Nephrol Dial Transplant (2002) 17: 512-515
© 2002 European Renal Association-European Dialysis and Transplant Association
Nephroquiz
Transplant-associated inflammatory breast disease
(Section Editor: M. G. Zeier)
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 80–120 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: 2.5–7.5 mmol/l), creatinine 80 µmol/l (50–110 µmol/l), albumin 45 g/l (35–48 g/l), corrected calcium 2.45 mmol/l (2.05–2.60 mmol/l), phosphate 0.91 mmol/l (0.8–1.45 mmol/l), and alkaline phosphatase 122 IU/l (30–200 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 12–72 ng/l), alkaline phosphatase 111 IU/l, serum ACE 30 IU/l (8–59 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 (143–693 pmol/l), follicule stimulating hormone (FSH) 5.4 mIU/l (1–11 mIU/l), luteinizing hormone (LH) 3.2 mIU/l (1–18 mIU/l), and prolactin 280 mU/l (90–523 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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Rolles and Calne [4] in 1980 first highlighted the association between CsA therapy and the development of benign breast disease in women. Subsequent reports have added strength to the potentially causative role of CsA. However, the mechanisms involved remain unclear and are complex. To highlight this, the time receiving CsA before the onset of breast abnormalities, and the speed at which they develop, varies considerably between patients [5]. There also appears to be no correlation between the CsA blood concentration and the risk of developing breast disease [5]. Breast changes described have been both focal, with histological features of fibroadenomata [4,5], or more diffuse, as in our case, with histology similar to those found in men with gynaecomastia [6,7]. Cyclosporin is a well-recognized cause of gingival hypertrophy, most likely a consequence of direct action of the drug or its metabolites upon the gingival fibroblasts [8]. If a similar process is involved in causing breast hypertrophy one might expect an association between the two. However, in a prospective study of 29 female renal transplant recipients who were taking CsA, Baildam et al. [5] found no such association. Cyclosporin may still affect breast tissue directly but through a different pathway as several CsA-binding proteins have now been identified in lymphoid and non-lymphoid cells [9]. Animal studies have indicated that humoral effects of CsA may be important in pathogenesis [10]. Pan et al. [6] described a case similar to ours where a female renal transplant recipient developed diffuse breast hypertrophy requiring mammoplasty. The serum prolactin level was noted to be high post mammoplasty, and there was a large amount of milk secretion in the mastectomy specimens. It was postulated that CsA and the calcium antagonist felodipine together had induced breast hypertrophy by causing hyperprolactinaemia. However, this is the only case described where the prolactin level has been found to be unequivocally elevated.
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
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