure, previous pregnancy termination, pregnancy loss, and cesarean delivery have not been associated with increased risk of ectopic pregnancy. 

Confirming a Diagnosis of Ectopic Pregnancy

  • We covered this pretty extensively in our episode with Dr. Cleary - there we do a great job of talking you through the “pregnancy of unknown location” workup, especially when you see a patient in ED/triage with bleeding/pain and early pregnancy. 

  • We won’t go through it all again today, as we want to focus primarily on management, but a few big points:

    • Trending bHCG every 48 hours helps to determine if the pregnancy is normal or abnormal.

      • If a bHCG is higher than the DZ and you don’t see anything - that’s a good indicator of an abnormal pregnancy, with 50-70% being ectopic. 

    • Transvaginal ultrasound to assess the uterus and adnexae will help you identify any unusual mass that might be an ectopic.

  • So let’s start from the point of abnormally rising bHCG, so we know our suspicion is for an abnormal IUP versus ectopic. What options are available?

    • Expectant Management

      • We can continue to trend bHCG in a stable patient, particularly in the case of highly desired pregnancy or low bHCG values that may need more time to declare itself.

      • These patients should be counseled strongly about presenting for care should they experience significant bleeding, severe pain, or other symptoms worrisome for ectopic rupture. 

    • Uterine Aspiration

      • If we are reasonably certain the pregnancy is abnormal, a uterine aspiration can be done to determine if the pregnancy is intrauterine or not.

        • The aspirate can be sent to pathology or floated to quickly identify chorionic villi – if found, then you know it was an IUP.

        • If villi are not found, then hCG should be measured again at 12-24 hours after aspiration.

          • If the hCG drops at least 10-15%, it was likely successful aspiration of a failed IUP; however, drops of 50% or greater are more indicative. 

            • Serial hCG should be followed to zero in these patients since no pathology was identified.

          • If the hCG is plateaued or rising, then the pregnancy is ectopic, and the patient will need additional treatment. 

    • Proceeding Directly to Treatment

      • The PB mentions there is debate whether aspiration is necessary before treating an abnormal pregnancy with methotrexate.

        • On one hand, confirmation of the diagnosis with the procedure helps avoid unnecessary exposure to MTX.

        • On the other hand though, the procedure adds at least 12-24 hours of additional time (and potential ectopic rupture) before giving treatment.

      • ACOG notes that the risk of rupture during this time period overall is low, and that presumptive treatment with MTX doesn’t confer cost savings

        • However, it reserves the choice for patients and their physicians after discussion of risks and benefits.

Medical Treatment of Ectopic Pregnancy

  • The standard, as we’ve mentioned, is methotrexate.

    • Folate antagonist binding to catalytic site of dihydrofolate reductase → inhibits synthesis of nucleotides and amino acids, thus inhibiting DNA synthesis, cell repair, and cell replication.

    • MTX affects all rapidly-proliferating cells because of it – marrow, mucosa, cancers, and trophoblasts. 

      • This is helpful to keep in mind to thinking about side effects of MTX:

        • Nausea, vomiting

        • Stomatitis 

        • Abdominal pain

        • Alopecia (rare)

        • Pneumonitis (rare)

      • There are no recommended alternatives to MTX for medical therapy.

  • Contraindications to MTX:

    • Absolute:

      • Intrauterine pregnancy

      • Chronic liver or kidney disease

      • Bone marrow dysfunction (anemia, blood dyscrasia, thrombocytopenia, leukopenia).

      • Active GI disease (i.e., PUD) or respiratory disease.

      • Breastfeeding

      • Hemodynamically unstable patient.

      • Inability to participate in follow up. 

    • Relative:

      • Cardiac activity in the ectopic pregnancy

      • High hCG concentration (>5000 mIU/mL)

        • Reviews demonstrate a failure rate of 14.3% or higher at this concentration (vs 3.7% when under 5000 mIU/mL)

      • Ectopic size greater than 4cm on TVUS

      • Refusal to accept blood transfusion

  • MTX Regimens:

    • ACOG in the PB 191 mentions three primary regimens: single-dose, two-dose, and fixed multi-dose.

  • Single-dose is the simplest but may require additional dose in up to 25% of patients.

  • Two-dose has high success rate with similar monitoring to single-dose regimen.

    • A recent review article suggested the two-dose protocol was more successful while also exposing patients to only minimal, transient side effects versus single dose, and has higher success rates with higher hCG levels.

  • Multi-dose fixed regimen requires up to 8 days of treatment with alternating MTX and folinic acid for rescue and minimization of MTX side effects.

  • What about surveillance / labs for MTX?

    • Before administration (day 1), you should obtain:

      • bHCG

      • CBC

      • CMP

    • Patients should be counseled about side effects of MTX, and should avoid medications, foods, and supplements that may worsen efficacy

      • Have them stop prenatal vitamins at this time, so the folate doesn’t counteract the MTX!

        • Folate-rich foods and NSAIDs may also decrease the efficacy of MTX.

        • Narcotics, alcohol, and gas-producing foods should also be avoided so as not to mask or be confused with signs of rupture.

        • Patients should also avoid vigorous activity and sex until confirmation of resolution so as not to induce ectopic rupture. 

    • With single and two-dose protocols, you’ll evaluate bHCG again on days 4 and day 7.

      • Success in these protocols is noted with a 15% or more decline between days 4 and 7. 

        • If the decline is less than that, or bHCG increases, then an additional dose of MTX should be administered on day 7. 

        • With repeat doses of MTX, it’s reasonable to consider repeat laboratories to evaluate for any toxicity. 

      • bHCG should continue to decline to zero, and should be followed at least weekly once the initial 15% decline is noted.

        • Resolution can take up to 8 weeks, though average:

          • Two dose: 25.7 +/- 13.6 days

          • One dose: 31.9 +/- 14.1 days

    • Finally, patients should consider avoiding pregnancy for at least 3 months after the last dose of MTX.

      • Studies have found MTX still detectable in cells up to 116 days past exposure. 

      • However, limited evidence also suggests that anomalies and pregnancy loss is not elevated in those who become pregnant shortly after MTX exposure.

    • MTX does not have a measurable effect on fertility.

Surgical Therapy

  • For patients who do not desire MTX or are not candidates, surgical therapy is the other option. Surgical therapy is also needed for the patient with hemodynamic instability or symptoms of rupture/intraperitoneal bleeding. 

    • Can also be reasonably considered in stable patients with an indication for another procedure, like salpingectomy for sterilization or hydrosalpinx removal. 

  • Surgeries available include salpingectomy (removal of the tube) or salpingostomy (opening the tube).

    • These are generally accomplished laparoscopically – laparotomy is reserved for unstable patients or patients with large bleeding and compromised laparoscopic visualization. 

  • Surgery may be more effective than medical therapy and requires less follow up, but does expose patient to surgical risk. 

  • Salpingectomy is technically easier to perform, and that’s likely how most of us have trained.

    • Salpingostomy can be considered in patients with desired fertility and damage to the contralateral fallopian tube, and would require ART for future pregnancy.

    • To perform, typically you make an incision along the long axis of the tube over the ectopic, and resect the pregnancy tissue. 

      • Achieving hemostasis is rather tricky in these cases, and may additionally cause damage to the tube. The tube is usually left to heal on its own and not sutured as this may crimp the tube and cause further damage. 

      • Because you may not resect all of the pregnancy tissue at salpingostomy, bHCG monitoring after salpingostomy is needed to ensure complete resolution.

      • MTX may also be given prophylactically if incomplete resection is considered. 

Expectant Management

  • We bet you weren’t expecting this one… but ACOG does mention there may be a role for expectant management of ectopic.

  • They note that candidates for EM should be:

    • Asymptomatic

    • Objective evidence of resolution (i.e., plateau or decreasing bHCG)

    • Accepting of potential risks after counseling, including tubal rupture, hemorrhage, emergent surgery.

      • EM should be abandoned if hCG insufficiently decreases or begins to rise or with any suspicion for tubal rupture. 

  • If initial hCG is under 200 mIU/mL, 88% of patients will have spontaneous resolution.

  • In a single small RCT of patients with hCG < 2000 mIU/mL, EM was not associated with lower treatment success than single dose MTX (59% vs 76%).

Interstitial Cystitis, feat. Dr. Edward Kim

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Here’s the RoshReview Question of the Week!

A 41-year-old woman presents to your office for dysuria. She states that she has been having persistent urinary urgency and frequency for the past six months. She reports discomfort with bladder filling, pain with urination, and relief after voiding. A review of her history reveals normal fluid intake. A workup for pelvic pain performed by her primary care provider and gastroenterologist was negative. On physical exam, you note suprapubic tenderness. Her urinalysis and culture are negative. Which of the following is the best therapeutic option?

Check out if you answered correctly at the links above!

Today we welcome Dr. Edward Kim to the podcast. He is a urogynecology fellow at the University of Pennsylvania, performing research on a challenging topic: interstitial cystitis. Dr. Kim is looking to recruit more patients into a study on quality of life and patient education in IC — if you have questions or someone to refer, let us know by emailing us or contacting us with the form on the website!

Overview

  • IC: kind of a misnomer!

    • There is no conclusive evidence that there is an inflammation nor distinct pathology in the bladder interstitium.

    • Contemporary thinking: chronic pain condition related to or perceived to be originating from the bladder.

      • Newer terminology has been proposed: bladder pain syndrome.

      • In clinical practice, some patients seem to prefer ‘interstitial cystitis’ because to them is sounds more like a more medical diagnosis and they don’t want to be labeled as having a pain syndrome. So IC/BPS are used interchangeably.

Epidemiology

  • Can affect men and women but more common in women.

    • High prevalence in age 40s.

    • Don’t know the precise prevalence given complexity of syndrome.

Clinical Presentation

  • Variable

  • Persistent urinary urgency, urinary frequency, and pain or discomfort related to voiding.

    • Note that we say pain or discomfort. Some patients describe what they’re feeling as discomfort and not pain.

    • Classic: patient with these symptoms who had been treated multiple times for urinary tract infections despite having negative urine cultures. They also may report going to the bathroom frequently or spending a lot of their day on the toilet to relieve their urgency and discomfort or pain.

      • Many of these patients may also have associated conditions like irritable bowel syndrome, fibromyalgia, and pelvic floor muscle dysfunction.

      • They also may have concurrent psychiatric comorbidities such as depression or anxiety.

Diagnosis

  • American Urological Association: “An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes.”

    • In other words, IC is a clinical diagnosis and diagnosis of exclusion.

    • Differential diagnosis should include:

      • Infection

      • Overactive bladder

      • Bladder or urethral cancer, gynecologic cancer

      • Uterine fibroids with compression effect on the bladder

      • Bladder stone

      • Bladder diverticulum

      • Foreign material such as synthetic mesh or suture

      • Neurologic conditions that may cause urinary retention in particular

      • Other chronic pelvic pain conditions such as endometriosis.

    • This is why it’s important to perform a thorough history and physical and obtain a post void residual and urine tests as an initial evaluation to rule out these other etiologies.

  • Hunner lesions can be seen on cystoscopy.

    • They are specific for IC, but they only are seen in about 10% of patients with IC.

  • Potassium sensitivity test KCl is instilled into the bladder.

    • This is not performed anymore due to its low sensitivity and specificity and also it’s very painful!

  • Urodynamics is not typically used to diagnose IC but it can be done to rule out other etiologies.

Treatment

  • Management strategy is multi-faceted.

  • First-line treatments are patient education, behavior and diet modification, and general stress management.

    • There is good evidence behind teaching patients bladder retraining where they learn to increase the interval between each voids.

    • Avoidance of things like artificial sweetener, caffeine, alcohol, spicy food, citrusy or acidic foods can help with symptoms.

      • Doesn’t require elimination, but helps to make informed decisions about diet.

    • Applying heat or ice packs to the suprapubic or perineal regions can also be helpful.

    • Pelvic floor muscle tenderness or dysfunction on exam —> consider pelvic floor PT.

  • Second-line treatments include oral medications and bladder instillation.

    • PRN medication is usually pyridium or over the counter AZO.

      • Warn patients that their urine will turn orange and may stain clothing.

    • Daily medications, the most commonly used ones are: amitriptyline, hydroxyzine and pentosan polysulfate sodium (Elmiron).

      • Note that Elmiron is the only FDA approved medication for IC. However, use of Elmiron has been associated with macular eye disease. Thus, in 2020, the FDA inserted a warning label to reflect this and use of Elmiron has been declining.

      • Between amitriptyline and hydroxyzine, currently there is more data on amitriptyline. Some patients find amitriptyline helpful in controlling their symptoms but some cannot tolerate its sedative and anticholinergic side effects.

    • If there is inadequate response to medications, then bladder instillation can be considered. This involves instilling a mixture of local anesthetic, heparin, DMSO, etc. via a catheter. Usually this involves repeated treatments.

  • Third-line treatment is hydrodistention.

    • Hyper-distention of the bladder under anesthesia for about 10 minutes and emptying the bladder.

      • The thought is that sensory nerves in the bladder are disrupted due to the hyper distention.

      • For patients who see prolonged and significant benefit, repeat treatments are considered.

    • If on cystoscopy Hunner lesions are found, they can be addressed with cautery, resection or injection with steroids.

  • Fourth-line treatments include neuromodulation using Botulinum toxin A injection into the bladder and sacral neuromodulation.

    • These techniques have been used for overactive bladder and neurogenic bladder but recent clinical trials have reported efficacy for interstitial cystits. 

  • Fifth-line treatment is cyclosporine A. Use is limited due to its side effects and paucity of convincing data.

  • Sixth-line and last resort is surgical diversion of the bladder with or without cystectomy.

    • Fortunately, patients seldom have to go past fourth-line treatments. As with any chronic pain condition, it is a difficult journey for many of them and it is critical for providers to listen and empathize with them.

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.

Choosing The Route of Hysterectomy

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Here’s the RoshReview Question of the Week!

​​A 49-year-old P3003 woman presents to the clinic with a complaint of heavy menses for several years and asks for definitive management. She has a history of type 4 fibroids, all < 3 cm, and hypercholesterolemia. Her obstetrical history is significant for two vaginal deliveries and one cesarean section. On physical examination, her BMI is 31 kg/m2. Her uterus is anteverted, and the fundus reaches 3 fingerbreadths below the umbilicus. What surgical intervention would be most cost- and clinically effective for this patient?

Check if you got the right answer at the links above!

Reading: Committee Opinion 701 - Choosing the Route of Hysterectomy for Benign Disease 

Why do we do a hysterectomy?  

  • Hysts are one of the most common surgeries in the United States (per the CDC, over 600,000 are performed annually) 

  • Many of them are elective - ie. patients are choosing surgical option over medical for example  

What exactly are the ways to do a hyst anyway and why does route matter?

Note: We won’t go into exact techniques here since we are a podcast. However, some great resources include the Atlas of Pelvic Surgery online: http://www.atlasofpelvicsurgery.com/home.html

Also the textbook by Baggish and Karam: Atlas of Pelvic Anatomy and Gynecologic Surgery 

Vaginal hysterectomy 

  • First type of minimally invasive hysterectomy 

  • Advantages 

    • Preferred type of hysterectomy when possible due to no incisions on the abdomen and minimally invasive route 

    • High safety and low cost

      • Meta-analysis of seven trials report similar rates of visceral injury and long-term complication among vaginal and laparoscopic procedures 

    • Minimally invasive approach associated with faster recovery compared to laparotomy 

  • Disadvantages

    • Unfortunately, despite advantages, there are fewer vaginal hysts performed compared to others due to limited training, fewer numbers of hysts overall being performed and greater diversity of operative approaches 

    • Must remove cervix with this type of procedure - no option for supracervical hyst 

    • Small chance of converting to laparotomy 

Laparoscopic hysterectomy 

  • Usually performed with laparoscopic instruments via 3-4 small ports in the abdomen. Uterus can be morcellated and removed through a bag (morcellate in bag) or via the vagina 

  • Increasing in popularity 

  • Advantages 

    • Better visualization with minimally invasive surgery 

    • Can perform supracervical hyst if needed 

    • Can also perform last part vaginally for ease if needed 

    • May be easier in some obese patients 

  • Disadvantages 

    • Requires surgeon skilled in use of laparoscopy 

    • Certain patient populations with certain medical illnesses may not tolerate Trendelenburg position or pneumoperitoneum 

    • Possibility of conversion to laparotomy 

    • Slightly higher rate of vaginal cuff dehiscence compared to other routes of hyst (still low, like 0.64-1.1%) 

Robotic hysterectomy 

  • Very similar overall in terms of advantages and disadvantages to laparoscopic hysterectomy due requiring Trendelenburg and pneumoperitoneum, as well as minimally invasive course 

  • Advantages 

    • Superior visualization compared to traditional laparoscopy due to ability to move camera and 3D vision 

    • Mechanical improvement - wrists with robots 

    • Better stabilization of instruments 

    • Improved ergonomics for surgeons - you can sit down (as someone who has definitely passed out during a long case) 

    • Even more options for minimally invasive routes (ie. single port hyst) 

  • Disadvantages 

    • Additional surgical training 

    • Does not necessarily decrease time (in fact can increase cost and operating room times) 

      • Cost of instruments overall + cost of robot 

    • Lack of haptics (no tactile feedback) 

Abdominal hysterectomy  

  • Only non minimally-invasive technique 

  • Advantages

    • Visualization 

    • Ability to remove large masses and large uteruses 

    • Tactile feedback  

    • Lowest risk of vaginal cuff dehiscence compared to other methods 

    • Studies like the VALUE study and the eVALuate trial showed decreased rates of complications of abdominal hyst compared to laparoscopic hyst, but these studies are also old (1990s) 

  • Disadvantages 

    • Increased postoperative pain and length of stay (average LOS is 3 days after abdominal hyst) 

    • Increased risk of bleeding and infection 

    • Increased risk of VTE (also may be due to increased stasis) 

    • Increased risk of colonic stasis 

How do we pick the route of hysterectomy? 

Consideration of minimally invasive routes 

  • MIS should be considered whenever possible because of well-documented advantages over abdominal hysterectomy 

  • Vaginal hyst is preferred over other types due to cost, effectiveness, and overall outcomes 

  • Even if opportunistic salpingectomy is desired, these can be performed with vaginal hysterectomy 

Anatomy 

  • Size and shape of vagina and uterus + descent of uterus 

  • More difficult to perform a vaginal hysterectomy if there is no descent, if there is large uterus (bulky fibroids) and small introitus 

    • However, nulliparity is not a contraindication to vaginal hysterectomy 

    • Study showed that 92% of vaginal hysterectomies planned for women with no prior vaginal deliveries could be successfully completed 

  • Accessibility of the uterus also important - is there likely to be a lot of pelvic adhesive disease? (endometriosis) 

    • Large uterine size - morcellation has come under scrutiny previously 

    • However, still can morcellate in a bag 

    • Even if large, bulky uterus, can refer to skilled MIS surgeon

  • Need of concurrent procedures (ie. will the patient need their appendix removed as well?) 

  • Work up: 

    • Physical exam with evaluation of mobility of uterus on bimanual 

    • Evaluation for adnexal masses on bimanual 

    • Feel for fundal height 

    • Pelvic ultrasound may be helpful 

Surgeon comfort/preference 

  • Surgeon preference for other operative routes - no longer considered an appropriate reason to avoid vaginal approach 

  • Surgeon experience 

    • Average case volume

    • Available hospital technology, devices, and support 

Patient preference 

  • If patient desires supracervical hysterectomy, will need laparoscopic or abdominal approach 

  • However, no clinically significant difference in complication and uncertain benefit in terms of patient outcomes (ie. sexual function, urinary function, bowel function)

ACOG CO 701