- Email: [email protected]
Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies?
Accepted Manuscript Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies?
Eric T. Foo, Amie Y. Lee, Kimberly M. Ray, Genevieve A. Woodard, Rita I. Freimanis, Bonnie N. Joe PII: DOI: Reference:
S0899-7071(17)30113-4 doi: 10.1016/j.clinimag.2017.06.004 JCT 8263
To appear in: Received date: Revised date: Accepted date:
26 March 2017 25 May 2017 7 June 2017
Please cite this article as: Eric T. Foo, Amie Y. Lee, Kimberly M. Ray, Genevieve A. Woodard, Rita I. Freimanis, Bonnie N. Joe , Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies?, (2017), doi: 10.1016/ j.clinimag.2017.06.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies?
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Eric T. Foo, BS1 Amie Y. Lee, MD1 Kimberly M. Ray, MD1 Genevieve A. Woodard MD, PhD1 Rita I. Freimanis MD1 Bonnie N. Joe, MD, PhD1
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1. Department of Radiology and Biomedical Imaging, University of California San Francisco, 1600 Divisadero Street, San Francisco, CA 94115
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Address correspondence to: Amie Y. Lee, M.D. University of California, San Francisco Department of Radiology and Biomedical Imaging 1600 Divisadero Street, Room C250, Box 1667, San Francisco, CA 94115, USA Phone: 415-885-8464 Fax: 415-885-7876 Email: [email protected]
Manuscript Type: Original Research
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Disclosures: The authors have no relevant financial or nonfinancial reltationships to disclose.
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IRB Statement: This study was performed with approval from our insititutional review board.
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Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ABSTRACT Purpose:
To review the use of diagnostic breast imaging and outcomes for symptomatic male patients. Methods:
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ACCEPTED MANUSCRIPT We retrospectively evaluated 122 males who underwent diagnostic imaging for breast symptoms at our academic center. Results: The majority (94%) of cases had negative or benign imaging, with gynecomastia
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being the most common diagnosis (78%). There were two malignancies, both of
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which had positive imaging. Fifteen patients underwent percutaneous biopsy,
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and over half (53%) were palpation-guided biopsies initiated by the referring clinician despite negative imaging. Diagnostic imaging demonstrated 100%
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sensitivity and 96% specificity for identifying cancer.
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Conclusions:
Malignancy is rarely a cause of male breast symptoms. Diagnostic breast
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imaging is useful to establish benignity and avert unnecessary biopsies.
Keywords: mammography, male breast symptoms, gynecomastia, male breast
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cancer
1.1 INTRODUCTION A breast symptom is the most common reason male patients present for breast imaging. Gynecomastia, the most frequent cause of such symptoms, is a benign enlargement of male breast tissue, predominantly composed of ductal, stromal, and adipose tissue. It is a common condition, with one study reporting a
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ACCEPTED MANUSCRIPT prevalence of 65 percent in the hospitalized male population [1]. The majority of cases of gynecomastia are idiopathic or related to puberty; however, medications, cirrhosis and primary hypogonadism also play important roles [2, 3]. In contrast, male breast cancer is rare, with only 2,350 new cases
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diagnosed per year in the US, which accounts for less than 1% of all breast
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cancer cases [4]. Unfortunately, the majority (81-90%) of male breast cancers
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are invasive at presentation [5, 6]. Thus, prompt evaluation and diagnosis are crucial. In certain instances, male breast cancer and gynecomastia can be
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difficult to confidently differentiate based on clinical breast exam alone. In such
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instances, further evaluation with mammography and/or ultrasound may be warranted.
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In a recent study of 557 male breast patients who underwent breast
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imaging, Lapid et al. [7] detected malignancy in five patients (0.89%). The authors concluded that male breast cancer is rare and routine imaging of
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gynecomastia is not warranted. Most patients (93%) in this study had negative or
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benign (BI-RADS 1 or 2) imaging. While only nine patients had suspicious findings on imaging (BI-RADS 4 or 5), 160 patients underwent biopsy based on
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clinical findings, suggesting that many of the biopsies were unnecessary. According to the American College of Radiology (ACR) appropriateness criteria [8], targeted ultrasound is recommended for the initial evaluation of males under the age of 25 years with an indeterminate palpable breast mass. For males age 25 years and older, diagnostic mammography is recommended for initial evaluation with supplemental ultrasound as needed. If imaging reveals a lesion
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ACCEPTED MANUSCRIPT that is suspicious or highly suggestive of malignancy (BI-RADS 4 or 5), biopsy is indicated for definitive diagnosis. The purpose of this study was to review the use and outcomes of diagnostic breast imaging in symptomatic male patients at our academic breast
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imaging center. We hypothesize that breast imaging adds clinical value by safely
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and accurately excluding breast cancer, establishing benign diagnoses, and
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averting unnecessary breast biopsies for patients with negative or benign
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imaging results.
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1.2 MATERIALS AND METHODS 1.2.1 Patient Population:
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This study was performed with approval from our Institutional Review
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Board, and all procedures were compliant with the Health Insurance Portability and Accountability Act. A retrospective chart review was completed on all male
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patients who received breast imaging in our radiology department over the
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course of 10 years, from August 2004 to October 2014. A total of 211 patients were identified and all available data was retrieved
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from the patient’s electronic medical records. Exclusion criteria included high-risk screening mammography (19), female to male transgender patients (6), male to female transgender patients (1), imaging for non-breast symptoms (1), insufficient (less than one year) clinical follow-up to confirm benignity (58), and imaging not in accordance with ACR appropriateness criteria recommendations (4), which included initial workup with breast MRI or ultrasound without
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ACCEPTED MANUSCRIPT mammography in patients 25 years of age or older. This yielded a final study cohort of 122 patients. 1.2.2 Imaging Technique and Interpretation: Mammography, targeted ultrasound, or a combination of mammography
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and ultrasound were used in accordance with ACR guidelines. Diagnostic
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mammography was performed for the initial evaluation in males age 25 years
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and older. This consisted of craniocaudal (CC) and mediolateral oblique (MLO) full field digital mammographic images of both breasts. Additional mammographic
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images, such as other orthogonal views or spot compression magnification
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images, were obtained at the discretion of the interpreting radiologist. If the mammogram was clearly negative or benign, no further imaging was performed.
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Targeted breast ultrasound was performed for patients younger than 25
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years or if there were indeterminate mammographic findings in older patients. Breast ultrasound was performed using standard technique specifically targeted
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to the site of clinical concern. All ultrasounds were performed directly by the
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interpreting radiologist or by a radiology trainee under the direct supervision of the interpreting attending radiologist.
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All images were interpreted in real-time and reported by an attending radiologist subspecializing in breast imaging (Range of attending experience 1 year to >30 years). Reporting and assignment of final BI-RADS categories were based on the most current edition of the ACR BI-RADS Atlas at the time of imaging, which spanned three editions [9-11]. In patients who underwent both
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ACCEPTED MANUSCRIPT mammography and ultrasound, a combined final BI-RADS assessment was assigned by the interpreting radiologist based on findings of both modalities. 1.2.3 Percutaneous Biopsy Ultrasound guided percutaneous sampling was performed with either core
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needle biopsy or fine-needle aspiration. Core needle biopsies were performed
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using a 14-G spring-loaded automatic biopsy device. Fine needle aspirations
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were performed with a 25-G needle with a cytopathologist immediately present for real-time review of the aspiration sample to determine diagnostic adequacy.
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All palpation-guided fine-needle aspirations were performed by the
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cytopathologist in the cytology clinic without imaging guidance. 1.2.4 Data Collection and Analysis:
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Patient demographics and clinical history were recorded from review of
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the patient’s electronic medical records and radiology reports. Imaging data, including BI-RADS assessment categories, were obtained from the radiology
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reports. Biopsy results were obtained from the pathology and cytology reports.
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All data were collected in REDCap, a web based, secure, data capture software. Malignant diagnoses were confirmed with histopathology from
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percutaneous biopsy and from subsequent surgical excisions. For negative or benign cases diagnosed by imaging and/or percutaneous biopsy, the absence of malignancy was confirmed based on at least one year of clinical and/or imaging follow-up. Descriptive statistics and 2x2 table analyses were performed. BI-RADS assessment categories were dichotomized into negative (BI-RADS 1 and 2) and
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ACCEPTED MANUSCRIPT positive (BI-RADS 4 and 5). As noted above, in patients who underwent both mammography and ultrasound, a combined final BI-RADS assessment was assigned by the interpreting radiologist based on the findings of both modalities. For examinations assigned a different BI-RADS category for each breast, a
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single examination-level BI-RADS was assigned according to the following
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hierarchy: BI-RADS categories 5, 4, 2, 1. There were no BI-RADS 0, 3, or 6
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assessments in this study population. Sensitivity, specificity, negative predictive
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values and positive predictive values were calculated.
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1.3 RESULTS 1.3.1 Patient Characteristics:
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A total of 122 patients met inclusion criteria. Mean patient age was 57
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years (range 17-92). The majority of patients (53%) were 60 years or older. Patients were most frequently referred for breast imaging by their primary care
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(40%), oncology (16%), surgery (4%), and urology (4%) providers. The most
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common indications for imaging were a palpable mass (68%), pain/tenderness (46%), and/or swelling/enlargement (20%). Imaging indications are summarized
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in Table 1. Relevant patient past medical history, including clinical diagnoses associated with gynecomastia and personal histories of malignancy, are summarized in Table 2. 1.3.2 Imaging Evaluation: Eighty-three (68%) patients underwent diagnostic mammography alone, two (2%) underwent ultrasound alone, and 37 (30%) had a combination of
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ACCEPTED MANUSCRIPT diagnostic mammography and ultrasound. The majority of exams had no suspicious finding and were assigned a BI-RADS assessment of 1 or 2 (115; 94%). Seven (6%) exams had a suspicious or highly suggestive of malignancy finding and were given a BI-RADS assessment of 4 or 5. Of those with breast
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imaging findings, 46 (41%) were unilateral and 65 (59%) were bilateral.
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Gynecomastia was the most common benign finding on imaging, present
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in 95 (78%) exams. Of those with gynecomastia, 62 (65%) were bilateral, and 33 (35%) were unilateral. Pseudogynecomastia, or fatty breast enlargement, were
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reported to correspond to the patient’s symptom in 11 (9%) patients. Benign
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lipomas accounted for the palpable mass in 2 patients (2%). In all seven cases with a positive BI-RADS assessment (BI-RADS 4 or 5),
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a palpable mass was the presenting symptom. The mammographic correlate was
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a mass in 2 cases, a focal asymmetry (seen on 2 orthogonal views) in 3 cases, and an asymmetry (seen on only 1 orthogonal view) in 1 case. One case had no
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mammographic correlate. On ultrasound, six patients had masses and one had
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no sonographic correlate. In one patient with a suspicious mass on ultrasound, no mammographic correlate was identified due to technical difficultly in
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positioning the patient on mammography. 1.3.3 Percutaneous Biopsy Results: For the purposes of our analysis, BI-RADS assessment categories were dichotomized into negative (BI-RADS 1 and 2) and positive (BI-RADS 4 and 5). All seven patients with positive imaging exams (BI-RADS 4 or 5) underwent percutaneous biopsies; two were ultrasound guided and five were
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ACCEPTED MANUSCRIPT palpation guided (Table 3). Percutaneous biopsies revealed gynecomastia (4; 57%), ruptured epidermal inclusion cyst (1; 14%), and invasive ductal carcinoma (2; 29%). Of the 115 patients with negative imaging exams (BI-RADS 1 or 2), 8 (7%)
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underwent palpation guided biopsy for further evaluation initiated by the referring
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clinician due to clinical suspicion and not due to any imaging finding. Pathology
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from all of these cases revealed gynecomastia (Figure 1). All negative or benign diagnoses made by imaging and/or percutaneous biopsy were confirmed with at
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least 1 year of clinical and/or imaging follow-up. Therefore, the negative
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predictive value of imaging for cancer was 100%.
Imaging successfully detected all cases of malignancy, demonstrating
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both a high sensitivity (100%) and high specificity (96%) (Table 4). Five patients
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1.3.4 Malignant Cases:
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had false positive imaging results and no patients had false negative imaging
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Two patients were diagnosed with invasive ductal carcinoma. The first patient was a 62 year old man who presented with a palpable lump in the upper
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outer quadrant of the right breast. Diagnostic mammography showed an irregular, high density mass with associated linear and amorphous calcifications on a background of gynecomastia (Figure 2). Ultrasound showed a corresponding hypoechoic, solid, mass with spiculated margins, measuring 20 mm. This mass was assessed as suspicious (BI-RADS 4). Ultrasound also demonstrated right axillary adenopathy. Ultrasound-guided core biopsy of the right breast mass
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ACCEPTED MANUSCRIPT confirmed an invasive ductal carcinoma, grade 2, with metastatic adenocarcinoma to the right axillary lymph nodes. Immunohistochemical tests were ER+, PR+, HER2-. The second patient was an 83 year old man who presented with a
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palpable left, retroareolar breast mass. Diagnostic mammography showed an
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asymmetry in the central left breast, visible only on CC and XCCL views (Figure
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3). On ultrasound, an 8 mm hypoechoic, irregular, non-parallel mass with spiculated margins was identified. These findings were assessed as highly
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suggestive of malignancy (BI-RADS 5). Palpation guided fine needle aspiration
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demonstrated adenocarcinoma. Immunohistochemical tests were ER+, PR+,
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HER2-. Surgical excision revealed invasive ductal carcinoma.
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1.4 DISCUSSION
In this study, we assessed the utility of diagnostic breast imaging in the
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evaluation of symptomatic male patients at our academic breast-imaging center.
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We found that the majority (94%) of patients had negative or benign imaging, with gynecomastia being the most common imaging finding (78%). There were
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only two diagnoses of malignancy (2%), visible on both mammography and ultrasound.
Breast imaging demonstrated high sensitivity (100%), specificity (96%), and negative predictive value (100%), supporting its role in evaluating symptomatic male patients. Our results are consistent with prior studies, which reported negative predictive values of 100%, 99.8%, and 99%, respectively [7, 12,
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ACCEPTED MANUSCRIPT 13]. Approximately half of the biopsies in our study were performed on the basis of clinical suspicion by the referring provider, despite having no suspicious findings on imaging. All of these biopsies performed in this setting yielded gynecomastia. Furthermore, no cancers were found on at least 1 year follow up
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of all cases assessed as negative or benign at imaging. Taken together, our
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results suggest that biopsy may be safely averted in the setting of negative or
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benign imaging findings.
In keeping with prior studies, male breast cancer was rarely a cause of
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breast symptoms in our series. Due to the low incidence of breast cancer in
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males, some authors have suggested that imaging is over utilized. Lapid et al. [7] conducted a study of 557 patients, identifying malignancy in 5 (0.89%),
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concluding that imaging provided little value to the overall diagnosis and was not
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recommended due to the low prevalence of malignancy and agreement between clinical and imaging findings in the cases of malignancy. Hines et al. [14]
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published a similar study, analyzing the role of mammography in 198 men,
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identifying 2 (1%) cases of malignancy. Given the low prevalence of malignancy in males and hallmark features on clinical breast exam, the authors concluded
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that mammography is unnecessary and malignant diagnosis can be made on the basis of clinical findings alone. Similarly, it has been shown by Sonnenblick et al. [15] that mammography is unnecessary in patients with recent chest CT scans and clinical gynecomastia, due to the high level of concordance in mammography and CT features in patients without suspicious clinical findings.
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ACCEPTED MANUSCRIPT While male breast cancer is rare and the majority of diagnostic imaging exams in our study yielded no suspicious findings, we also found that over half of percutaneous biopsies could have been avoided based on the negative imaging results. This is in keeping with the study by Lapid et al, in which 160 patients
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underwent biopsy despite only 9 patients having suspicious imaging findings.
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Clinical breast examination alone can sometimes be challenging given its
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subjective nature and variable provider expertise with a male clinical breast exam. Clinical features that are typical for malignancy such as a hard painless mass
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can also be encountered with more dense, mass-like gynecomastia. The two
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patients diagnosed with malignancy in our study had similar clinical presentations to some benign cases, with palpable, non-painful, retroareolar breast masses.
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Therefore, reliance upon clinical exam alone may result in unnecessary biopsies.
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Clinical exam may also be more challenging in the setting of pronounced gynecomastia or pseudogynecomastia. Therefore, if suspicious or indeterminate
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findings are encountered on clinical breast exam, imaging should be performed
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first to establish a diagnosis and rule out malignancy before biopsy is considered. It is worth noting that 11 (9%) patients in our study had
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pseudogynecomastia or only prominent fatty tissue on imaging, thereby excluding a diagnosis of gynecomastia. In these instances, the negative imaging findings could have important clinical implications by preventing medical interventions for falsely presumed gynecomastia, such as altering medication regimens or even in some instances surgical excision.
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ACCEPTED MANUSCRIPT Rather than replacing clinical history and breast examination, we believe that imaging should be considered a complementary tool. In clinically suspicious cases, imaging can help to reliably confirm or exclude the presence of breast cancer. Given the high negative predictive value of imaging, clinicians may
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reconsider the need to continue with biopsy after a negative or benign diagnostic
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imaging evaluation, reserving biopsies for imaging-positive cases (BI-RADS 4 or
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5 assessment). Muñoz Carrasco et al. [16] proposed a similar conclusion in a study of 628 patients with male breast disease who underwent mammography,
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ultrasound, or both. With a negative predictive value for malignancy of 99.7%, the
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authors concluded that surgical procedures in men could be avoided based on imaging findings alone. Following this algorithm, the proportion of false positive
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biopsies can be effectively reduced. In the remainder of symptomatic male
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patients with equivocal clinical breast exam findings, noninvasive imaging can identify specific benign causes of patient symptomatology, thus providing patient
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reassurance and enabling conservative management.
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A limitation of our study is its retrospective design, which resulted in selection bias for those male patients who underwent imaging for their breast
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symptoms. We were unable to determine outcomes of patients who did not undergo imaging for their breast symptoms, including those patients who underwent palpation guided breast biopsy on the basis of clinical findings alone without imaging evaluation. In addition, our small sample size of 122 patients who presented at a single academic institution and the practice variability among referring providers for pursuing biopsy based on clinical breast exam findings
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ACCEPTED MANUSCRIPT even when imaging is negative limits the generalizability of our results. Future larger multi-institutional studies would help to quantify the added benefit derived from imaging in the setting of male breast symptoms.
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1.5 CONCLUSIONS
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Although malignancy is rare in the symptomatic male breast, imaging can
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be useful to exclude malignancy, to diagnose benign causes of patient symptomatology, and to potentially avoid unnecessary biopsies. Diagnostic
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breast imaging demonstrates high specificity, sensitivity, and negative predictive
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value, identifying all cases of cancer at our institution. In our single institution study, over half of biopsies performed could have been avoided based on
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negative imaging results. Given the effectiveness of breast imaging in excluding
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malignancy in the symptomatic male breast, our findings suggest that imaging is
[1]
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REFERENCES:
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a valuable tool to establish a diagnosis and to avert unnecessary biopsies.
Niewoehner, CB, Nuttall, FQ. Gynecomastia in a hospitalized male
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population. The American Journal of Medicine 1983; 77: 633-8. Braunstein, GD Gynecomastia. The New England Journal of Medicine
1993; 328: 490-5. [3]
Goldman, RD. Drug-induced gynecomastia in children and adolescents.
Canadian Family Physician 2010; 56: 344-345.
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Alteri, R. Cancer Facts & Figures 2015. American Cancer Society: Atlanta
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Siegel, R, Naishadham, D, Jemal, A. Cancer statistics, 2012. CA: a cancer
journal for clinicians 2012; 62: 10-29. Fentiman, IS, Fourquet, A, Horobagyi, GN. Male breast cancer. The
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Lapid, O, Siebenga, P, Zonderland, HM. Overuse of Imaging the Male
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Lancet 2006; 367: 595-604.
Breast—Findings in 557 Patients. The Breast Journal 2015; 21: 219-223. Mainiero, MB, Lourenco, AP, Barke, LD, Argus, AD, Bailey, L. ACR
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Appropriateness Criteria - Evaluation of the Symptomatic Male Breast. American College of Radiology 2014.
American College of Radiology. Breast Imaging Reporting and Data
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[9]
[10]
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System® (BI-RADS®) 3. Reston, Va: American College of Radiology 1998. American College of Radiology. Breast Imaging Reporting and Data
American College of Radiology. Breast Imaging Reporting and Data
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[11]
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System® (BI-RADS®) 4. Reston, Va: American College of Radiology 2003.
System® (BI-RADS®) 5. Reston, VA, American College of Radiology 2013. Patterson, SK, Helvie, MA, Aziz, K, Nees, AV. Outcome of men presenting
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with clinical breast problems: the role of mammography and ultrasound. The Breast Journal 2006; 12: 418-423. [13]
Evans, GF, Anthony, T, Turnage, RH, Schumpert, TD, Levy, KR. The
diagnostic accuracy of mammography in the evaluation of male breast disease. Am J Surg 2001; 181: 96-100.
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ACCEPTED MANUSCRIPT [14]
Hines, SL, Tan, WW, Yasrebi, M, DePeri, ER, Perez, EA. The role of
mammography in male patients with breast symptoms. Mayo Clin Proc 2007; 82: 297-300. [15]
Sonnenblick, EB, Salvatore, M, Szabo J, Lee, KA, Margolies, LR.
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Incremental Role of Mammography in the Evaluation of Gynecomastia in Men
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who Have Undergone Chest CT. American Journal of Radiology 2016; 207:234-
[16]
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240.
Muñoz Carrasco, RM, Benito, MA, Gomariz, EM, Povedano, JR, Paredes,
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MM. Mammography and ultrasound in the evaluation of male breast disease. Eur
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Radiology 2010; 20: 2797-2805.
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TABLES (4 total):
Table 1: Indications for Breast Imaging Indications for Imaging Palpable Mass Pain/Tenderness Swelling/Enlargement Sensitivity Erythema Skin Thickening Hard Lump
Total (Percent)* 83 (68.0) 56 (45.9) 24 (19.7) 3 (2.5) 3 (2.5) 2 (1.6) 1 (0.8)
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ACCEPTED MANUSCRIPT *Percent is calculated from total 122 patients. Some patients presented with more than one symptoms, such as a palpable mass with associated pain/tenderness. Table 2: Past Medical History
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12 (9.8) 8 (6.6) 6 (4.9) 6 (4.9) 5 (4.1) 3 (2.5) 2 (1.6) 1 (0.8)
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Past Medical History Kidney Failure Hypothyroidism Hypogonadism Cardiac Failure Cirrhosis Kidney Transplant Heart Transplant Hyperthyroidism
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Total (Percent)*
9 (7.4) 7 (5.7) 4 (3.3) 3 (2.5) 2 (1.6) 2 (1.6) 2 (1.6) 2 (1.6)
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Personal Cancer History Prostate Cancer Skin Cancer Leukemia Bladder Cancer Testicular Cancer Breast Cancer Lung Cancer Renal Cancer
Table 3: BI-RADS Assessments and Results of Biopsies Performed
Image Guided (Total) Benign Malignant Palpation Guided (Total)
Negative Imaging BI-RADS 1 or 2 (n=115) 0 0 0
Positive Imaging BI-RADS 4 or 5 (n = 7) 2 1 1
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5
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ACCEPTED MANUSCRIPT Benign Malignant
8 0
4 1
Table 4: Contingency table demonstrating sensitivity and specificity of breast imaging for malignancy in symptomatic males
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115
2
120
Sensitivity =100%
Specificity = 95.8%
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Disease Negative (Benign) 5
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Test Positive BI-RADS 4 or 5 Test Negative BI-RADS 1 or 2 Total
Disease Positive (Malignant) 2
FIGURES (3 total):
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Total 7 115 122
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Fig. 1 – Gynecomastia
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55 year old man with left breast tenderness and a palpable lump in the left
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retroareolar breast. CC view of the left breast from diagnostic mammography shows a flame shaped retroareolar density, consistent with benign gynecomastia
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(arrow). Imaging finding was assessed as BI-RADS 2 (benign), with a
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recommendation of clinical management of gynecomastia. Palpation guided fine needle aspiration was pursued by the primary care provider despite benign
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imaging findings due to suspicious clinical breast exam and confirmed gynecomastia.
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Fig. 2 – Invasive Ductal Carcinoma
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62 year old man presenting with a palpable right breast mass. (A) MLO view of
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the right breast from diagnostic mammogram shows a high-density irregular mass in a background of gynecomastia. (B) Targeted ultrasound shows a
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ductal carcinoma.
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corresponding hypoechoic, irregular solid mass. Core biopsy identified invasive
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Fig. 3 – Invasive Ductal Carcinoma
83 year old man with a palpable left breast mass. (A) XCCL of the left breast
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from diagnostic mammography shows an asymmetry, only seen on one view,
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deep in the left breast (arrow). This was not included in the field of view on the MLO projection. (B) Targeted ultrasound shows a corresponding hypoechoic,
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non-parallel, irregular solid mass (arrows). Palpation guided fine needle
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aspiration (FNA) identified adenocarcinoma and subsequent surgical excision identified invasive ductal carcinoma.
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ACCEPTED MANUSCRIPT Highlights: Malignancy is rarely a cause of breast symptoms in males.
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Diagnostic breast imaging successfully detected all cases of malignancy, demonstrating both high sensitivity and specificity.
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Breast imaging in symptomatic male patients can be useful to establish benign diagnoses and avert unnecessary biopsies.
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Eric T. Foo, Amie Y. Lee, Kimberly M. Ray, Genevieve A. Woodard, Rita I. Freimanis, Bonnie N. Joe PII: DOI: Reference:
S0899-7071(17)30113-4 doi: 10.1016/j.clinimag.2017.06.004 JCT 8263
To appear in: Received date: Revised date: Accepted date:
26 March 2017 25 May 2017 7 June 2017
Please cite this article as: Eric T. Foo, Amie Y. Lee, Kimberly M. Ray, Genevieve A. Woodard, Rita I. Freimanis, Bonnie N. Joe , Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies?, (2017), doi: 10.1016/ j.clinimag.2017.06.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies?
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Eric T. Foo, BS1 Amie Y. Lee, MD1 Kimberly M. Ray, MD1 Genevieve A. Woodard MD, PhD1 Rita I. Freimanis MD1 Bonnie N. Joe, MD, PhD1
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1. Department of Radiology and Biomedical Imaging, University of California San Francisco, 1600 Divisadero Street, San Francisco, CA 94115
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Address correspondence to: Amie Y. Lee, M.D. University of California, San Francisco Department of Radiology and Biomedical Imaging 1600 Divisadero Street, Room C250, Box 1667, San Francisco, CA 94115, USA Phone: 415-885-8464 Fax: 415-885-7876 Email: [email protected]
Manuscript Type: Original Research
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Disclosures: The authors have no relevant financial or nonfinancial reltationships to disclose.
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IRB Statement: This study was performed with approval from our insititutional review board.
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Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ABSTRACT Purpose:
To review the use of diagnostic breast imaging and outcomes for symptomatic male patients. Methods:
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ACCEPTED MANUSCRIPT We retrospectively evaluated 122 males who underwent diagnostic imaging for breast symptoms at our academic center. Results: The majority (94%) of cases had negative or benign imaging, with gynecomastia
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being the most common diagnosis (78%). There were two malignancies, both of
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which had positive imaging. Fifteen patients underwent percutaneous biopsy,
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and over half (53%) were palpation-guided biopsies initiated by the referring clinician despite negative imaging. Diagnostic imaging demonstrated 100%
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sensitivity and 96% specificity for identifying cancer.
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Conclusions:
Malignancy is rarely a cause of male breast symptoms. Diagnostic breast
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imaging is useful to establish benignity and avert unnecessary biopsies.
Keywords: mammography, male breast symptoms, gynecomastia, male breast
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cancer
1.1 INTRODUCTION A breast symptom is the most common reason male patients present for breast imaging. Gynecomastia, the most frequent cause of such symptoms, is a benign enlargement of male breast tissue, predominantly composed of ductal, stromal, and adipose tissue. It is a common condition, with one study reporting a
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ACCEPTED MANUSCRIPT prevalence of 65 percent in the hospitalized male population [1]. The majority of cases of gynecomastia are idiopathic or related to puberty; however, medications, cirrhosis and primary hypogonadism also play important roles [2, 3]. In contrast, male breast cancer is rare, with only 2,350 new cases
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diagnosed per year in the US, which accounts for less than 1% of all breast
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cancer cases [4]. Unfortunately, the majority (81-90%) of male breast cancers
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are invasive at presentation [5, 6]. Thus, prompt evaluation and diagnosis are crucial. In certain instances, male breast cancer and gynecomastia can be
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difficult to confidently differentiate based on clinical breast exam alone. In such
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instances, further evaluation with mammography and/or ultrasound may be warranted.
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In a recent study of 557 male breast patients who underwent breast
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imaging, Lapid et al. [7] detected malignancy in five patients (0.89%). The authors concluded that male breast cancer is rare and routine imaging of
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gynecomastia is not warranted. Most patients (93%) in this study had negative or
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benign (BI-RADS 1 or 2) imaging. While only nine patients had suspicious findings on imaging (BI-RADS 4 or 5), 160 patients underwent biopsy based on
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clinical findings, suggesting that many of the biopsies were unnecessary. According to the American College of Radiology (ACR) appropriateness criteria [8], targeted ultrasound is recommended for the initial evaluation of males under the age of 25 years with an indeterminate palpable breast mass. For males age 25 years and older, diagnostic mammography is recommended for initial evaluation with supplemental ultrasound as needed. If imaging reveals a lesion
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ACCEPTED MANUSCRIPT that is suspicious or highly suggestive of malignancy (BI-RADS 4 or 5), biopsy is indicated for definitive diagnosis. The purpose of this study was to review the use and outcomes of diagnostic breast imaging in symptomatic male patients at our academic breast
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imaging center. We hypothesize that breast imaging adds clinical value by safely
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and accurately excluding breast cancer, establishing benign diagnoses, and
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averting unnecessary breast biopsies for patients with negative or benign
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imaging results.
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1.2 MATERIALS AND METHODS 1.2.1 Patient Population:
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This study was performed with approval from our Institutional Review
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Board, and all procedures were compliant with the Health Insurance Portability and Accountability Act. A retrospective chart review was completed on all male
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patients who received breast imaging in our radiology department over the
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course of 10 years, from August 2004 to October 2014. A total of 211 patients were identified and all available data was retrieved
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from the patient’s electronic medical records. Exclusion criteria included high-risk screening mammography (19), female to male transgender patients (6), male to female transgender patients (1), imaging for non-breast symptoms (1), insufficient (less than one year) clinical follow-up to confirm benignity (58), and imaging not in accordance with ACR appropriateness criteria recommendations (4), which included initial workup with breast MRI or ultrasound without
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ACCEPTED MANUSCRIPT mammography in patients 25 years of age or older. This yielded a final study cohort of 122 patients. 1.2.2 Imaging Technique and Interpretation: Mammography, targeted ultrasound, or a combination of mammography
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and ultrasound were used in accordance with ACR guidelines. Diagnostic
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mammography was performed for the initial evaluation in males age 25 years
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and older. This consisted of craniocaudal (CC) and mediolateral oblique (MLO) full field digital mammographic images of both breasts. Additional mammographic
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images, such as other orthogonal views or spot compression magnification
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images, were obtained at the discretion of the interpreting radiologist. If the mammogram was clearly negative or benign, no further imaging was performed.
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Targeted breast ultrasound was performed for patients younger than 25
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years or if there were indeterminate mammographic findings in older patients. Breast ultrasound was performed using standard technique specifically targeted
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to the site of clinical concern. All ultrasounds were performed directly by the
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interpreting radiologist or by a radiology trainee under the direct supervision of the interpreting attending radiologist.
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All images were interpreted in real-time and reported by an attending radiologist subspecializing in breast imaging (Range of attending experience 1 year to >30 years). Reporting and assignment of final BI-RADS categories were based on the most current edition of the ACR BI-RADS Atlas at the time of imaging, which spanned three editions [9-11]. In patients who underwent both
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ACCEPTED MANUSCRIPT mammography and ultrasound, a combined final BI-RADS assessment was assigned by the interpreting radiologist based on findings of both modalities. 1.2.3 Percutaneous Biopsy Ultrasound guided percutaneous sampling was performed with either core
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needle biopsy or fine-needle aspiration. Core needle biopsies were performed
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using a 14-G spring-loaded automatic biopsy device. Fine needle aspirations
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were performed with a 25-G needle with a cytopathologist immediately present for real-time review of the aspiration sample to determine diagnostic adequacy.
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All palpation-guided fine-needle aspirations were performed by the
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cytopathologist in the cytology clinic without imaging guidance. 1.2.4 Data Collection and Analysis:
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Patient demographics and clinical history were recorded from review of
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the patient’s electronic medical records and radiology reports. Imaging data, including BI-RADS assessment categories, were obtained from the radiology
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reports. Biopsy results were obtained from the pathology and cytology reports.
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All data were collected in REDCap, a web based, secure, data capture software. Malignant diagnoses were confirmed with histopathology from
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percutaneous biopsy and from subsequent surgical excisions. For negative or benign cases diagnosed by imaging and/or percutaneous biopsy, the absence of malignancy was confirmed based on at least one year of clinical and/or imaging follow-up. Descriptive statistics and 2x2 table analyses were performed. BI-RADS assessment categories were dichotomized into negative (BI-RADS 1 and 2) and
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ACCEPTED MANUSCRIPT positive (BI-RADS 4 and 5). As noted above, in patients who underwent both mammography and ultrasound, a combined final BI-RADS assessment was assigned by the interpreting radiologist based on the findings of both modalities. For examinations assigned a different BI-RADS category for each breast, a
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single examination-level BI-RADS was assigned according to the following
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hierarchy: BI-RADS categories 5, 4, 2, 1. There were no BI-RADS 0, 3, or 6
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assessments in this study population. Sensitivity, specificity, negative predictive
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values and positive predictive values were calculated.
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1.3 RESULTS 1.3.1 Patient Characteristics:
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A total of 122 patients met inclusion criteria. Mean patient age was 57
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years (range 17-92). The majority of patients (53%) were 60 years or older. Patients were most frequently referred for breast imaging by their primary care
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(40%), oncology (16%), surgery (4%), and urology (4%) providers. The most
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common indications for imaging were a palpable mass (68%), pain/tenderness (46%), and/or swelling/enlargement (20%). Imaging indications are summarized
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in Table 1. Relevant patient past medical history, including clinical diagnoses associated with gynecomastia and personal histories of malignancy, are summarized in Table 2. 1.3.2 Imaging Evaluation: Eighty-three (68%) patients underwent diagnostic mammography alone, two (2%) underwent ultrasound alone, and 37 (30%) had a combination of
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ACCEPTED MANUSCRIPT diagnostic mammography and ultrasound. The majority of exams had no suspicious finding and were assigned a BI-RADS assessment of 1 or 2 (115; 94%). Seven (6%) exams had a suspicious or highly suggestive of malignancy finding and were given a BI-RADS assessment of 4 or 5. Of those with breast
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imaging findings, 46 (41%) were unilateral and 65 (59%) were bilateral.
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Gynecomastia was the most common benign finding on imaging, present
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in 95 (78%) exams. Of those with gynecomastia, 62 (65%) were bilateral, and 33 (35%) were unilateral. Pseudogynecomastia, or fatty breast enlargement, were
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reported to correspond to the patient’s symptom in 11 (9%) patients. Benign
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lipomas accounted for the palpable mass in 2 patients (2%). In all seven cases with a positive BI-RADS assessment (BI-RADS 4 or 5),
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a palpable mass was the presenting symptom. The mammographic correlate was
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a mass in 2 cases, a focal asymmetry (seen on 2 orthogonal views) in 3 cases, and an asymmetry (seen on only 1 orthogonal view) in 1 case. One case had no
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mammographic correlate. On ultrasound, six patients had masses and one had
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no sonographic correlate. In one patient with a suspicious mass on ultrasound, no mammographic correlate was identified due to technical difficultly in
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positioning the patient on mammography. 1.3.3 Percutaneous Biopsy Results: For the purposes of our analysis, BI-RADS assessment categories were dichotomized into negative (BI-RADS 1 and 2) and positive (BI-RADS 4 and 5). All seven patients with positive imaging exams (BI-RADS 4 or 5) underwent percutaneous biopsies; two were ultrasound guided and five were
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ACCEPTED MANUSCRIPT palpation guided (Table 3). Percutaneous biopsies revealed gynecomastia (4; 57%), ruptured epidermal inclusion cyst (1; 14%), and invasive ductal carcinoma (2; 29%). Of the 115 patients with negative imaging exams (BI-RADS 1 or 2), 8 (7%)
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underwent palpation guided biopsy for further evaluation initiated by the referring
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clinician due to clinical suspicion and not due to any imaging finding. Pathology
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from all of these cases revealed gynecomastia (Figure 1). All negative or benign diagnoses made by imaging and/or percutaneous biopsy were confirmed with at
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least 1 year of clinical and/or imaging follow-up. Therefore, the negative
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predictive value of imaging for cancer was 100%.
Imaging successfully detected all cases of malignancy, demonstrating
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both a high sensitivity (100%) and high specificity (96%) (Table 4). Five patients
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1.3.4 Malignant Cases:
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had false positive imaging results and no patients had false negative imaging
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Two patients were diagnosed with invasive ductal carcinoma. The first patient was a 62 year old man who presented with a palpable lump in the upper
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outer quadrant of the right breast. Diagnostic mammography showed an irregular, high density mass with associated linear and amorphous calcifications on a background of gynecomastia (Figure 2). Ultrasound showed a corresponding hypoechoic, solid, mass with spiculated margins, measuring 20 mm. This mass was assessed as suspicious (BI-RADS 4). Ultrasound also demonstrated right axillary adenopathy. Ultrasound-guided core biopsy of the right breast mass
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ACCEPTED MANUSCRIPT confirmed an invasive ductal carcinoma, grade 2, with metastatic adenocarcinoma to the right axillary lymph nodes. Immunohistochemical tests were ER+, PR+, HER2-. The second patient was an 83 year old man who presented with a
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palpable left, retroareolar breast mass. Diagnostic mammography showed an
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asymmetry in the central left breast, visible only on CC and XCCL views (Figure
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3). On ultrasound, an 8 mm hypoechoic, irregular, non-parallel mass with spiculated margins was identified. These findings were assessed as highly
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suggestive of malignancy (BI-RADS 5). Palpation guided fine needle aspiration
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demonstrated adenocarcinoma. Immunohistochemical tests were ER+, PR+,
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HER2-. Surgical excision revealed invasive ductal carcinoma.
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1.4 DISCUSSION
In this study, we assessed the utility of diagnostic breast imaging in the
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evaluation of symptomatic male patients at our academic breast-imaging center.
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We found that the majority (94%) of patients had negative or benign imaging, with gynecomastia being the most common imaging finding (78%). There were
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only two diagnoses of malignancy (2%), visible on both mammography and ultrasound.
Breast imaging demonstrated high sensitivity (100%), specificity (96%), and negative predictive value (100%), supporting its role in evaluating symptomatic male patients. Our results are consistent with prior studies, which reported negative predictive values of 100%, 99.8%, and 99%, respectively [7, 12,
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ACCEPTED MANUSCRIPT 13]. Approximately half of the biopsies in our study were performed on the basis of clinical suspicion by the referring provider, despite having no suspicious findings on imaging. All of these biopsies performed in this setting yielded gynecomastia. Furthermore, no cancers were found on at least 1 year follow up
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of all cases assessed as negative or benign at imaging. Taken together, our
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results suggest that biopsy may be safely averted in the setting of negative or
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benign imaging findings.
In keeping with prior studies, male breast cancer was rarely a cause of
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breast symptoms in our series. Due to the low incidence of breast cancer in
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males, some authors have suggested that imaging is over utilized. Lapid et al. [7] conducted a study of 557 patients, identifying malignancy in 5 (0.89%),
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concluding that imaging provided little value to the overall diagnosis and was not
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recommended due to the low prevalence of malignancy and agreement between clinical and imaging findings in the cases of malignancy. Hines et al. [14]
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published a similar study, analyzing the role of mammography in 198 men,
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identifying 2 (1%) cases of malignancy. Given the low prevalence of malignancy in males and hallmark features on clinical breast exam, the authors concluded
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that mammography is unnecessary and malignant diagnosis can be made on the basis of clinical findings alone. Similarly, it has been shown by Sonnenblick et al. [15] that mammography is unnecessary in patients with recent chest CT scans and clinical gynecomastia, due to the high level of concordance in mammography and CT features in patients without suspicious clinical findings.
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ACCEPTED MANUSCRIPT While male breast cancer is rare and the majority of diagnostic imaging exams in our study yielded no suspicious findings, we also found that over half of percutaneous biopsies could have been avoided based on the negative imaging results. This is in keeping with the study by Lapid et al, in which 160 patients
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underwent biopsy despite only 9 patients having suspicious imaging findings.
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Clinical breast examination alone can sometimes be challenging given its
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subjective nature and variable provider expertise with a male clinical breast exam. Clinical features that are typical for malignancy such as a hard painless mass
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can also be encountered with more dense, mass-like gynecomastia. The two
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patients diagnosed with malignancy in our study had similar clinical presentations to some benign cases, with palpable, non-painful, retroareolar breast masses.
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Therefore, reliance upon clinical exam alone may result in unnecessary biopsies.
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Clinical exam may also be more challenging in the setting of pronounced gynecomastia or pseudogynecomastia. Therefore, if suspicious or indeterminate
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findings are encountered on clinical breast exam, imaging should be performed
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first to establish a diagnosis and rule out malignancy before biopsy is considered. It is worth noting that 11 (9%) patients in our study had
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pseudogynecomastia or only prominent fatty tissue on imaging, thereby excluding a diagnosis of gynecomastia. In these instances, the negative imaging findings could have important clinical implications by preventing medical interventions for falsely presumed gynecomastia, such as altering medication regimens or even in some instances surgical excision.
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ACCEPTED MANUSCRIPT Rather than replacing clinical history and breast examination, we believe that imaging should be considered a complementary tool. In clinically suspicious cases, imaging can help to reliably confirm or exclude the presence of breast cancer. Given the high negative predictive value of imaging, clinicians may
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reconsider the need to continue with biopsy after a negative or benign diagnostic
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imaging evaluation, reserving biopsies for imaging-positive cases (BI-RADS 4 or
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5 assessment). Muñoz Carrasco et al. [16] proposed a similar conclusion in a study of 628 patients with male breast disease who underwent mammography,
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ultrasound, or both. With a negative predictive value for malignancy of 99.7%, the
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authors concluded that surgical procedures in men could be avoided based on imaging findings alone. Following this algorithm, the proportion of false positive
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biopsies can be effectively reduced. In the remainder of symptomatic male
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patients with equivocal clinical breast exam findings, noninvasive imaging can identify specific benign causes of patient symptomatology, thus providing patient
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reassurance and enabling conservative management.
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A limitation of our study is its retrospective design, which resulted in selection bias for those male patients who underwent imaging for their breast
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symptoms. We were unable to determine outcomes of patients who did not undergo imaging for their breast symptoms, including those patients who underwent palpation guided breast biopsy on the basis of clinical findings alone without imaging evaluation. In addition, our small sample size of 122 patients who presented at a single academic institution and the practice variability among referring providers for pursuing biopsy based on clinical breast exam findings
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ACCEPTED MANUSCRIPT even when imaging is negative limits the generalizability of our results. Future larger multi-institutional studies would help to quantify the added benefit derived from imaging in the setting of male breast symptoms.
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1.5 CONCLUSIONS
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Although malignancy is rare in the symptomatic male breast, imaging can
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be useful to exclude malignancy, to diagnose benign causes of patient symptomatology, and to potentially avoid unnecessary biopsies. Diagnostic
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breast imaging demonstrates high specificity, sensitivity, and negative predictive
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value, identifying all cases of cancer at our institution. In our single institution study, over half of biopsies performed could have been avoided based on
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negative imaging results. Given the effectiveness of breast imaging in excluding
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malignancy in the symptomatic male breast, our findings suggest that imaging is
[1]
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REFERENCES:
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a valuable tool to establish a diagnosis and to avert unnecessary biopsies.
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Hines, SL, Tan, WW, Yasrebi, M, DePeri, ER, Perez, EA. The role of
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TABLES (4 total):
Table 1: Indications for Breast Imaging Indications for Imaging Palpable Mass Pain/Tenderness Swelling/Enlargement Sensitivity Erythema Skin Thickening Hard Lump
Total (Percent)* 83 (68.0) 56 (45.9) 24 (19.7) 3 (2.5) 3 (2.5) 2 (1.6) 1 (0.8)
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ACCEPTED MANUSCRIPT *Percent is calculated from total 122 patients. Some patients presented with more than one symptoms, such as a palpable mass with associated pain/tenderness. Table 2: Past Medical History
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12 (9.8) 8 (6.6) 6 (4.9) 6 (4.9) 5 (4.1) 3 (2.5) 2 (1.6) 1 (0.8)
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Past Medical History Kidney Failure Hypothyroidism Hypogonadism Cardiac Failure Cirrhosis Kidney Transplant Heart Transplant Hyperthyroidism
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Total (Percent)*
9 (7.4) 7 (5.7) 4 (3.3) 3 (2.5) 2 (1.6) 2 (1.6) 2 (1.6) 2 (1.6)
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Personal Cancer History Prostate Cancer Skin Cancer Leukemia Bladder Cancer Testicular Cancer Breast Cancer Lung Cancer Renal Cancer
Table 3: BI-RADS Assessments and Results of Biopsies Performed
Image Guided (Total) Benign Malignant Palpation Guided (Total)
Negative Imaging BI-RADS 1 or 2 (n=115) 0 0 0
Positive Imaging BI-RADS 4 or 5 (n = 7) 2 1 1
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ACCEPTED MANUSCRIPT Benign Malignant
8 0
4 1
Table 4: Contingency table demonstrating sensitivity and specificity of breast imaging for malignancy in symptomatic males
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115
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Sensitivity =100%
Specificity = 95.8%
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Disease Negative (Benign) 5
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Test Positive BI-RADS 4 or 5 Test Negative BI-RADS 1 or 2 Total
Disease Positive (Malignant) 2
FIGURES (3 total):
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Total 7 115 122
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Fig. 1 – Gynecomastia
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55 year old man with left breast tenderness and a palpable lump in the left
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retroareolar breast. CC view of the left breast from diagnostic mammography shows a flame shaped retroareolar density, consistent with benign gynecomastia
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(arrow). Imaging finding was assessed as BI-RADS 2 (benign), with a
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recommendation of clinical management of gynecomastia. Palpation guided fine needle aspiration was pursued by the primary care provider despite benign
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imaging findings due to suspicious clinical breast exam and confirmed gynecomastia.
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Fig. 2 – Invasive Ductal Carcinoma
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62 year old man presenting with a palpable right breast mass. (A) MLO view of
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the right breast from diagnostic mammogram shows a high-density irregular mass in a background of gynecomastia. (B) Targeted ultrasound shows a
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ductal carcinoma.
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corresponding hypoechoic, irregular solid mass. Core biopsy identified invasive
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Fig. 3 – Invasive Ductal Carcinoma
83 year old man with a palpable left breast mass. (A) XCCL of the left breast
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from diagnostic mammography shows an asymmetry, only seen on one view,
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deep in the left breast (arrow). This was not included in the field of view on the MLO projection. (B) Targeted ultrasound shows a corresponding hypoechoic,
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non-parallel, irregular solid mass (arrows). Palpation guided fine needle
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aspiration (FNA) identified adenocarcinoma and subsequent surgical excision identified invasive ductal carcinoma.
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ACCEPTED MANUSCRIPT Highlights: Malignancy is rarely a cause of breast symptoms in males.
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Diagnostic breast imaging successfully detected all cases of malignancy, demonstrating both high sensitivity and specificity.
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Breast imaging in symptomatic male patients can be useful to establish benign diagnoses and avert unnecessary biopsies.
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