Risk of Developing Fibroadenoma with the Use of Cyclosporine A in Renal Transplant Recipients

Abstract

To investigate the effect of cyclosporine A (Cyc A) on the development of fibroadenomas, 30 renal transplant patients and 20 chronic renal failure patients on dialysis were breast examined with ultrasonography and/or mammography. Of the renal transplant patients, 17 were receiving Cyc A-based combination therapy for immunosuppression. All patients were female with the age range of 29.7 ± 9.2 years in the transplant group and 33.95 ± 9.91 in the dialysis group. Eight of the 17 patients receiving Cyc A had fibroadenomas, 5 of them having bilateral lesions. None of the other patients, those on dialysis and on non-Cyc A combination therapy had fibroadenomas. A significant difference for fibroadenoma incidence in patients receiving Cyc A combination immunosuppression was found.

• cyclosporine A (Cyc A)
• fibroadenoma
• renal transplantation
• chronic renal failure (CRF)
• ultrasonography

Introduction

Chronic renal failure (CRF) can be considered as an immunosuppressed state. Studies have suggested an incidence of cancer that is greater in dialysis patients than in the age- and sex-matched nondialysis population.[1] Also, one of the major complications of long-term transplantation is the risk of developing malignancy. Skin and lip cancers and lymphoproliferative disorders are the most common malignant tumors in renal transplant patients. Unlike other cancers, breast cancer does not occur at an increased frequency in renal transplant patients; however, fibroadenoma may be more common as a result of exposure to cyclosporine A (Cyc A).[2-4]

Cyc A has been widely used as a potent immunosuppressive agent in solid organ and bone marrow transplantation. Fibroadenomas, in contrast, are the most frequent benign breast neoplasias. Multiple or bilateral masses are present in 10% to 15% of women. Fibroadenomas greater than 5 cm in diameter are referred to as “giant” fibroadenomas.[5] Exposure to endogenous and exogenous estrogens increases the risk of developing fibroadenomas. In contrast, smoking has been shown to have antiestrogenic effects.[6&7]

Whereas there are limited reports suggesting an association between breast diseases, especially fibroadenoma and renal transplant (Tx) recipients (RTRs), according to our knowledge there is no report about the risk of development of breast lesions in patients on dialysis. This study was designed to investigate incidence of fibroadenomas in a population of RTRs and in CRF patients on dialysis. Moreover, whether there is a difference or not in fibroadenoma incidence attributable to variance in immunosuppressive agents is questioned.

Material and Methods

In this cross-sectional study, 30 patients with renal transplants and 20 patients with CRF on dialysis were evaluated. Family history of breast disease and history of hormone replacement therapy (HRT) were recorded. In the Tx group, immunosuppressive regimens consisted of Cyc A-based, tacrolimus-based, or other combinations. All lesions were evaluated primarily with ultrasonography (US). Although 10 patients (20%) older than 40 years had undergone both mammographic and ultrasonographic imaging, the remainder, ages 16 to 40 years (80%), was examined only with US. Mammography was obtained using a Senographe DMR unit (GE Medical Systems, Milwaukee, WI, USA). Mediolateral oblique and craniocaudal mammograms were taken routinely. Breast US examinations were performed by a radiologist specialized in breast imaging with a Logic 500 9-MHz linear transducer (GE Medical Systems, Milwaukee, WI, USA). Both breasts were scanned in the radial and antiradial directions, following the ductal system with the patient in supine position. Findings were scored according to the Breast Imaging Reports and Data System (BI-RADS) of the American College of Radiology.[8]

As part of the clinical management and follow-up, full medical details and clinical examination findings were recorded and blood samples, including serum creatinine, cholesterol, and triglycerides, were taken for routine laboratory workup. The imaging findings were correlated with age, serum biochemistry, duration of dialysis and renal transplantation, and the type of immunosuppressive agent used in the Tx group.

Statistical analysis was performed with chi-square test using SPSS version 12.0 for Windows.

Results

All patients were female. The mean age of the 30 RTRs was 29.7 ± 9.2 years and that of the 20 dialysis patients (dial P) 33.95 ± 9.91, p = 0.129. The mean of duration of dialysis before patients received a kidney transplant was 29.3 ± 8.9 months. The duration of renal transplantation was 69.07 ± 49.6 months. Five patients (10%) had cadaveric, 21 (42%) had living related, and 4 (8%) had living unrelated renal transplants. Seventeen patients had received Cyc A-based combination, 11 tacrolimus-based, 1 only sirolimus, and 1 prednisolone + azathioprine combination for immunosuppression.

Fourteen patients were on hemodialysis, six on peritoneal dialysis in CRF group. The duration of hemodialysis and peritoneal dialysis were 53.7 ± 41.8 (median: 57, range: 12–120) and 44 ± 22.3 (median 48, range: 12–72) months, respectively. None of the patients reported any family history of breast disease. In addition, none of the patients were on HRT. Blood biochemistry results are shown on Table 1.

Table 1. Biochemical parameters of the patients

	RTRs (n = 30)	Dial P (n = 20)	p Value
Glucose (mg/dL)	82.0 ± 16.4	91.2 ± 34.5 (n = 19)	0.95
BUN (mg/dL)	19.3 ± 10.3	74.1 ± 29.6 (n = 20)	0.00
Creatinin (mg/dL)	0.9 ± 0.09	10.2 ± 2.9 (n = 20)	0.00
T-cholesterol (mg/dL)	178.3 ± 42.4	195.06 ± 61.5 (n = 17)	0.42
HDL-chol. (mg/dL)	60.7 ± 15.0	40.06 ± 10.8 (n = 16)	0.00
LDL-chol. (mg/dL)	93.2 ± 36.7	107.0 ± 45.0 (n = 16)	0.23
Trigyliceride (mg/dL)	127.4 ± 62.6	237.7 ± 167.0 (n = 17)	0.00
AST (U/L)	16.3 ± 8.0	14.8 ± 7.8 (n = 19)	0.31
ALT (U/L)	13.4 ± 9.2	16.6 ± 11.8 (n = 19)	0.34
Htc (%)	34.1 ± 4.8	31.0 ± 4.8 (n = 18)	0.04
Ca (mg/dL)	9.9 ± 0.4	9.1 ± 0.8 (n = 20)	0.00
P (mg/dL)	3.6 ± 0.8	5.7 ± 1.9 (n = 20)	0.00

RTRs, renal transplant recipients; dial P, dialysis patients.

Eight of the patients using Cyc A in the Tx group were diagnosed with fibroadenomas. Seven of these patients had multiple fibroadenomas, and five were affected bilaterally. One patient also developed giant fibroadenomas. Six patients had palpable masses. Three of six had previous biopsy-proven fibroadenomas, diagnosed within 1 to 3 years following renal Tx. They were recommended only radiologic and clinical follow-up. Three other patients with fibroadenomas did not accept biopsy. Because the masses in the remaining two patients were nonpalpable, follow-up was advised according to BI-RADS criteria.

US revealed sharply circumscribed hypoechoic masses surrounded by highly echogenic stroma highly suggestive of fibroadenoma. All the masses were homogeneous in echotexture (Figure 1). The masses ranged in size from 0.5 to 6 cm in diameter.

Figure 1. Ultrasonogram of the right breast demonstrates well-circumscribed hypoechoic mass against a background of echogenic stroma.

No fibroadenoma was detected in dialysis patients.

Fibroadenoma was not detected in any of the patients who received tacrolimus. There was significant difference between CycA and tacrolimus receiving patients for fibroadenoma incidence (p = 0.023) (Table 2). The mean time for fibroadenoma detection after renal Tx was 51.75 ± 54.68 (median 30, range: 10–144).

Table 2. Comparison incidence of fibroadenoma in renal Tx recipients between cyclosporine A and tacrolimus

	Cyclosporine A (n = 17)	Tacrolimus (n = 11)	p Value
Duration of Tx (months) mean ± S.D	88.9 ± 49.1	35.1 ± 25.3	0.001
Median (min − max)	84 (36–92)	26 (6–96)
Fibroadenoma ±	7/10	0/11	0.023

Tx, transplantation.

Discussion

The incidence of benign breast diseases in the female transplant patients is far greater than the general population. Short-term immunosuppression does not increase the risk of development of benign breast lesions in young women. Unlike other cancers, breast cancer does not occur at an increased frequency in renal transplant patients.[3], [9] No incidental breast cancer was found in any of our patients in both study groups.

US is the method of choice for differentiating solid from cystic breast masses. US scans show the classic benign features of a fibroadenoma: a well-circumscribed hypoechoic mass that may be oval, round, or microlobulated. Fibroadenomas usually appear as solitary 1- to 2-cm lesions that are characteristically firm, rubbery, nontender, well circumscribed, and found in women younger than 30 years of age. Fibroadenomas more than 5 cm in diameter are known as giant fibroadenomas. Cases of multiple fibroadenomas appear to have familial or hormonally related origin.[10-12]

A relationship between Cyc A and fibroadenoma occurrence is known. The mechanism by which fibroadenomas occur is not understood. Various mechanisms for the association of Cyc A and multiple fibroadenomas have been suggested, including effect on fibroblasts (some fibroblasts have cyclosporin receptors), effect on hypothalamic-pituitary axis (demonstrated in rats), and, less likely, resolution of uremia.[2], [11] Cyc A-related fibroadenomas tend to be multiple and bilateral as seen in our series. In one of our patients, fibroadenomas were multiple, bilateral, and giant (4–6 cm) in character. To our knowledge, no malignant degeneration has been reported in patients with multiple giant fibroadenomas[13] (Figure 2).

Figure 2. In the same patient, bilateral mediolateral-oblique mammograms demonstrate heterogenously dense parenchyma and multiple large, scattered, circumscribed masses bilaterally.

Our analysis revealed a statistically significant increase in fibroadenoma incidence with the use of Cyc A, whereas no association with the use of tacrolimus was found (p = 0.0023). Whether this is a result of relatively short duration of tacrolimus use because it is a newer agent is yet to be seen in time.

An association of fibroadenoma and Cyc A treatment was first reported by Rolles and Calne in 1980.[14] The authors described two patients who developed fibroadenomas after Cyc A therapy. Another study was reported by Baildam et al.[2] in 1996. The authors performed a prospective study on 39 women with renal transplants treated with or without Cyc A. They found that 13 (45%) of the 29 women treated with Cyc A developed fibroadenomas. The tumor was multiple in 10 patients and bilateral in 5 patients. None of the 10 patients who received steroids or azathioprine had abnormal breast findings. A retrospective study of 87 women by Campbell et al.[15] showed a similar but lower incidence of fibroadenomas (11%) in patients treated with Cyc A and other immunosuppressors.

We found fibroadenoma in 8 of 17 women treated with Cyc A (41%). Our incidence was higher than that of Campbell et al., but lower than Baildam et al.

In conclusion, although the number of patients in this study is limited, an increase in the incidence of fibroadenomas with the use of Cyc A in RTRs is strongly suggested. Awareness of this association should help in arriving at the correct diagnosis in Tx patients without subjecting them to unnecessary procedures. Perhaps in patients with fibroadenomas, use of combinations not containing Cyc A should be considered.