Imaging Evaluation of Nipple Discharge: Review of Literature and Management Considerations

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Nipple discharge is a common and problematic symptom reported by many women seeking evaluation in primary care practices, surgery clinics, and breast radiology facilities. Discharge has been cited as the second to third most reported breast symptom, next to palpable lumps and tenderness.1-3 Numerous groups have discussed management strategies regarding nipple discharge, and there has been a significant evolution away from surgical intervention.

For the radiologist, nipple discharge can be a dilemma for many reasons. For academic medical centers with the availability of a network of clinical breast care personnel, subspecialty-trained breast radiologists, and breast surgeons, a comprehensive evaluation and management strategy is more realistic. In the community setting, managing a patient with nipple discharge can be challenging due to limited time and resources. Fortunately, the vast majority of patients presenting with nipple discharge can be appropriately triaged with a thorough history and physical examination.

For those requiring imaging, mammography and ultrasound are widely available for initial work-up. MRI has also become more commonplace in recent years and has become an important tool in the evaluation process of nipple discharge. Ductography, which is decreasing in popularity, may continue to play a specific role in managing nipple discharge; however, the availability of skilled practitioners may be limited. Our aim in this review is to discuss features that differentiate physiologic from pathologic nipple discharge, provide a literature summary to guide imaging recommendations, and introduce a flow chart as an overview for step-by-step management for the radiologist.

Physiologic vs Pathologic Nipple Discharge

When evaluating a patient with nipple discharge, one of the first steps in a management approach is obtaining a clinical history as well as performing a thorough focused physical examination. In many radiology practices, this is limited given the demands of daily workflow. A clinical office visit may not occur before imaging evaluation, and the patient’s history may not be routinely available upon presentation. One option for radiology practices could be to elicit specific information on a history sheet from each patient presenting with discharge to help guide management. An example of a patient survey is provided, which outlines several of the salient clinical questions pertinent to work-up (Figure 1).

The definitions of physiologic and pathologic nipple discharge pertain to processes that happen within epithelial cells that line the ductal system. Fluctuations in hormone levels including prolactin, estrogen, and progesterone impact the production of fluid secretions. In addition to hormone stimulation, the natural process of cell death with continuous sloughing of the epithelial lining contributes to such secretions. These processes are responsible for physiologic discharge and account for the nonmalignant etiologies.4

Features of physiologic nipple discharge commonly discussed throughout literature include the following: bilaterality, nonbloody (yellow, green, milky, gray) color, multiduct location, and nonspontaneous expression.5 The consensus for work-up of this type of discharge makes the imaging algorithm fairly simple for the radiologist. Once discharge is identified as physiologic, the likelihood of malignancy significantly diminishes.6 In addition, this type of discharge frequently resolves over 1 to 6 months.6 Standard imaging evaluation typically involves ensuring the patient has undergone recent mammographic evaluation and performing a target ultrasound if requested; however, the American College of Radiology (ACR) appropriateness criteria does not recommend any imaging for this type of discharge.7 For physiologic discharge, the color may direct subsequent management. For instance, lab work may be indicated in the setting of milky (prolactin level) or purulent (complete blood count [CBC]) discharge. Discharge that potentially meets these benign criteria may still cause unpleasant symptoms and warrant evaluation and treatment.

Pathologic discharge is discussed throughout literature as being serous or bloody, spontaneous, unilateral, and single duct.4,5 Numerous studies discuss features of discharge and factors predictive of malignancy. Bloody discharge has been demonstrated as a significant predictor of malignancy.8 In addition, single duct discharge is also known to have a significant association with malignancy.9 While such factors may prompt more vigorous work-up, discharge that is persistent or copious without single duct or bloody characteristics may still raise clinical concern.

Mammography and Ultrasound

According to the ACR appropriateness criteria, the management of nipple discharge depends on numerous factors including patient age (under 30 or over 40), biological gender, characteristic of discharge (pathologic or nonpathologic), and availability of advanced imaging modalities.7 The first specification of the appropriateness criteria separates physiologic discharge from the management tree. No imaging is recommended in the setting of physiologic discharge. Because patients are often sent for evaluation without a thorough assessment of the nature of discharge and since these patients commonly have not undergone recent mammography, they may need work-up in a diagnostic clinic to discern the type of examination needed. If possible in a breast imaging center, the ideal scenario would involve a discussion with these symptomatic patients, triaging those in need of imaging. Furthermore, physical examination may confirm discharge characteristics or redirect management strategy. This ideal setting is less common than the typical scenario, which involves a patient presenting with no provided information regarding discharge characteristics and no reported physical examination findings. For this reason, mammography is often performed in women over age 40 who have not undergone mammographic imaging for the past year. With the supportive information of physiologic discharge, this should be a screening mammogram.4

In the setting of pathologic discharge, the recommendation is to begin with diagnostic mammography and ultrasound in patients over age 30. Under age 30, the recommendation supports ultrasound as the initial imaging modality.7 Although mammography is not the most sensitive modality in the assessment of nipple discharge, normal mammography and ultrasound imaging combined with an otherwise normal physical examination (no palpable abnormality) have been shown to be predictive in confirming benignity with only 1 out of 287 malignancies found by Sabel et al.10 In this study, the 1 malignancy was found in a patient who had a history of breast cancer. Excluding this history resulted in no malignancies diagnosed in patients with normal diagnostic mammosonography.10 Gray et al had a similar experience in 204 patients, finding that abnormal mammograms and ultrasounds were predictive of malignancy. In addition, suspicious discharge (in this study, spontaneous, bloody, unilateral, or serous) in the setting of a negative mammogram resulted in an overall risk of malignancy of 3%. When combined with a subareolar ultrasound, the risk was 0%.11

Ultrasound has also been widely used in assessing nipple discharge with studies showing increased cancer detection when added to mammography.12 During routine investigation of discharge, ultrasound plus mammography significantly increases sensitivity.13 Elastography has been investigated as a tool to better characterize intraductal masses. In a study by Zhu et al, supplemental elastography increased both specificity and accuracy compared with ultrasound alone.14 Numerous studies have also documented the benefit of ultrasound in conjunction with galactography15,16 as well as combining ultrasound with galactography and MRI.17

Imaging with mammography in cases of nipple discharge, whether due to benign or malignant causes, is often normal. Several mammographic findings have been described including the following: mass, duct ectasia, focal asymmetry, solitary dilated duct, and microcalcifications. Pathologic causes of nipple discharge manifest on ultrasound as masses (sometimes intraductal, typical of papillomas or ductal carcinoma in situ [DCIS]), duct ectasia, or cysts. Calcifications can also be seen on ultrasound, either within a mass, outside of a mass, or inside the ductal system. A fluid collection can also be seen in cases of nipple discharge. For example, cases of nipple discharge with infectious causes may detect an abscess and cases of postoperative discharge may find seromas or hematomas. Characteristics of malignant ultrasound-detected masses have been reported more commonly as hypoechoic with irregular margins. Benign characteristics tend to favor anechoic and hypoechoic masses with circumscribed margins. Heterogeneity and complex cystic solid features can be seen in both benign and malignant cases but tend to be more common in the malignant category.18 Figures 2-14 demonstrate mammographic and sonographic findings from initial work-up of three cases of pathologic discharge, one due to a papilloma (Figures 2-5), one due to high-grade DCIS (Figures 6-8), and one case of low-grade DCIS (Figures 9-14). Each of these cases also underwent MRI evaluation (Figures 4, 8, and 14).

MRI

Although for over 20 years the role of MRI has been studied in the assessment in nipple discharge,19 many radiologists still debate its utility. The added value of MRI to the work-up of nipple discharge is supported by multiple studies, including a 2011 study by Lorenzon et al, which showed better sensitivity and specificity compared with mammography and ultrasound.20 A 2015 study by Bahl et al showed that in patients with benign sonomammography, negative/benign/probably benign MRI assessments had 100% sensitivity and 100% negative predictive value (NPV).21 In 2017, a retrospective review by Bahl et al confirmed these findings (those with MRI of BI-RADS 1, 2, or 3) with demonstrating a < 4% risk of malignancy in women with negative or inconclusive mammograms.22 Recently, Zacharioudakis et al discussed the use of MRI in the management of nipple discharge in a prospective study involving 82 patients over a 9-year period who underwent mammography and ultrasound examinations with the detection of malignancy in 14 patients who had normal mammographic and sonographic evaluation. MRI was performed on all patients as a part of standard protocol and demonstrated sensitivity, specificity, positive predictive value (PPV), and NPV of 85.71%, 98.53%, 92.31%, and 97.1%, respectively.23 In 2019, a similar study by Zaky et al reported these measures as 100%, 83.3%, 63.6%, and 100%, respectively.24

The ACR appropriateness criteria addresses the use of MRI in the evaluation of nipple discharge; however, for the variants listed in the appropriateness criteria, MRI is listed as a ‘usually not appropriate’ radiologic procedure. This rating is given because each variant addresses only the initial imaging examination for the given scenario. The literature summary in the ACR Appropriateness Criteria goes on to discuss MRI as a valuable tool.7

MRI has been compared with numerous other imaging modalities. In 2003, Nakahara et al reported that compared with galactography and ultrasound, MRI better demonstrated the imaging features of ductal carcinoma DCIS in patients presenting with bloody nipple discharge.25 In 2015, Manganaro et al concluded that MRI had higher sensitivity and specificity compared to galactography in those with clear or bloody discharge.26 Berger et al performed a review of MRI compared to galactography, published in AJR in 2017. They reviewed 10 studies involving 921 patients. Their findings support the use of MRI over galactography in the setting of negative mammosonography.27 In 2014, Lubina et al reported a prospective study of patients with nipple discharge performed using a 3 Tesla (3T) MRI and compared findings to galactography. Based on their results, the recommendation was to replace galactography with 3T MRI due to the improved correlation with lesion size.28

On MRI, various features have been described to correlate with suspicious nipple discharge. Nonmass enhancement (previously described as nonmass-like enhancement) was most common with a segmental distribution, heterogeneous internal enhancement, and plateau kinetics. Additional malignant appearance included clustered-ring enhancement.29 Benign features responsible for pathologic discharge may include nonenhancing proteinaceous debris within the ducts, duct ectasia, cysts, and fluid collections (similar to ultrasound). Other common MRI findings that have been reported in patients presenting with nipple discharge include masses that vary in appearance from those with irregular margins to those with circumscribed margins. Diffuse enhancement has also been noted, which is by far a benign characteristic.18 Figures 4, 8, and 14 are selected images from MRIs performed in patients experiencing nipple discharge. Characteristics include linear nonmass enhancement (Figure 4) corresponding to a papilloma, an irregular mass (Figure 8) corresponding to high-grade DCIS, and clumped segmental nonmass enhancement (Figure 14) corresponding to low-grade DCIS. In Figures 15-23, the use of MRI is illustrated in both benign and malignant scenarios. In Figure 17, MRI was utilized for management purposes in a 23-year-old woman who underwent biopsy of a papilloma (producing nonspontaneous single-duct unilateral bloody nipple discharge) with vacuum-assistance. Figures 15 (ultrasound) and 16 (ductogram) provided depiction of the lesion of interest, which was the intraductal mass (papilloma). MRI (Figure 17) changed management when numerous bilateral similar-appearing enhancing masses were seen, any of which could represent additional papillomas. Discharge had resolved after biopsy and no enhancement was seen at the biopsy site. Surveillance with MRI was, therefore, chosen instead of surgical excision.

Ductography

Ductography, or galactography, involves injection of a contrast agent into the discharging duct followed by mammography. The utility of ductography has been questioned in recent years with several publications documenting the improved performance of other imaging modalities. Ductography has been utilized for decades in the assessment of nipple discharge. While it may not be needed for many cases, galactography provides anatomic information that can guide surgical management.

A clear benefit of galactography is the concept of isolating a specific ductal system. This has been supported throughout literature; for example in 1983 by Tabar et al, demonstrating the less invasive surgical measures needed with use of ductography.30 In assessing the use of galactography in unilateral discharge, Florio et al in 1999 noted an improved detection of malignancy and high-risk lesions,31 and in 2001 Hou et al showed similar benefits.32As more studies investigated the utility of galactography, metrics were found to be less impressive, showing a sensitivity and specificity of 31.2% and 97.4%, respectively, according to Dinkel et al.33 Additional investigation in 2003 described certain features on galactography that had varying predictors with the following sensitivity/specificities: filling defect 55.6% and 62.1%, duct ectasia 22.2% and 94%, filling stop (termination of the duct) 5.6% and 77.6%. In contrast, a normal ductogram was 93% specific for absence of disease but only 78% sensitive.34 A similar description of such imaging features of galactography was supported by Kim et al in 2008.35 More recently in 2018, Istomin et al sought to revisit the role of galactography in the evaluation of pathologic nipple discharge in 146 patients. These patients underwent standard imaging as well as breast MRI, and the calculated sensitivity and specificity of those tests included 77.4%, 75.7% (galactogram) vs 85.7% and 71.4% (MRI).36

Galactography can isolate the site of interest specifically; however, internal features of the causative lesion itself are not assessed. Galactography does assess the changes of the ductal system that occur due to mass effect. Reported galactogram findings include most commonly a solitary filling defect. Other reported findings include irregular appearance of the duct wall, multiple filling defects, and a duct cut-off. Normal ductography as well as a limited or incomplete galactogram are also reported.18 Figures 16, 18, 24, and 27 demonstrate ductography findings in patients with pathologic nipple discharge. The pathologies include papilloma, papillary DCIS, atypical ductal hyperplasia (ADH) with other high-risk lesions (radial scar, complex sclerosing lesion and papilloma), and papilloma with atypia, respectively. Figures 24-26 demonstrate a work-up of unilateral single-duct bloody nipple discharge, for which mammography and initial ultrasound were negative. After ductogram (Figure 24), ultrasound (Figure 25) was able to appropriately identify a small intraductal mass corresponding to a filling defect. Ductogram also aided in localizing the abnormal ductal system for surgery. Figures 27-29 provide a similar management technique. Neither case underwent MRI evaluation, which may have impacted management.

Less Commonly Used Imaging Modalities

Molecular breast imaging (MBI) and positron emission mammography (PEM) currently are not recommended in the evaluation of nipple discharge per the ACR appropriateness criteria.7 Both modalities can identify metabolically active processes within the breast; however, evidence is lacking for their routine use in the evaluation or management of discharge.

Contrast-enhanced spectral mammography (CESM) has not been widely studied in patients presenting with nipple discharge. Certain causes of nipple discharge, such as papillomas and DCIS, are known to be visualized with CESM. The performance of CESM compared with MRI was evaluated by Hegazy et al in a 2020 retrospective review of 37 biopsy-proven papillomas. This study reported that CESM was significantly lacking in specificity for papillomas of all sizes and sensitivity for lesions < 5 mm.37At this time, CESM is not recommended in the routine evaluation of nipple discharge.7

MR ductography, which uses a heavily T2-weighted sequence to better identify intraductal lesions, has been described by several authors. It can be performed in conjunction with the administration of IV contrast and, subsequently, the T2-weighted and contrast-enhanced images are fused.38 In 2010, this technique was compared to conventional galactography and was proposed as a comparable alternative by Wenkel et al.39 In 2015, Nicholson et al similarly used contrast-enhanced MRI, conventional galactography, and MR galactography to evaluate a small group of patients (n = 20) in a feasibility study. They reported sensitivity, specificity, PPV, and NPV as 65, 33.3, 76.5, and 22.2 for conventional galactography, vs 95, 66.7, 90.5, and 80.8 for contrast-enhanced MRI, and 55, 66.7, 84.6, and 30.8 for MR galactography.40 As recently as 2020, the use of MR ductography was retrospectively evaluated by a group in Thailand, showing a sensitivity of 100%, NPV of 100%, but specificity of 38%.41 Currently, the use of MR ductography for evaluating nipple discharge is not endorsed by the ACR appropriateness criteria.7

CESM has not been utilized for large volume studies in evaluating nipple discharge at this time, but findings on CESM have been reported in cases involving patients with nipple discharge, most recently by Hegazy et al as previously referenced.37 In studying papillomas for which 84% presented with nipple discharge, the contrast mammography findings were most commonly described as nonmass enhancement, followed by no enhancement and, least commonly, an enhancing mass.37 Specific use of MBI or PEM to evaluate nipple discharge may be available in case reports or pictorial reviews; however, no large studies have been designed to evaluate imaging characteristics of nipple discharge with these modalities.

Surgery

For many years, central duct excision (CDE or subareolar excision, SAE) was the mainstay of treatment for pathologic nipple discharge. The various imaging modalities previously described, primarily mammography, ultrasound, galactography, and MRI, have been used to localize and guide surgical intervention. Prior to the wide use of MRI, the lack of imaging to provide a consistently high negative predictive value prompted routine CDE due to the rate of malignancy in patients presenting with nipple discharge, up to 12.7% in postmenopausal females according to Lau et al.42 A review from a 20-year follow-up in patients presenting with pathologic nipple discharge reported outcomes from CDE, citing no missed malignancies.43 In 2010, Alcock and Layer also retrospectively evaluated patients with pathologic nipple discharge with a final recommendation of either major or minor duct excision as the recommended diagnostic and therapeutic intervention.44 Morrogh et al echoed this recommendation after review of 287 cases.45 Sabel et al contradicted these recommendations more recently in 2011, only finding one malignancy in follow-up of a group of 142 patients with pathologic nipple discharge after complete imaging work-up and surgical intervention appropriately diagnosed and treated malignancy in seven.46 One suggested alternative to surgery is the use of interventional ductoscopy in the treatment of nipple discharge; however, this is not as widely reported. Filipe et al described this procedure involving 215 patients (60 eventually undergoing surgery), and reported no major complications.47 Recently, CDE has become less favored due to the improved diagnostic capabilities of imaging combined with appropriate triage of symptomatic patients.

Risk Stratification

Risk stratification of patients has been discussed as a means of potentially averting surgery. A study by Gray et al in 2007 found that age (> 50 years) and abnormal imaging (mammography and ultrasound) were factors predictive of malignancy.48 Cytologic examination has also been evaluated and found to have a PPV of 85% when breast imaging was abnormal.49 Regarding the characteristics of discharge, unilateral, bloody, and single-duct discharge have strong associations with malignancy according to Wong Chung et al. Unfortunately, they found that the lack of such characteristics alone was not sufficient to exclude malignancy. It is important to note that the advanced imaging modalities discussed above were not utilized for work-up in this study.50

Throughout literature, risk stratification has been discussed when concerning management strategies. In 2015, Dupont et al found that a prior history of ipsilateral breast cancer, BRCA mutation, or atypia on core-needle biopsy were associated with malignancy. Without these findings, the cancer risk was < 2%.51 The presence of symptoms other than nipple discharge has also been associated with higher risk for breast cancer, noted by Li et al who found that palpable masses were independently associated with suspicious malignancy in patients presenting with pathologic nipple discharge.52

Management Algorithm

Considering the data regarding the imaging options discussed, Figure 30 provides a flow chart geared toward radiologists caring for patients presenting with nipple discharge. Using the questionnaire provided in Figure 1, the characterization of discharge can be categorized into either pathologic or physiologic. It is important to note that if any one of the suspicious characteristics of discharge is present (unilateral, bloody, brown, clear, single-duct, or spontaneous), the pathologic algorithm should be considered. Mammography and ultrasound are recommended in accordance with ACR appropriateness criteria, and if no lesion is identified, MRI is recommended if available. If a lesion is identified, biopsy should follow, and malignant results should be handled as oncologic guidance deems appropriate. Depending on breast density and patient age, this may include MRI. If no malignancy or culprit for discharge is found or if a papilloma or other high-risk lesion is identified, MRI is suggested. As indicated in the algorithm, MRI should be considered for preoperative evaluation even in nonmalignant cases. MRI may identify occult lesions that could need work-up, may delineate greater extent of disease than expected (change surgical planning), or may provide information that could allow for nonsurgical management altogether (in the setting of multiple bilateral similar-appearing masses). In the setting of mammographically and sonographically occult lesions, MRI has an obvious role for evaluation. If the culprit mass is identified, MRI also provides a method for biopsy. If no mass is identified, symptoms should be re-addressed and management determined by the clinical scenario. Ductography provides the additional step needed in cases where nonmalignant but clinically problematic issues continue (such as surgical localization for cases of persistent yet benign discharge), primarily if there is involvement of only one or two ducts. Unfortunately, clinically problematic cases of multiduct (greater than two) discharge may still warrant CDE for symptomatic relief.

Conclusion

The evaluation, management, and treatment of nipple discharge has evolved significantly to allow for less invasive measures while appropriately identifying those with malignancy. For this strategy to be effective, all elements of work-up must be addressed, beginning with the basic patient history, including characterization of discharge, personal history of breast cancer, and elevated lifetime risk of breast cancer, and ideally this should be followed by physical examination of discharge. Furthermore, an imaging strategy can be introduced to allow for appropriate triage of patients in need of more advanced imaging. The role of MRI has altered the course of nipple discharge management due to the high negative predictive value in certain cases. For many patients, surgical management can be averted due to MRI’s contribution to the imaging algorithm. For certain types of discharge, primarily involving one or possibly two ducts, galactography can not only minimize surgical intervention but can isolate a specific duct system that may be problematic yet not malignant. For this reason, none of the aforementioned primary imaging modalities should be obsolete when discussing nipple discharge.

References

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Woodard SA, Allen E, Ahuja K.  Imaging Evaluation of Nipple Discharge: Review of Literature and Management Considerations.  J Am Osteopath Coll Radiol.  2021;10(1):19-32.

About the Author

Stefanie Woodard, D.O.; Elizabeth Allen, M.D.; Kriti Ahuja, M.B.B.S.

Stefanie Woodard, D.O.; Elizabeth Allen, M.D.; Kriti Ahuja, M.B.B.S.

1Dr. Woodard and Dr. Allen are with the Department of Radiology, The University of Alabama at Birmingham, Birmingham, AL and Dr. Ahuja is with the Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL.



 

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