Adnexal Masses Part II: Epithelial Neoplasms

On today’s episode, we start into epithelial neoplasms of the ovary, which comprise about 90% of cancers of the ovary, fallopian tube, and peritoneum. Here are the show notes in outline format!

Benign epithelial  neoplasms 

  1. Serous cystadenoma 

    1. Among the most common benign ovarian neoplasms (20-25%); sized 5-20 cm

    2. Benign, but if persistently symptomatic, can have surgical removal 

    3. There is no good data regarding the decision to observe or remove if they are asymptomatic, but decision to operate may be guided by age, size of mass, ultrasound appearance, family history or other risk factors for ovarian cancer + medical comorbidities 

  2. Mucinous cystadenoma, lining similar to viscera or gastric lining  

    1. <5% of ovarian neoplasms 

    2. Contains mucin 

    3. Treatment same as above 

  1. Borderline ovarian epithelial neoplasms 

    1. Serous borderline neoplasms - most common histologic subtype of borderline tumors and accounts for 65% of all borderline ovarian neoplasms 

      1. Usually confined to the ovary and is slow growing

      2. 10 year survival rate is 95-100%, though late recurrences are not uncommon 

      3. Prognosis is still excellent even if there is presence of peritoneal implants and regional lymph node involvement 

      4. Histology: serous epithelial proliferation; more complex architectural patterns than a serous cystadenoma, and can have areas of microinvasion (area of cells <5 mm that are invading into the stromal core of the papillae or cyst wall); if it’s >5 mm, then it should be classified as a low-grade serous carcinoma 

      5. In fact, serous borderline neoplasms have similar immunophenotype and molecular biology to LGSC and may suggest that LGSC can arise from borderline neoplasms 

      6. Treatment: surgery 

    2. Mucinous borderline neoplasm - nearly always confined to ovary, unlike serous 

      1. Usually appears large, unilateral, multilocular cyst with smooth, white capsule 

      2. Epithelial lining with two general types: GI type and endocervical (or seromucinous) type 

      3. Approximately 10-20% exhibit microinvasion 

      4. Treatment: surgery 

    3. Endometrioid borderline neoplasm - biologic potential between cystadenomas/adneofibromas and invasive endometrioid adenocarcinoma of the ovary 

      1. Uncommon - 2-10% of borderline neoplasms 

      2. General appearance: firm, with smooth surface and multiple small cysts with clear or hemorrhagic fluid  

      3. Histologically, have adenofibromatous pattern with nodular architecture, but more proliferative with appearance similar to complex atypical hyperplasia of the endometrium 

      4. Actually same criteria exist to differentiate it from invasive carcinoma as there is between complex atypical hyperplasia and well-differentiated endometrioid adenocarcinoma of the endometrium 

      5. Microinvasion can be seen 

  2. Carcinomas 

    1. We will talk about staging and treatment in another episode! 

    2. High-grade serous carcinoma (70-80% epithelial carcinomas) 

      1. Most common type of ovarian cancer, and accounts for 70-80% of  all malignant ovarian neoplasms 

      2. Peak age range is 45-65 years; usually diagnosed at advanced stage 

      3. Histologically, HGSC will infiltrate and destroy 

      4. BRCA1 or BRCA2 germline mutations are found in up to 10% of women with HGSC 

      5. Women with these mutations have a 30-50% risk of developing ovarian carcinoma by age 70 

    3. Low-grade serous carcinoma (<5%)

      1. Uncommon 

      2. Typically diagnosed at advanced stage; therefore, long-term prognosis is poor 

      3. Slow-growing, indolent tumors with relative insensitivity to platinum-based chemo 

      4. Can be found alongside noninvasive serous borderline tumors

      5. LGSC differentiated from HGSC by cytologic features; usually have more uniform nuclei, lower mitotic activity; also has numerous psammoma bodies 

    4. Endometrioid carcinoma (10%) 

      1. Unlike serous carcinomas, it is usually identified at an early stage, and therefore, patients have a better prognosis 

      2. Tend to be relatively chemosensitive 

      3. Thought to arise from endometriosis and is associated with carcinoma of the endometrium in 15-20% of cases 

      4. Histologically, this type of carcinoma resembles the uterine counterparts 

    5. Clear cell carcinoma (10%) 

      1. Present most commonly in perimenopausal women in 40s or 50s 

      2. Often presents at an early stage, relatively good prognosis due to absence of distant metastases 

      3. However, if it is present at advanced stage, it has worse prognosis than serous or endometrioid carcinoma, because it is not as sensitive to platinum-based chemo 

      4. Possibly arises from endometriosis 

    6. Mucinous carcinoma (3%)  

      1. Nearly all present in early stages, usually stage I; often seen with borderline neoplasm 

      2. Reason it’s found early is because it is usually large upon discovery: 8-20 cm, but can be even larger

      3. Tends to be cystic or solid, unilateral, and confined to the ovary

      4. There are two patterns of “invasion” - infiltrative invasion and expansile growth pattern

      5. Infiltrative: obvious destructive stromal invasion -  worse prognosis 

      6. Expansile growth pattern: does not demonstrate obvious stromal invasion, but has complex architecture; better prognosis 



Adnexal Masses Part 1: Imaging

Today we’re embarking on a multi-part series through adnexal masses.

To frame our initial conversation on imaging features of adnexal masses, we’ve relied heavily on a golden piece of literature from the Radiological Society of North America, detailing the features and management of these findings on imaging. This paper contains a super nice table that should be considered a table-side reference for your own viewing of images.

Generally speaking, signs more suggestive of malignancy include:

  • Patient age/menopausal status: One of the biggest contributing risk factors, even before you know what the cyst looks like. In postmenopausal women with asymptomatic adnexal masses, the incidence of malignancy approaches 30%, while it is only 6-11% in premenopausal women.

  • Large size: cysts greater than 5cm should receive consideration for surgical intervention or closer follow up in premenopausal women. In postmenopausal women though, even small 1cm cysts should be considered for close interval follow up at a minimum.

  • Thickness: thicker walls (>3mm) portend more significant pathology.

  • Septations: multiple septations are also concerning for malignancy, though again this corresponds with the thickness; thinner septations may suggest more likely benign disease.

  • Nodularity: cysts with nodules or calcifications, particularly with vascularity, are more concerning.

  • Contents: one of the more nuanced findings; however, can help determine etiology: i.e., cysts with a reticular or lacy appearance are more suggestive of hemorrhagic cysts, while hyper echoic lines and dots with areas of acoustic shadowing are more suggestive of dermoid cysts.

Be sure to also check out ACOG PB 174 (membership required) and/or the OBG Project’s helpful bulleted summary! We definitely think looking through images alongside descriptive text is the primary way to learn this information, and we hope the podcast can help supplement that for some of you.

Diagnostic Imaging During Pregnancy and Lactation

Today we’re going to review a source of constant consultation and confusion: diagnostic imaging during pregnancy and breastfeeding. ACOG CO 723 is the definitive reading on this subject, and we use it to structure this episode. Critical take home: ACOG states that critical imaging studies should not be withheld from a pregnant patient if needed to make a diagnosis. 

Ultrasound

  • Sonography utilizes sound waves to produce a visible image, and is not a form of ionizing radiation.

    • Thus, it is considered the safest mode of imaging in pregnancy.

    • However, ACOG still recommends sticking to the ALARA principle of exposure in pregnancy (“As Low As Reasonably Achievable”) to minimize any potential untoward effects. 

    • One of these theoretical effects involves color or spectral flow Doppler. Due to its intensity, the theoretical temperature increase surrounding the area being study can be as high as 2deg C, or 3.6deg F. It’s unlikely than any temperature increase would be sustained at any fetal anatomic site to cause harm. However, for this reason, even ultrasound exposure should be used judiciously. 

MRI

  • Allows for visualization of soft-tissue structures like ultrasound

    • However, as MRI is operator-independent, pick up rates for certain pathologies like appendicitis tend to be higher.

    • There are no special contraindications or considerations in pregnancy for non-contrast MRI, other than the usual screening surrounding metal or magnet-sensitive implants, such as pacemakers. 

  • Non-contrast MRI is sufficient for diagnosis; however, some diagnoses or studies may be improved by the use of gadolinium-based contrast, for which there is uncertainty regarding fetal effects.

    • Gadolinium is water-soluble, and thus crosses the placenta into fetal circulation.

    • Free gadolinium is toxic, so it is bound, or chelated, when administered for studies.

      • There is concern that since this bound gadolinium can enter fetal circulation, it can recycle in the fetal circulation. This potentially could sit for long enough that the gadolinium could dissociate and become free; thus become toxic. 

      • Given at least the concern for potential poor outcomes, gadolinium-based contrast should be limited in use to cases where there is an absolute clear benefit to its administration.

    • Gadolinium’s water-solubility makes it an OK contrast agent to use during lactation.

      • Less than 0.04% of a dose of gadolinium will be excreted in breastmilk in the first 24 hours, and less than 1% of this will be absorbed in the infant GI tract. Thus, breastfeeding should not be interrupted after gadolinium contrast studies.

CT, XRAY, and other ionizing radiation studies
Before talking about ionizing radiation studies, it’s important to know some vocabulary and measurements of radiation:

  • Exposure is the number of ions produced by radiation in the form of X-rays or gamma rays per kilogram of air. This is measured in Roentgen units.

  • Dose is the amount of energy deposited per kilogram of tissue. This is the usual consideration when we talk about radiation in pregnancy. This is measured in rads or in Gray units; 100 rad is equivalent to 1 Gray.

  • Relative effective dose is the amount of energy deposited per kilogram of tissue, and normalized for biological effectiveness on the tissue. This is measured in Roentgen equivalent men (rem) or Sievert units.


Again, the dose is what we usually consider and track with respect to radiation in pregnancy.

  • The background dose of radiation a fetus is exposed to during pregnancy is around 1 mGy.

  • From CO 723 — a reference for doses associated with different imaging studies.

ACOG CO 723

ACOG CO 723

The risk of radiation exposure on a developing fetus depends on both the dose of radiation, as well as the gestational age at which the exposure occurs.

  • For instance, if an exposure of 50-100 mGy occurs prior to implantation (0-2 weeks post fertilization), there is generally an all or none effect; that is to say, this usually results in miscarriage, or no consequence at all.

  • During organogenesis, or 2-8 weeks post-fertilization, congenital anomalies or growth restriction can be seen with cumulative doses of 200-250 mGy.

  • The risk of severe intellectual deficit or microcephaly is most prominent around 8-15 weeks, with doses between 60 - 300 mGy.

    • There is an estimated 25 point IQ loss per 1000 mGy exposure during this time period. 

    • A lower risk of severe intellectual disability may persist through 25 weeks gestation, though again with exposures of 250mGy or more.

  • Other risks include childhood cancer. With respect to leukemia, it is estimated the risk of childhood leukemia increases 1.5-2 fold with a 10-20mGy dose, over a background leukemia risk of 1 in 3000.

  • Radiologists and radiation physicists can help to calculate doses for patients exposed to multiple studies or with occupational hazards. 

With respect to contrast:

  • Oral contrast poses no real or theoretical harm to pregnant or lactating mothers and their infants.

  • IV contrast tends to be iodinated, but is also water-soluble.

    • So similarly to gadolinium, in pregnant patients this crosses the placenta.

    • Animal studies have demonstrated no teratogenic effects from its use, but it is recommended to limit use of iodinated contrast unless necessary.

    • Also similarly to gadolinium, because of this water solubility, iodinated contrast is excreted minimally in breastmilk, and breastfeeding should be continued without interruption.

Nuclear medicine studies

Radioisotopes for nuclear medicine studies, such as VQ scans, thyroid scans, and bone scans, are variable in their potential effects on the fetus.

  • Technetium-99 is one of the most common radioisotopes used for these studies, and given its short half life of 6 hours as well as its pure gamma ray emission, is generally accepted as safe to use when indicated in pregnancy.

  • Radioactive iodine (I-131), by contrast (punny!), readily crosses the placenta and has a half-life of 8 days, and has known adverse effects on the fetal thyroid. Thus, it is contraindicated for use in pregnancy, and is also recommended against use in breastfeeding mothers until breast milk has been cleared of the radioisotope. 


Abnormal Uterine Bleeding: The Basics

Today we talk through the varied etiologies and a basic workup for a common GYN complaint: abnormal uterine bleeding. ACOG PB 128 makes for good companion reading for women of reproductive age.

The terminology of AUB has changed quite a bit, and you may still hear older terms being used. “Dysfunctional uterine bleeding” or DUB has fallen out of favor, as have terms such as metrorrhagia or menorrhagia, yielding instead to simpler terminology such as prolonged menstrual bleeding and heavy menstrual bleeding, respectively. The terms such as oligomenorrhea (bleeding cycles > 35 days apart) and polymenorrhea (cycles < 21 days apart) are also in use to some degree.

Heavy bleeding is difficult to discern, but for research purposes has been described as >80cc blood loss per cycle. In clinical practice, this is obviously impractical, so we rely on subjective descriptions of heavy bleeding to guide care.

The biggest takeaways from this episode include the PALM-COIEN classification of bleeding by FIGO, as well as the common culprits of bleeding by age group. Remember also the criteria for working up for disorders of coagulation, which we’ve put here (though contained in the practice bulletin).

Stay tuned for future episodes about the treatments of these various etiologies, or check out our friends at The OBG Project for excellent summaries of guidelines and new literature!

ACOG PB 128

ACOG PB 128

ACOG PB 128

Cervical Cancer Screening and Prevention

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

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

Follow along with ACOG PB 168!

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • There are adequate negative prior results:

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

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

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

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

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

However, two particular conditions do merit changes to screening:

  • In utero diethylstilbestrol (DES) exposure:

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

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

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

  • HIV or immunocompromising conditions:

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

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

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

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

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

What about HPV vaccination?

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

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

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

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

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

Further Reading from the OBG Project:

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

Cervical Cancer Screening Strategies and Cost-Effectiveness: Which is the Best?