1 Department of Renal Medicine 2 Department of Radiology 3 Department of Cellular Pathology 4 Department of General Surgery Birmingham Heartlands Hospital Birmingham, UK
Case
In March 1999, a 21-year-old woman received a cadaveric renal transplant. The cause of her renal failure was unknown but she had required haemodialysis for 18 months prior to transplantation. There was excellent transplant function from the time of surgery with a baseline creatinine of 90 µmol/l reached within 2 weeks. After a period of 3 months her prednisolone had been tailed off from her immunosuppression regimen leaving azathioprine 75 mg o.d. (2 mg/kg/24 h) and cyclosporin (CsA) (Neoral, Novartis) 75 mg b.d. (maintenance trough levels of 80120 µg/l achieved). Other medication included atenolol 50 mg o.d. and amlodipine 10 mg o.d. for hypertension, which had been started many months prior to transplantation. At 6 months, serum biochemistry showed urea 4.2 mmol/l (normal range: 2.57.5 mmol/l), creatinine 80 µmol/l (50110 µmol/l), albumin 45 g/l (3548 g/l), corrected calcium 2.45 mmol/l (2.052.60 mmol/l), phosphate 0.91 mmol/l (0.81.45 mmol/l), and alkaline phosphatase 122 IU/l (30200 IU/l).
In October 1999, the patient complained of a gradual painful enlargement of the breasts over the preceding 6 weeks. She had not developed a nipple discharge or menstrual irregularities, and remained otherwise generally well. On examination, she was noted to have marked breast hypertrophy (Figure 1). The right breast was larger than the left, with the skin being warm, erythematous and tense. There was no associated axillary lymphadenopathy. Examination was otherwise unremarkable. Investigations at presentation revealed an abnormally high corrected serum calcium of 3.36 mmol/l. Phosphate was low at 0.68 mmol/l, PTH undetectable (normal 1272 ng/l), alkaline phosphatase 111 IU/l, serum ACE 30 IU/l (859 IU/l), and transplant renal function was preserved (creatinine 92 µmol/l). Blood tests taken during the follicular stage of the patient's menstrual cycle revealed a serum oestradiol of 259 pmol/l (143693 pmol/l), follicule stimulating hormone (FSH) 5.4 mIU/l (111 mIU/l), luteinizing hormone (LH) 3.2 mIU/l (118 mIU/l), and prolactin 280 mU/l (90523 mU/l). Mammography revealed very dense and glandular breasts, but there were no discrete areas of abnormality, in particular there was no suspicious calcification. Ultrasound of the breasts found them to be diffusely inflamed with no focal abnormality. Biopsies were taken from each quadrant of both breasts during the secretory phase of the menstrual cycle. Histology revealed a marked increase in fibrous stroma, with predominantly periductal proliferation of fibroblasts and oedema. The ducts showed mild epithelial hyperplasia but no atypia. A slight degree of fibrosis had developed but there was no evidence of malignancy (Figure 2
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Question
What is the likely diagnosis?
Answer to quiz on preceding page
The diffuse abnormalities detected clinically and radiologically in our patient were consistent with a diagnosis of inflammatory breast cancer, infiltrative lymphoma or leukaemic breast disease [1,2]. However, rapid multidisciplinary assessment excluded malignancy. A drug-induced cause of benign mammary hyperplasia, with associated pseudohyperparathyroidism, was considered [3]. At the end of December 1999 she was therefore converted from CsA to Tacrolimus whilst continuing azathioprine, atenolol and amlodipine as before. Within 2 weeks there was a decrease in breast pain, engorgement and erythema. Serum calcium and phosphate returned to within normal limits. At review in April 2000, the breasts were still not engorged or erythematous but remained uncomfortably enlarged (Figure 3), and was therefore listed for breast reductive surgery.
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Discontinuing the CsA in our case led to some improvement but the breasts did not return to pre-transplantation size, perhaps representing the development of established fibrosis. There has been only one other case describing an improvement in breast pathology with CsA discontinuation [4]. Modification of immunosuppressive regimen is usually not deemed necessary as the degree of gynaecomastia is small and/or the abnormalities are focal, such as fibroadenomas, which are either removed by lumpectomy or monitored. Our patient's symptomatic improvement and arrest in breast enlargement with the substitution of CsA with Tacrolimus suggests that earlier conversion may have prevented the development of such gross breast hypertrophy. Such a conversion has been successful in patients who have developed marked gingival hypertrophy [11]. In conclusion, CsA appeared to cause breast fibroblast proliferation, hypercalcaemia and breast enlargement. Early conversion to Tacrolimus should be considered in future patients who appear to be developing CsA-induced breast disease.
Notes
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References