(Radiology. 2001;220:465-468.)
© RSNA, 2001
Cyclosporin A–induced Fibroadenomas of the Breast: Report of Five Cases1
Susan P. Weinstein, MD,
Susan G. Orel, MD,
Lisa Collazzo, MD,
Emily F. Conant, MD,
Thomas J. Lawton, MD and
Brian Czerniecki, MD, PhD
1 From the Departments of Radiology (S.P.W., S.G.O., E.F.C.) and Surgery (B.C.), University of Pennsylvania Medical Center, 3400 Spruce St, 1 Silverstein Bldg, Philadelphia, PA 19104; the Department of Radiology, Crozer-Chester Medical Center, Upland, Pa (L.C.); and the Division of Hospital Pathology, University of Washington Medical Center, Seattle (T.J.L.). Received June 13, 2000; revision requested July 24; revision received December 22; accepted January 23, 2001. Address correspondence to S.P.W.
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ABSTRACT
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Five female patients undergoing cyclosporin A therapy had newly developed breast masses. Masses were bilateral in three of the five patients and palpable in four patients. The imaging findings were suggestive of fibroadenomas, and biopsy results were used to confirm the diagnosis. With the development of new breast lesions in patients after transplantation surgery, the diagnosis of cyclosporin A–induced fibroadenomas should be considered.
Index terms: Breast neoplasms, 00.311 • Breast neoplasms, diagnosis, 00.311
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INTRODUCTION
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Fibroadenoma is the most common solid breast mass found in young adult women. They are benign tumors composed of varying proportions of fibrous and stromal tissue, which are responsive to hormonal stimulation. Most fibroadenomas cease growth at approximately 2–3 cm in size (1). Although multiple in 20% of cases, it is uncommon to find more than five fibroadenomas in the breast (2). While there are descriptions in the literature of familial or hormonally related syndromes of multiple bilateral fibroadenomas, reports of individuals with such syndromes have been rare (2,3). Fibroadenomas most commonly occur in young women, and it is unusual for fibroadenomas to arise de novo in an older patient (4). The surgical and medical literature (5,6) also reports an association of cyclosporin A with the development of fibroadenomas. A case study has also been reported (7) in the radiology literature. We present imaging findings in a group of female patients who underwent transplantation surgery and presented with newly developed breast masses after cyclosporin A therapy.
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Materials and Methods
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Between 1997 and 2000, five female patients with histories of transplantation surgery who were receiving cyclosporin A were referred to our imaging center with newly developed breast masses. Four of the patients were evaluated with mammography and ultrasonography (US). However, breast US alone was performed in a 16-year-old patient. Mammography was performed with one of four units: Instrumentarium IQ, Instrumentarium RT, GE DMR I, and GE DMR II (GE Medical Systems, Milwaukee, Wis). A routine four-view mammogram was initially obtained, with additional views obtained as needed. Breast US examinations were performed by a radiologist specializing in breast imaging with either a Logic 700 MR 7.5-MHz transducer or variable 9–13-MHz transducer (GE Medical Systems; Milwaukee, Wis) or a 7.5-MHz transducer (Acoustic Imaging, Phoenix, Ariz).
One patient also underwent a magnetic resonance (MR) imaging evaluation with a 1.5-T system (Signa; GE Medical Systems). The patient was placed in the prone position with the breast compressed medial to lateral by using a specially designed breast multicoil array. The following parameters were used: sagittal T1-weighted spin-echo and sagittal fat-suppressed T2-weighted fast spin-echo sequences with a field of view of 16 cm, 3-mm section thickness, 1-mm gap, and 256 x 256 matrix. The breast was imaged before and after the administration of gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ) with a sagittal three-dimensional–volume fat-suppressed fast spoiled gradient-echo sequence. The patient received gadopentetate dimeglumine (0.1 mmol per kilogram of body weight), which was injected as a bolus and followed with 20 mL of saline. Imaging began during the saline injection. The imaging time for each three-dimensional–volume fast spoiled gradient-echo sequence was 90 seconds. One set of precontrast images was obtained. After the administration of contrast medium, the entire breast was imaged two times in succession by using the three-dimensional volume fast spoiled gradient-echo sequence. The MR image was prospectively read by one radiologist.
In all of the patients, core-needle biopsy was performed with a 14-gauge needle (Bard Monopty biopsy instrument or Bard Magnum; Bard, Covington, Ga) under US guidance. At least five representative passes were made, with additional samples obtained as needed on the basis of sample quality.
The clinical interpretations of the mammograms, US images, and breast MR images were performed by a radiologist specializing in each modality. The pathology specimen slides were reviewed by a pathologist (T.J.L.). The radiographic images, imaging reports, pathology results, and medical charts of all the patients were reviewed by one or more of the authors (S.P.W., L.C., B.C.).
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Results
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The ages of the five patients ranged from 16 to 60 years (mean age, 36.8 years). Four patients were renal transplant recipients, and one patient had undergone liver transplantation.
Four patients had palpable breast masses, which were bilateral in three patients. The size of the masses ranged from 4 to 16 cm. The fifth patient, a postmenopausal woman, had a newly developed nonpalpable 3-cm mass at mammography. Three patients had undergone prior mammography 9–20 months earlier, and the masses were not visible at retrospective re-examination. Two patients, aged 16 and 27 years, did not have prior mammograms; however, both had new bilateral palpable breast masses. US evaluation of the palpable masses or of the mammographic findings showed solid masses in all the patients. The masses, ovoid or round, were homogeneous in echotexture, with circumscribed borders suggestive of fibroadenomas.
Core-needle biopsy was performed in all the patients (Table 1). Pathology results described fibroadenomas in four of the patients. In the first patient of our series, from 1997, there was concern about a possible discrepancy between the pathologic diagnosis of fibroadenoma at core-needle biopsy and that the new large bilateral breast masses possibly represented a lymphoproliferative disorder (Fig 1). Therefore, the patient underwent MR imaging, which revealed multiple bilateral enhancing masses of various sizes; all had varying degrees of enhancement, and several had internal septa (Fig 2). The MR imaging findings were suggestive of fibroadenomas (8). Although the diagnosis of fibroadenoma was already established at core-needle biopsy, two patients subsequently underwent excisional biopsy for symptomatic relief of pain. The excisional biopsy findings confirmed the diagnosis of fibroadenomas.
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Figure 1a. Mediolateral oblique mammograms in a 34-year-old female patient. Views of (a) the normal left breast and (b) the normal right breast obtained prior to renal transplant. (c, d) Mammograms obtained 16 months after renal transplantation and cyclosporin A therapy, demonstrate (c) the left breast and (d) the right breast, both with newly developed multiple bilateral circumscribed masses.
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Figure 1b. Mediolateral oblique mammograms in a 34-year-old female patient. Views of (a) the normal left breast and (b) the normal right breast obtained prior to renal transplant. (c, d) Mammograms obtained 16 months after renal transplantation and cyclosporin A therapy, demonstrate (c) the left breast and (d) the right breast, both with newly developed multiple bilateral circumscribed masses.
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Figure 1c. Mediolateral oblique mammograms in a 34-year-old female patient. Views of (a) the normal left breast and (b) the normal right breast obtained prior to renal transplant. (c, d) Mammograms obtained 16 months after renal transplantation and cyclosporin A therapy, demonstrate (c) the left breast and (d) the right breast, both with newly developed multiple bilateral circumscribed masses.
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Figure 1d. Mediolateral oblique mammograms in a 34-year-old female patient. Views of (a) the normal left breast and (b) the normal right breast obtained prior to renal transplant. (c, d) Mammograms obtained 16 months after renal transplantation and cyclosporin A therapy, demonstrate (c) the left breast and (d) the right breast, both with newly developed multiple bilateral circumscribed masses.
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Figure 2a. Images in same patient as in (a) Transverse US image of the left breast shows multiple well-circumscribed solid masses (arrows). (b) Sagittal fast spin-echo T2-weighted nonenhanced MR image (5,000/84) of the left breast reveals a lobulated mass of intermediate signal intensity with internal septa (arrows). (c) Sagittal three-dimensional gadolinium-enhanced fast spoiled gradient-echo MR image of the left breast demonstrates two lobulated masses (arrows). The superior one corresponds to the mass in b. Both masses demonstrate contrast enhancement and low-signal-intensity nonenhancing septa that are suggestive of fibroadenomas.
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Figure 2b. Images in same patient as in (a) Transverse US image of the left breast shows multiple well-circumscribed solid masses (arrows). (b) Sagittal fast spin-echo T2-weighted nonenhanced MR image (5,000/84) of the left breast reveals a lobulated mass of intermediate signal intensity with internal septa (arrows). (c) Sagittal three-dimensional gadolinium-enhanced fast spoiled gradient-echo MR image of the left breast demonstrates two lobulated masses (arrows). The superior one corresponds to the mass in b. Both masses demonstrate contrast enhancement and low-signal-intensity nonenhancing septa that are suggestive of fibroadenomas.
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Figure 2c. Images in same patient as in (a) Transverse US image of the left breast shows multiple well-circumscribed solid masses (arrows). (b) Sagittal fast spin-echo T2-weighted nonenhanced MR image (5,000/84) of the left breast reveals a lobulated mass of intermediate signal intensity with internal septa (arrows). (c) Sagittal three-dimensional gadolinium-enhanced fast spoiled gradient-echo MR image of the left breast demonstrates two lobulated masses (arrows). The superior one corresponds to the mass in b. Both masses demonstrate contrast enhancement and low-signal-intensity nonenhancing septa that are suggestive of fibroadenomas.
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In the fifth patient, core biopsy findings revealed proliferative fibrocystic change with mild ductal atypia and prominent myxoid mucinous stroma (Fig 3). The pathologist was unclear of the relevance of the myxoid findings, and due to the presence of atypia, pathologic evaluation of the entire lesion was recommended. The patient underwent excisional biopsy that revealed a fibroadenoma with mucinous stroma.
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Figure 3a. Mammograms in a 60-year-old renal transplant recipient with a mass in the left breast. Subsequent biopsy revealed a fibroadenoma. (a) Normal mediolateral oblique view of the left breast obtained in 1997. (b) Mediolateral oblique view of the left breast obtained in 1998 shows a newly developed mass (arrow) in the posterior breast.
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Figure 3b. Mammograms in a 60-year-old renal transplant recipient with a mass in the left breast. Subsequent biopsy revealed a fibroadenoma. (a) Normal mediolateral oblique view of the left breast obtained in 1997. (b) Mediolateral oblique view of the left breast obtained in 1998 shows a newly developed mass (arrow) in the posterior breast.
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Discussion
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Multiple fibroadenomas of the breast or fibroadenomas occurring after menopause are uncommon. Cases of multiple fibroadenomas appear to have familial or hormonally related origin, with the latter being described in women using hormonal contraceptives (2). Fibroadenomas occurring in postmenopausal patients are also uncommon, although enlargement of fibroadenomas have been reported in postmenopausal women undergoing hormone replacement therapy (4). In our patient group, two patients (aged 49 and 60 years) had new mammographic masses, and a malignancy needed to be excluded.
In a letter from 1980, Rolles and Calne (6) noted the development of fibroadenomas in two patients using cyclosporin A. In one of the patients, after the withdrawal of cyclosporin A, the breast masses rapidly resolved. In 1996, Baildam et al (5) reported a group of renal transplant patients, aged 27–50 years, who were receiving cyclosporin A and who developed bilateral breast fibroadenomas. In their study of 39 renal transplant patients, fibroadenomas were found in 13 of 29 patients who received cyclosporin A, as compared with none of 10 patients who did not. In those 13 patients who developed fibroadenomas, four had five or more lesions. In the study by Baildam et al (5), the duration of cyclosporin A therapy in the patients in whom fibroadenomas were diagnosed ranged from 23 to 126 months. In our group, the duration of cyclosporin A therapy had a similarly broad range of 16 to 130 months. The summary of our results is listed in Table 2.
Cyclosporin A has many known adverse effects, and common ones include impairment of renal function, hypertension, increased predilection for infections, hypertrichosis, fine tremor, liver function derangement, and gingival hyperplasia (9). Benign mammary hyperplasia has been noted (9) to occur, although with a low 0.7% frequency.
The mechanism by which these effects occur is poorly understood. Possible mechanisms for the trophic effects in the breasts may involve cyclosporin A receptors in some populations of fibroblasts or may be due to the effect of cyclosporin A on the hypothalamic-pituitary axis (5,10). An alternative mechanism involves antagonism of the prolactin receptor sites on B and T lymphocytes by cyclosporin A (11,12). It has been noted (11) that the use of cyclosporin A results in elevated prolactin levels in rats; the effect is dose dependent. Since fibroadenomas comprise the same type of tissue as normal mammary tissue, their hormonal response would be expected to be similar (13). It is feasible that elevated prolactin levels may result in the development of the fibroadenomas or that cyclosporin A may have direct trophic effects on fibroblasts.
We believe that the patients in our study represent cases of cyclosporin A–induced fibroadenomas, similar to those described in the study of Baildam et al (5) and as mentioned in the letter by Rolles and Calne (6). In three of the patients with previous mammograms, new masses were detected at mammography. Both the 16- and 27-year-old patients, who did not have prior studies, had new bilateral palpable breast masses. Although the precise mechanism of cyclosporin A and its action in the development of breast fibroadenomas still need to be elucidated, we want to bring to attention to the association between the use of this medication and this underappreciated complication. This is especially important in light of an increasing number of transplant surgeries, as well as the increasing number of indications for cyclosporin A therapy in disorders such as inflammatory bowel disease and autoimmune hepatitis.
In patients with breast masses that are possibly related to cyclosporin A therapy, the diagnosis may be confirmed with core-needle biopsy. In cases of multiple lesions, core biopsy of all the lesions is impractical. Core-needle biopsy of one of the lesions may be performed, with MR imaging serving as an adjunctive tool to help assess the characteristic MR imaging features of fibroadenomas (8,14). The features suggestive of fibroadenomas at MR imaging include a lobular, oval, or round shape with internal septa (8,14). With benign core biopsy results and concordant imaging features, follow-up examination may be performed as an alternative to excisional biopsy. Depending on the patient’s age, follow-up with mammography and/or US at 6-month intervals is a feasible management option. In recognizing the entity of cyclosporin A–induced fibroadenomas, close clinical and breast imaging follow-up after diagnosis with core-needle biopsy may be suggested as an alternative to excisional biopsy in this patient population. As awareness of this entity in breast imaging is increased, it may lead to increased recognition of this underappreciated complication of cyclosporin A therapy.
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FOOTNOTES
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Author contributions: Guarantors of integrity of entire study, S.P.W., S.G.O.; study concepts, S.G.O., L.C.; study design, S.P.W., S.G.O.; literature research, S.P.W., L.C.; clinical studies, S.P.W., B.C., L.C.; data acquisition, S.P.W., L.C.; data analysis/interpretation, S.P.W., T.J.L.; L.C.; manuscript preparation and definition of intellectual content, S.P.W., L.C.; manuscript editing, revision/review, and final version approval, all authors.
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ABSTRACT
INTRODUCTION
