Ilana Cass, MD

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These ten images can help ob/gyns recognize the additional information GBCA administration provides in MRIs.

The value of GBCA in MRI images

Gadolinium-based intravenous contrast agents (GBCA) provide additional information based on signal intensity changes after GBCA administration. 

8 examples of how GBCA improves MRI

Magnetic resonance imaging (MRI) uses magnetic fields to provide detailed anatomic images that reflect distribution and magnetic properties of tissues (specifically of hydrogen nuclei in water and fat) to aid in diagnosis of many pathologic conditions. Gadolinium-based intravenous contrast agents (GBCA) provide additional information based on signal intensity changes after GBCA administration. GBCA are used in approximately 45% of MRI exams in the United States. In the 30 years since the first GBCA was introduced into clinical practice, almost a half billion enhanced MRI studies have been performed worldwide. In the field of gynecology, MRI is widely used to enhance detection of early breast cancers in women at elevated risk, or to better delineate complex pelvic anatomy in the setting of prior pelvic surgery, severe endometriosis, distorting fibroids, cervical, uterine cancer or ovarian cancer.

A recent concern with use of GBCA surfaced in 2014, when the link between permanent high T1 signal in the dentate nucleus and globus pallidus of the brain and repeated prior GBCA exposure was identified.

 Post-mortem analysis of these deep brain structures confirmed that gadolinium deposition in the brain of patients who had GBCA-enhanced MRI of any part of the body. Specifically, higher signal intensities were seen in patients who had undergone at least six contrast-enhanced MRI examinations compared to patients who had undergone only non-contrast MRI. Case reports in children noted the same pattern of gadolinium deposition as that seen in adult patients following GBCA.

Industry-sponsored studies in rats serially exposed to GBCA found progressively higher signal intensity on imaging, which correlated with post-mortem gadolinium concentrations in the brain.

 Notably, at the time of this writing, no human or animal data have shown any association between GBCA exposure and neurologic toxicity or neurological symptoms related to gadolinium deposition in the dentate nucleus of globus pallidus.

Ob/gyns need to be aware of the current data about gadolinium-based contrast and the potential implications of its use when they order MRI for their patients.


	In response to the reports of gadolinium deposition in the brain of GBCA-exposed individuals, the US Food and Drug Administration (

) required a new class warning and other safety measures for all GBCA for MRI in December 2017. Updates to GBCA labeling in May 2018 stated that GBCA was safe and should be used when medically necessary, and directed MRI centers to make educational information available to every outpatient the first time they receive GBCA.

 includes risk of gadolinium retention associated with the two types of GBCA (linear and macrocyclic) and indicates that linear GBCA appears to result in higher retention for longer periods of time than macrocyclic GBCA. Providers are encouraged to consider patient characteristics that may result in increased risk of gadolinium retention, and to minimize closely spaced or multiple GBCA MRI. 

Gulani and colleagues, on behalf of the International Society for Magnetic Resonance in Medicine (

) summarized the evidence and offered guidelines to clinicians in 

 They highlighted incomplete understanding of the clinical implications and mechanisms that drive gadolinium deposition, and discordant data comparing different types of gadolinium. The authors advised health care professionals to use caution when administering GBCA and to carefully document 

a specific GBCA is given to a patient. They did not endorse macrocyclic over linear GBCA, and suggested that patient and clinical factors in addition to pharmacokinetics of the available agents should guide selection of the best GBCA. The American College of Radiology independently endorsed the same recommendation.

 Finally, the ISMRM Summary urged ongoing research to elucidate clinical implications of gadolinium deposition. The Pharmacovigilance 

Risk Assessment Committee of the European Medicines Agency

 has proposed a ban on all linear agents. Radiologists from the 

 have recommended that use of macrocyclic rather than linear agents be considered, if possible.

Implications for MRI utilization in gynecology


	MRI imaging of the pelvis is indicated to further characterize masses seen on computed tomography (CT) or ultrasound. An MRI without contrast offers sensitivity comparable to CT with contrast and superior specificity in diagnosis of adnexal malignancy following an indeterminate ultrasound.

 MRI provides better assessment of soft tissue structures and improved localization of pelvic masses, which is useful to discriminate between ovarian and uterine pathology. T2-weighted imaging is helpful in determining whether the lesion is a unilocular cyst, mixed solid and cystic, or homogeneously solid. T1-weighted imaging without and with fat saturation allows for detection of adnexal lesions containing macroscopic fat. Fat-saturated T1-weighted imaging is useful for identifying ovarian endometriomas, extraovarian endometriosis, and other lesions with blood degradation products, such as hemorrhagic cysts.

 Adding contrast may allow better discrimination between benign and malignant pathology due to the kinetics of contrast enhancement and washout, although its use may vary by institutional MRI protocol. 

The incremental additional clinical information that is gained with use of GBCA in MRI evaluation of variant pelvic anatomy and suspected benign pathology is small. Adding GBCA has been shown to improve evaluation of myometrial invasion from endometrial carcinoma

 and identification of the correct primary tumor when there are multiple sites of biopsy-proven uterine adenocarcinoma.

 Contrast may also be useful in identifying vulvar cancers and occult inguinal metastases

 and it has shown to be useful in identifying neoplastic nodules within complex adnexal lesions and distinguishing endometriosis from pelvic inflammatory disease.

Breast cancer screening in high-risk women


	Intensive breast cancer surveillance is advised for women at the highest risk of breast cancer. Women with inherited genetic susceptibility due to 

 and other less well-known germline mutations (CHEK2, ATM, PALB2), family history, prior chest radiation (cumulative dose > 10 Gy before age 30), or calculated lifetime risk of breast cancer exceeding 20% or more are advised to start breast cancer screening between ages 25 and 30.

 While mammography remains the gold standard for breast cancer screening in the general population, it has been less successful in detection of early, curable cancers in higher-than-average-risk patients. Prospective studies of annual mammography in 

-positive women showed an interval cancer rate of 35% to 50% and the majority of invasive cancers were > 1 cm and 20% to 56% of them had lymph node involvement.

 Some factors cited to explain the poorer detection of 

-associated breast cancer may relate to the confounding effect of breast density, which is more common in younger women. Mammography relies upon abnormal tissue density, tissue distortion, and calcifications to identify breast cancers. 

-associated breast cancers tend to be less mammographically detectable than sporadic breast cancers, which has been attributed to their distinctive histologic growth patterns, such as pushing borders, the relative absence of associated ductal carcinoma in situ, and high cellularity.

In observational studies, adding contrast-enhanced MRI to annual mammography in BRCA mutation carriers significantly improved detection of early, treatable breast cancers with a combined sensitivity of 94% compared to 39% with mammography alone.

 MRI provides a functional assessment of breast tissue. Contrast- enhanced MRI can detect microvascular changes and peritumoral inflammation as the contrast accumulates rapidly, and is then washed out rapidly, in more vascular tumors compared to benign breast tissue. Consequently, annual contrast-based MRI has been incorporated into breast cancer surveillance guidelines for women at the highest risk of breast cancer.

There has been no change to the recommendation of annual breast MRI by the 

 due to the increased benefit of early detection of cancer in these high-risk patients.

 In view of the concerns raised over GBCA, macrocyclic agents are advised, and alternatives to conventional MRI imaging are being investigated. These include investigations of lower-dose gadolinium scans

 or alternative MRI contrast agents such as Feraheme (ferumoxytol an ultrasmall, superparamagnetic iron oxide nanoparticle), which is currently used for vascular imaging.

Some high-volume centers enriched with populations of BRCA mutation carriers have amended the recommended surveillance for women at high risk of breast cancer. Breast ultrasound may be alternated with annual MRI, in addition to annual mammography. Ongoing study of novel strategies to improve the mammogram, such as use of iodinated contrast and breast tomosynthesis, which creates a 3-D image of the breast by stacking multiple 2D mammographic renderings, are underway in women with BRCA mutations. Such advances may allow reduction in cumulative exposure to GBCA in these high-risk women.

Weighing risks and benefits in women at high risk


	While it’s discomforting to consider progressive accumulation of gadolinium in the body over time, the clinical consequences and level of risk associated with GBCA are, as yet, unknown. On the contrary, the consequences of missing an aggressive breast cancer are all too well known. In the absence of an effective non-gadolinium alternative to GBCA, until we have more definitive data on the true risk of gadolinium deposition, we forego surveillance of women at high risk of breast cancer with contrast-enhanced MRI at our peril. Best practice suggests that providers consider the necessity of contrast based upon clinical circumstances, and that macrocyclic rather than linear agents be used when necessary.

 Judicious use of gadolinium, coupled with vigilance in identifying women who might be pregnant, can minimize inadvertent fetal exposure to gadolinium, which is estimated to occur in 1 in 860 pregnancies in the United States.

The authors report no potential conflicts of interest with regard to this article.

Kanda T, Osawa High signal intensity in dentate nucleus on unenhanced T1 weighted MRI images: association with linear versus macrocyclic gadolinium chelate administration. 

Roberts DR, Holden KR. Progressive in of T1 signal intensity in the dentate and nucleus and globus pallidus on unenhanced T1-weighted MR images in the pediatric brain exposed to multiple doses of gadolinium contrast. 

Robert P, Lehericy S, Grand S, et al. T1 weighted images hypersignal in the deep cerebellar nuclei after repeated administrations of gadolinium-based contrast agents in healthy rats: difference between linear and macrocyclic agents. 

Terashima KH, Reich DS. Gadolinium deposition: practical guidelines in the face of uncertainty. 

FDA Safety Communication 5/16/2018 Update https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body

Gulani V, Calamante FG, Shellock FG, et al. Gadolinium deposition in the brain: summary of evidence and recommendations 

American College of Radiology. Committee on Drugs and Contrast Media. ACR Manual on Contrast Media, Version 10.3. Available at https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf Accessed April 10, 2018.

European Medicines Agency. PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension of for some marketing authorizations. March 2017 Available at 

http://www.ema.europa.eu/docs/en_GB/documnent_library/Press_release/2017/03

Kinkel K, Lu Y, Mehdizade A, et al. Indeterminate ovarian mass at US: incremental value of second imaging test for characterization–meta-analysis and Bayesian analysis. 

Masch WR, Daye D and Lee SI. MRI imaging for incidental adnexal mass characterization. 

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Bazot M, Bharwani N, Huchon C, Kinkel K, et al. European society of urogenital radiology (ESUR) guidelines: MR imaging of pelvic endometriosis. 

Nougaret S, Horta M, Sala E, Lakhman Y, et al. Endometrial Cancer MRI staging: Updated Guidelines of the European Society of Urogenital Radiology. 

Vargas HA, Akin O, Zheng J, Moskowitz C, et al. The value of MR imaging when the site of uterine cancer origin is uncertain. 

Kataoka MY, Sala E, Baldwin P, et al. The accuracy of magnetic resonance imaging in staging of vulvar cancer: a retrospective multi-centre study. 

Suzuki S, Yasumoto M, Matsumoto R, Andoh A. MR findings of ruptured endometrial cyst: comparison with tubo-ovarian abscess. 

Tanaka YO, Okada S, Yagi T, et al. MRI of endometriotic cysts in association with ovarian carcinoma. 

Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. 

Monticciolo DL, Newell MS, Moy L, Niell B, Monsees B, Sickles EA. Breast cancer screening in women at higher-than-average risk: recommendations from the ACR. 

Brekelmans CTM, Saynaeve C, Bartels CC, et al. Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. 

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Warner E Messersmith H, Causer P, et al. Systematic review: Using MRI to screen women at high risk of breast cancer. 

Daly MB. PIlarski R, Berry MP, Buys SS et al. Genetic/familial high risk assessment: breast and ovarian cancers. Version 2.2019. Available at 

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Rowley H. To be alarmed or not to be alarmed over gadolinium contrast revelations: That is the question. European Congress in Radiology 2017 Annual Meeting. Available at 

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Articles

Concerns have been raised about the safety of GBCA. Experts review the latest data to support counseling of patients who may have repeated exposure.

Gadolinium-based contrast in breast MRI: What ob/gyns need to know

COMMITTEE ON PRACTICE BULLETINS-GYNECOLOGY 

Practice Bulletin #179: Breast Cancer Risk
	Assessment and Screening in Average-Risk Women. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;130:e1-16. Full text of Practice Bulletin #179 is available to ACOG members 

BREAST CANCER RISK ASSESSMENT AND SCREENING IN AVERAGE-RISK WOMEN

Breast cancer is the most commonly diagnosed cancer in women in the United States and the second leading cause of cancer 

 starting at age 40 years reduces breast cancer mortality in average-risk women

. Screening, however, also exposes women to harm through false-positive test results and overdiagnosis of biologically indolent lesions. Differences in balancing benefits and harms have led to differences among major guidelines about what age to start, what age to stop, and how frequently to recommend mammography screening in average-risk women

Breast cancer risk assessment is very important for identifying women who may benefit from more intensive breast cancer surveillance; however, there is no standardized approach to office-based breast cancer risk assessment in the United States. This can lead to missed opportunities to identify women at high risk of breast cancer and may result in applying average-risk screening recommendations to high-risk women. Risk assessment and identification of women at high risk allow for referral to health care providers with expertise in cancer genetics counseling and testing for breast cancer-related germline mutations (eg, 

), patient counseling about risk-reduction options, and cascade testing to identify family members who also may be at increased risk. 

The purpose of this Practice Bulletin is to discuss breast cancer risk assessment, review breast cancer screening guidelines in average-risk women, and outline some of the controversies
		surrounding breast cancer screening. It will present recommendations for using a framework of shared decision making to assist women in balancing their personal values regarding benefits and harms of screening at various ages and intervals to make personal screening choices from within a range of reasonable options. Recommendations for women at elevated risk and discussion of new technologies, such as tomosynthesis, are beyond the scope of this document and are addressed in other publications of the American College of Obstetricians and Gynecologists (ACOG)

Used with permission. Copyright the American College of Obstetricians and Gynecologists.

In 2009, the U.S. Preventative Services Task Force (USPSTF) updated their 2002 recommendations for breast cancer screening for average-risk women, based upon a systematic evidence review and decision analysis modeling, to lengthen the screening interval and accelerate the ending age of mammography.

 In 2015, the American Cancer Society issued an update of its 2003 screening mammography guidelines to reflect new evidence from long-term follow-up of population-based screening programs.

 Both of these updates departed significantly from prior screening guidelines by advocating for a later age to start screening, age-dependent screening intervals, and no longer recommending periodic clinical breast exams or self-breast exams in combination with mammography as effective screening tools. 

Interpretation of these guidelines, based upon a reasonable balance of the associated benefits and harm, has led to variation in major expert opinions and guidelines regarding breast cancer screening for average risk women. Differences between these guidelines, notably the ages to start and end screening, as well as the optimal interval between screening, has created challenges for both patients and providers in choosing the most appropriate approach to screening. 

In Practice Bulletin #179 published July 2017, which replaces #122, ACOG addresses some of the controversy surrounding optimal breast cancer screening for average risk women.

 ACOG confirms the benefit of screening mammography to reduce breast-cancer associated mortality and the need for advanced cancer treatment, while acknowledging the potential associated adverse consequences, including false-
			positive test results, anxiety/discomfort, overdiagnosis and overtreatment, and radiation exposure.

 These guidelines emphasize the importance of shared decision-making to allow patients to take an informed and active role in their health care.  

ACOG encourages physicians to use the clinical encounter as an opportunity to educate a patient about breast cancer risks and prevention, to elicit her family and medical risk, and to periodically determine if the patient’s risk factor profile has changed. ACOG recognizes that there is no single standardized model to assess breast cancer risk.  Women who are identified as having potentially increased breast cancer risk, based upon a combination of family or personal cancer history, demographic characteristics, reproductive history or hormonal exposure, and breast disorders, merit additional risk assessment using several validated tools outlined in Practice Bulletin #179. 

Shared decision-making involves candid dialogue between doctor and patient to elicit the patient’s values, goals of care, and perception of risk. To facilitate this discussion, Practice Bulletin #179 highlights the lifetime benefits and harms associated with commencing breast cancer screening in average-risk women at age 40 versus 50, and those associated with different screening intervals. Specifically, Tables 3 and 4 provide practical data on important considerations such as false-positive test results and unnecessary breast biopsies and balance these against life-years gained and disease-specific mortality to help guide decision making. 

Breast self-awareness and clinical breast exam

The updated ACOG guidelines do not recommend breast self-examination in average-risk women based upon an unfavorable harm/benefit ratio.  Breast self-awareness in average-risk women is endorsed by ACOG based upon the evidence that most breast cancers are detected by women themselves. ACOG encourages education about the signs and symptoms of breast cancer so women are alerted to changes in their breasts that require evaluation. ACOG suggests that the clinical breast exam may be offered to asymptomatic, average-risk women starting at age 25 until age 39 every 1 to 3 years and annually thereafter, despite the controversy over whether the small gain in enhanced detection of breast cancers results in improved patient outcomes. The clinical breast exam remains an important part of the evaluation for symptomatic or high-risk women.
			 

Some guidelines endorse screening until age 75. The utility of breast cancer screening for women over age 75 is limited based upon lack of data. This is a significant omission given that the average 75-year-old woman in the United States in 2018 is expected to live over 12 additional years.

 Amidst the controversy surrounding when to cease breast cancer screening, ACOG asserts that age alone should not be the basis for decisions regarding discontinuation of screening mammography. Practice Bulletin #179 suggests that shared decision-making and a general health assessment using clinical judgement and predictive models are the best tools to inform decisions about breast cancer screening. ACOG states that screening mammography is not appropriate for women who would not choose further evaluation of abnormal results.  
			 

Despite recent changes in breast cancer screening guidelines, there has been minimal impact on the interval or use of breast cancer screening.

A cohort study of 12 million Medicare fee-for-service women aged 65 or older found no significant decrease in frequency of mammograms between 2007-2009 (before) and 2010-2012 (after) despite the 2009 USPSTF recommendations for biennial, rather than annual, mammogram screening and to discontinue screening at age 75.

Another prospective study of women aged 40 to 74 who received screening mammograms between 2006 and 2012 using data from the Breast Cancer Surveillance Consortium reported no change in the intervals between mammograms following the 2009 USPSTF guidelines for any age group.

 The authors of both studies concluded that the lack of change may reflect patient choice and conflicting recommendations from clinicians. Further study is needed to evaluate the impact of the 2015 American Cancer Society guidelines on screening mammography, and patient perceptions of the guideline changes. In the interim, ACOG Practice Bulletin #179 offers a pathway to promote informed decision-making to align providers and patients to improve compliance with breast cancer screening recommendations.

The author reports no potential conflicts of interest with regard to this article.

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An examination of ACOG’s updated guidelines on breast cancer screening recommendations for the average-risk woman.

Author | Ilana Cass, MD

Articles

The value of GBCA in MRI images

8 examples of how GBCA improves MRI

Gadolinium-based contrast in breast MRI: What ob/gyns need to know

Breast cancer risk assessment and screening