Introduction Nipple adenomas are rare benign neoplasms that closely mimic malignant disease.  They arise from lactiferous ducts and milk sinuses. A retrospective review of nipple adenomas at our institution from 1992 to 2010 was performed with review of pathology, radiographic studies and clinical histories.
Methods and Results Twelve patients with a nipple adenoma were identified. Mean age at diagnosis was 58.5 years (range 43-76). Ten women (83%) were symptomatic. Symptoms included nipple discharge (58.3%), palpable lesions (50%), and ulcerative skin changes (25%). Workup included mammography (12), ultrasound (8) and magnetic resonance imaging (MRI) (1). The lesion size ranged from 0.4-1.5 cm (mean 0.7 cm). Four patients had complete nipple excision, six had partial nipple excision, one had removal via percutaneous biopsy, and one had a mastectomy for history of breast cancer. With 38.3 months follow-up, 3 women (25%) had a diagnosis of breast cancer prior to or after diagnosis of nipple adenoma, and there has been 1 recurrence of nipple adenoma.
Discussion Nipple adenoma is a rare condition with non-specific presentation. Diagnosis is usually made by complete surgical excision. It is important to differentiate these lesions from malignancy. Although no clear correlation has been shown between nipple adenoma and breast cancer, further investigation is warranted.

Molecular Breast Imaging for Women Presenting With a History of Non-Reproducible Bloody Nipple Discharge and Negative Findings on Routine Imaging Studies: A Pilot Study

Dietlind L. Wahner-Roedler, MD¹ ∙ Carrie B. Hruska, PhD² ∙ Michael K. O’Connor, PhD² ∙ Stephen W. Phillips, MD² ∙ Dana H. Whaley, MD² ∙ Ruth E. Johnson, MD³ ∙ Amy C. Degnim, MD⁴ ∙ Judy C. Boughey, MD⁴ ∙ Deborah J. Rhodes, MD³
 

Contact: Dietlind L. Wahner-Roedler, MD. E-mail This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

Citation: Wahner-Roedler DL, Hruska CB, O’Connor MK, Phillips SW, Whaley DH, Johnson RE, Degnim AC, Boughey JC, Rhodes DJ. Molecular breast imaging for women presenting with a history of non-reproducible bloody nipple discharge and negative findings on routine imaging studies: a pilot study. J Surg Radiol. 2011 Jan 1;2 (1). Download PDF Original Article: Molecular Breast Imaging for Women Presenting With a History o 2063 Kb Received: October 1, 2010; Accepted: November 17, 2010; Published: November 23, 2010 Copyright: © 2010 Surgisphere Corporation. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Contents - Introduction - Materials and Methods - Results - Discussion - References

Introduction

The appearance of secretion or discharge from nipple ducts is a common occurrence. As many as 80% of the women are able to express one or more drops of fluid from a nipple at some time during their reproductive years.1 Most isolated nipple discharge (ND) is benign in origin. In one series, for example, the overall incidence of malignancy was 4.8% in 1,145 women with ND evaluated between January 2, 1960, and December 1974.2 The risk of cancer is greater when the discharge is bloody or positive for guaiac, is unilateral, is associated with a breast mass, or occurs in a woman older than 40 years. Bloody nipple discharge (BND) occurs when a lesion in the duct is bleeding. There are three main causes of BND. Papillomata account for 35% to 48% of the cases; ductal ectasia associated with an inflammatory infiltrate accounts for 17% to 36%; and carcinoma accounts for 5% to 21% of cases.3

Evaluation of BND is focused on excluding a malignant cause. A thorough physical examination is imperative because associated palpable masses increase the risk of malignancy.4 Although a mammogram and an ultrasonographic scan (US) are indicated in the evaluation of unilateral, spontaneous ND, they do not exclude the possibility of a malignant cause.

When BND is clinically reproducible, management traditionally involves surgical excision, regardless of imaging findings. When BND is not reproducible and mammogram and US results are negative, management usually relies on watchful waiting – serial breast imaging and continued observation for recurrent BND. However, watchful waiting provokes anxiety among patients who do not have a clear explanation for their BND. Breast magnetic resonance imaging (MRI) has not been studied systematically in this context and is costly. The availability of a less costly method to either identify a cause or confirm the validity of a negative mammogram and US would be of great value to these patients and their physicians.

Scintimammography with technetium Tc 99m sestamibi was developed in the 1990s and has been the subject of considerable investigation. However, conventional scintimammography does not reliably detect tumors less than 10 mm,5 and thus this technique has not been widely adopted in the United States. In an attempt to overcome the limitations of conventional scintimammography, several gamma cameras with a small field of view have been developed that permit imaging of the breast in a similar manner and orientation to conventional mammography. The close proximity of small detectors to the breast provides a considerable improvement in resolution compared with conventional scintimammography.

Mayo Clinic in Rochester, Minnesota, developed an imaging system that uses two small, opposing semiconductor gamma camera detectors. This technique has been labeled molecular breast imaging (MBI).6 Previous studies have showed a high sensitivity for the detection of small breast tumors, including mammographically occult tumors.7 The purpose of the present pilot study was to evaluate MBI in the work-up of patients with a history of BND that was not reproducible in the clinic and had negative results on routine imaging studies.

Methods

Study Participants

Eligible participants were women who presented to a multidisciplinary breast clinic for evaluation of BND that was not reproducible in the clinic and who subsequently had negative results on a clinical breast examination and on diagnostic mammogram and US studies. Women who were pregnant or breastfeeding were excluded. Informed consent was obtained from all participants, and the protocol was approved by the Mayo Clinic Institutional Review Board and registered as NCT00566280 in ClinicalTrials.gov.

Equipment

A dual-detector cadmium-zinc-telluride gamma camera system mounted on a modified mammography gantry (Figure 1) was used to perform MBI. This system has been described in detail.6-8 Briefly, each 20 × 15 cm detector (Gamma Medica-Ideas, Inc, Northridge, California) consisted of pixilated arrays of 128 × 96 cadmium-zinc-telluride elements with pixel sizes of 1.6 × 1.6 mm. This small pixel size offers improved spatial resolution compared with continuous sodium iodide crystals used in conventional scintimammography. In addition, the cadmium-zinc-telluride material has superior energy resolution compared with conventional gamma cameras – about 3.8% at 140 keV – and offers improved ability to reject scattered gamma rays in the image.

Figure 1. Dual-Detector Molecular Breast Imaging System.

Imaging Procedure

Patients received an intravenous injection of 20 mCi of Tc 99m sestamibi. Craniocaudal and mediolateral oblique MBI views of each breast were obtained at 10 minutes per view. The breast was positioned between the two detectors, and light, pain-free compression (15-lb force) was applied to reduce breast thickness and limit movement artifact.

MBI Scoring System

A radiologist reviewed the MBI views for presence of abnormal radiotracer uptake. Clinical history details, mammographic images, and ultrasounds were available of each patient. The following scoring system was used to evaluate MBI images.

• Negative: uniform uptake of Tc 99m sestamibi in the breast, with no focal areas of uptake except nipple uptake.
• Benign: patchy (non-mass-like) uptake or uptake in areas of known inflammation, with mild nipple uptake.
• Possibly benign: One or more areas of mild focal uptake, and focal uptake seen on one view only.
• Suspicious for malignancy: One or more areas of moderate focal or diffuse uptake.
• Highly suggestive of malignancy: One or more focal areas of intense uptake.

In cases where the MBI was interpreted as negative or benign, the usual standard of care was followed with a recommendation of a 12-month follow-up screening mammogram or follow-up at any time if BND recurred. In cases with a positive finding on MBI (classified as probably benign, suspicious, or highly suggestive of malignancy), the radiologist determined appropriate additional work-up, which may have included special mammographic views, focused breast US, contrast-enhanced breast MRI, image-guided biopsy, or a 6-month follow-up mammogram, US, or MBI, or a combination of these techniques. Patients were advised to return at any time if BND recurred or for any breast changes of concern.

Results

Between October 1, 2006, and December 31, 2007, 14 women were recruited into the study. Their demographic characteristics and clinical and imaging findings are summarized in the table. Examples of a negative (patient 6), benign (patient 14), and probably benign (patient 12) MBI interpretation are depicted in figures 2-4. The median number of days between the episode of BND and presentation to the clinic were 22 (range, 2-76 d); the median number of days between presentation to the clinic and the performance of MBI was 22 (range, 0-163 d). The median length of follow-up after performance of MBI was 20 months (range, 0-35 mo).

For nine of the 14 patients with spontaneous non-reproducible BND, a surgical consultation was recommended by the breast clinic staff physician. Seven patients had this appointment with a surgeon. For five of these seven patients, observation was advised and the patients were asked to monitor for future episodes of BND, recording when possible the location of the involved duct or the subareolar quadrant to which the application of pressure elicited drainage. In the other two patients, subareolar duct excision was performed because of the patient’s concern about a family history of breast cancer. Pathologic evaluation showed a small radial scar in one patient (patient 1) and a small papilloma (0.3 × 0.2 × 0.2 cm) in the other (patient 4). These benign lesions were undetected by mammogram, US, and MBI.

All patients were advised to return if they noticed recurrent BND. One patient (patient 5) returned eight months after the initial visit with an episode of non-reproducible clear ND, but not BND. In consideration of her significant family history, an MRI of the breast was performed and showed negative results. Surgical consultation was obtained and observation advised. Another patient (patient 7) returned one year after the initial episode, with a history of non-reproducible greenish ND, but not BND. Clinical breast examination and standard imaging studies showed negative results. Observation was advised.

Patient 12 with both an MBI interpretation of probably benign and a spontaneous BND underwent post-MBI special mammographic views and targeted repeat US examinations, which showed negative results. At the radiologist’s recommendation, the patient returned for a 6-month follow-up MBI, and this study was interpreted as benign.

Two patients required subsequent breast surgery, one (patient 4) with a benign phyllodes tumor at 25 months and one (patient 8) with cancer at 17 months. Patient 4 had undergone subareolar duct excision after MBI, with a finding of benign intraductal papilloma. Follow-up for this patient included screening mammogram at 13 months and at 25 months after MBI. Screening mammography at 25 months after MBI showed a region of asymmetrical density in the ipsilateral breast. Directed US showed a 23 × 20 × 10 mm lesion and US-guided biopsy showed a phyllodes tumor with usual ductal hyperplasia. Excisional biopsy found a benign phyllodes tumor (1.8 × 1.6 × 1.4 cm).

Only one patient had breast cancer in the course of follow-up. Patient 8, a 75-year-old woman with a history of spontaneous right ND, received a diagnosis of invasive breast cancer of the right breast 17 months after undergoing evaluation in the breast clinic and an MBI. Mammogram at that time showed worrisome calcifications with some associated soft-tissue density in the upper outer quadrant of the right breast 12 cm from the nipple. US showed the area of calcification but did not show a classic malignant-appearing mass. Stereotactic biopsy showed invasive ductal carcinoma of Nottingham grade 3 of 3 with microcalcifications and associated ductal carcinoma in situ. Wide local excision found a 0.8 × 0.7 × 0.7 cm mass; three sentinel lymph nodes were negative.

During a mammographic examination 12 months after the diagnosis of breast cancer, the patient was noted to have an episode of BND. The mammogram showed negative results, US showed a hypoechoic mass, and excision biopsy found benign breast parenchyma with duct ectasia associated with intraductal necrotic debris and dense stromal fibrosis.

Discussion

Women presenting with a history of BND that cannot be reproduced in the clinic who have negative results on work-up with conventional imaging procedures (i.e., mammography and US) present a diagnostic problem in clinical practice. Usually, observation is advised and the patients are asked to return if BND recurs. This watchful waiting can provoke anxiety in the patient because of the inability to explain the cause of the discharge at presentation and since an underlying malignancy cannot be excluded. Patients or their clinicians, or both, may request an additional imaging procedure (such as MRI) to exclude a diagnosis of cancer.

Breast MRI is an effective diagnostic technique to identify clinically and mammographically occult cancers.9 The role of MRI has not been defined yet in the evaluation of patients with pathologic ND in whom other nonsurgical methods have failed to identify an underlying etiologic cause. There are isolated case reports of patients with pathologic ND in whom routine imaging studies had negative results and MRI was helpful in finding an underlying malignancy.10,11

A preliminary study reported retrospectively on 23 patients with ND who underwent MRI.12 Mammographic findings were negative in 22 patients. In 11 of the 15 patients who underwent an excisional biopsy, MRI findings correlated with histopathologic findings. The investigators concluded that MRI can help identify both benign and malignant causes of ND.

In a retrospective chart review of 306 patients with suspicious ND and negative results on standard evaluation (clinical breast examination, mammogram, US), 52 patients underwent an MRI.13 MRI detected seven cancers and three high-risk lesions but failed to identify one cancer and one high-risk lesion. The positive and negative predictive values of MRI in this review were 56% and 87%, respectively (sensitivity, 77%; specificity, 62%). The investigators concluded that MRI should not replace major duct excision as the gold standard to exclude malignancy in patients with ND and negative results on standard evaluation.

Although breast MRI is more sensitive than mammography for the detection of breast cancer, its low specificity limits its clinical utility.14 Diagnostic MRI may detect additional incidental lesions in either the ipsilateral or contralateral breast that require follow-up imaging or biopsy. In the series reported by Morrogh et al,13 24 of the 52 patients (46%) who underwent MRI for further evaluation of suspicious ND were reported to have additional incidental findings in the index breast. Repeat imaging was recommended and undertaken for all 24 patients, three of whom subsequently required biopsy, yielding benign results in all three cases. The median number of follow-up scans for these 24 patients was one (range, 1-7), and at last follow-up, no further cancers were identified. Of 45 women who had bilateral MRI, one patient required biopsy for a suspicious lesion in the contralateral breast, which ultimately proved to be benign.

These incidental findings can have an obvious impact on both the patient and the health care delivery system and as such should be considered when integrating breast MRI into the evaluation of patients with suspicious ND. In addition to these limitations, the high cost of MRI underscores the need for alternative imaging approaches in the evaluation of non-reproducible BND.

Preliminary patient studies with the MBI system of our institution indicate that this system is capable of reliably detecting 5-10 mm lesions in the breast with Tc 99m sestamibi. In our ongoing MBI studies of 150 patients with suspicious mammographic abnormalities, we have obtained an overall sensitivity of 91%. The sensitivity of MBI for cancer of 5 mm or less, 6 to 10 mm, and greater than 10 mm was 69%, 91%, and 97%, respectively.7 In addition, MBI has showed approximately 10% more carcinomas in these patients that were otherwise undetectable with conventional methods (mammogram and clinical examination).6,15

If BND is clinically reproducible, management traditionally involves surgical excision, even when results of imaging studies are negative.4,17 A terminal duct excision is both diagnostic and, for discharges that turn out to have a benign cause, therapeutic. Usually, the duct with discharge is cannulated before the incision, for use as a guide to dissection and to ensure removal of the involved duct.

In patients presenting with a history of BND that is not reproducible, caution must be exercised in assuming that a patient report of “bloody” discharge is indeed of blood. Many breast secretions, especially those that are green, black, or brown, may look like blood to a patient. In general, breast surgeons do not consider a patient report of a bloody discharge alone a sufficient indication for surgery.18 In a study by Dawes et al,18 4 of 91 patients with ND reported BND that could not be reproduced. The patients’ evaluation was unremarkable, and they had no further breast problem with observation alone.

Of our 14 patients, seven were seen in surgical consultation, and duct exploration was advised for two, mainly because of a positive family history. A subareolar duct excision was performed. In both patients, nonmalignant etiologic factors for the BND were found. These benign lesions were not detected on mammogram, US, and MBI.

We assume that the finding of an invasive ductal carcinoma in one patient (patient 8), diagnosed 17 months after her initial evaluation for non-reproducible, nonrecurrent BND, was not related to her ND since the location of her tumor was peripheral rather than central. It is unlikely that the ND in patient 4 was related to the phyllodes tumor, since this patient did undergo a subareolar duct excision for evaluation of her BND, showing a papilloma that explained her BND and resulted in resolution of the discharge.

To our knowledge, the present study is the first study to examine the role of MBI – an imaging procedure that has been shown to detect mammographically occult lesions – in the diagnostic evaluation of ND. This pilot study evaluated MBI as an additional diagnostic procedure for patients presenting with a history of non-reproducible BND. The concordance between MBI, mammogram, and US in regard to the absence of suspicious findings is reassuring. There were no false-positive findings on MBI, in contrast to the large number of false-positive MRI findings reported in the study by Morrogh et al.13 Although two patients who underwent duct excision were noted to have benign lesions, none of these lesions were visible on MBI. Advantages of MBI relative to MRI include the cost and the complexity of interpretation. It is estimated that the cost of MBI will be 4 to 6 times less than MRI. A bilateral MRI generates approximately 1,000 images, whereas dual-head bilateral MBI generates 4 to 8 images.

A larger study comparing MBI with MRI in this clinical context is needed to assess the sensitivity, specificity, and cost-effectiveness of each of these procedures for clinical practice.

Conclusion

Although the gold standard of diagnostic and therapeutic approach for patients presenting with BND regardless of imaging findings is surgical duct excision, the therapeutic management of patients presenting with a history of non-reproducible BND and negative findings on clinical examination and routine imaging studies relies on watchful waiting. The availability of an additional diagnostic method – less costly than MRI – to either identify a cause or confirm the validity of standard imaging tests would be of great value to clinical practice. In this pilot study, MBI was performed on 14 women presenting with a history of non-reproducible BND and negative findings on clinical examination and routine imaging studies. The concordance between MBI, mammography, and ultrasonography regarding absence of suspicious findings documented in this study is reassuring. Larger studies are needed to confirm these preliminary findings.

Disclosures

Presented in part at the 12th World Congress on the Menopause, Madrid, Spain, May 19-23, 2008.

Portions of this manuscript have been published in abstract form: Climacteric. 2008 Feb; 11 Suppl 1:290-1. PS-413.

The study sponsors had no role in any aspect of study design, collection, analysis and interpretation of data, or writing and submitting the manuscript. No competing financial interests exist.

References

1. Isaacs JH. Other nipple discharge. Clin Obstet Gynecol. 1994 Dec;37(4):898-902.
2. Murad TM, Contesso G, Mouriesse H. Nipple discharge from the breast. Ann Surg. 1982 Mar;195(3):259-64.
3. Vargas HI, Romero L, Chlebowski RT. Management of bloody nipple discharge. Curr Treat Options Oncol. 2002 Apr;3(2):157-61.
4. Morrogh M, Park A, Elkin EB, King TA. Lessons learned from 416 cases of nipple discharge of the breast. Am J Surg. 2010 Jan 13. Epub ahead of print.
5. Khalkhali I, Villanueva-Meyer J, Edell SL, Connolly JL, Schnitt SJ, Baum JK, et al. Diagnostic accuracy of 99mTc-sestamibi breast imaging: multicenter trial results. J Nucl Med. 2000 Dec;41(12):1973-9.
6. O’Connor M, Rhodes D, Hruska C. Molecular breast imaging. Expert Rev Anticancer Ther. 2009 Aug;9(8):1073-80.
7. Hruska CB, Boughey JC, Phillips SW, Rhodes DJ, Wahner-Roedler DL, Whaley DH, et al. Scientific Impact Recognition Award: Molecular breast imaging: a review of the Mayo Clinic experience. Am J Surg. 2008 Oct;196(4):470-6. Epub 2008 Aug 23.
8. Hruska CB, Phillips SW, Whaley DH, Rhodes DJ, O’Connor MK. Molecular breast imaging: use of a dual-head dedicated gamma camera to detect small breast tumors. AJR Am J Roentgenol. 2008 Dec;191(6):1805-15.
9. Morris EA, Libermann L. Breast MRI: diagnosis and intervention. New York (NY): Springer; c2005. p. 7.
10. Mortellaro VE, Marshall J, Harms SE, Hochwald SN, Copeland EM III, Grobmyer SR. Breast MR for the evaluation of occult nipple discharge. Am Surg. 2008 Aug;74(8):739-42.
11. Tjalma WA, Verslegers IO. Nipple discharge and the value of MR imaging. Eur J Obstet Gynecol Reprod Biol. 2004 Aug 10;115(2):234-6.
12. Orel SG, Dougherty CS, Reynolds C, Czerniecki BJ, Siegelman ES, Schnall MD. MR imaging in patients with nipple discharge: initial experience. Radiology. 2000 Jul;216(1):248-54.
13. Morrogh M, Morris EA, Liberman L, Borgen PI, King TA. The predictive value of ductography and magnetic resonance imaging in the management of nipple discharge. Ann Surg Oncol. 2007 Dec;14(12):3369-77. Epub 2007 Sep 26.
14. Fischer U, Kopka L, Grabbe E. Breast carcinoma: effect of preoperative contrast-enhanced MR imaging on the therapeutic approach. Radiology. 1999 Dec;213(3):881-8.
15. Rhodes DJ, O’Connor MK, Phillips SW, Smith RL, Collins DA. Molecular breast imaging: a new technique using technetium Tc 99m scintimammography to detect small tumors of the breast. Mayo Clin Proc. 2005 Jan;80(1):24-30.
16. O’Connor MK, Hruska CB, Phillips SW, Whaley DH, Blevis I, Wagenaar DJ, et al. Molecular breast imaging: a new technique for the accurate detection of smalls breast lesions [abstract]. Breast Cancer Res Treat. 2006;100(Suppl 1):S33-4.
17. Wahner-Roedler DL, Reynolds C, Morton MJ. Spontaneous unilateral nipple discharge: when screening tests are negative: a case report and review of current diagnostic management of a pathologic nipple discharge. Breast J. 2003 Jan-Feb;9(1):49-52.
18. Dawes LG, Bowen C, Venta LA, Morrow M. Ductography for nipple discharge: no replacement for ductal excision. Surgery. 1998 Oct;124(4):685-91.