CURRENTLY IN THE United States, 431,284

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1 Increased Breast Calcifications in Women With ESRD on Dialysis: Implications for Breast Cancer Screening Mario Castellanos, MD, Seema Varma, MD, Kathleen Ahern, PhD, RN, Sue-Jane Grosso, MD, Shalom Buchbinder, MD, Denis D Angelo, MD, Carolyn Raia, MD, Morton Kleiner, MD, and Suzanne Elsayegh, MD Background: Different appearances of breast calcification on mammography can differentiate benign from malignant disease. An increased incidence of breast calcifications in dialysis patients is established, but data for morphological characteristics in renal patients, incidence of benign and malignant calcifications, and clinical consequences are limited. In this study, we compare mammograms and the workup of abnormal calcifications of women on hemodialysis with that of women with normal renal function. Methods: This is a retrospective case-control study; 45 women on hemodialysis had their screening mammograms reviewed. A control group of 86 age-matched women with normal renal function was randomly obtained for comparison. Mammograms were examined and the recommended workup was traced. Breast calcification morphological characteristics, incidence of benign versus malignant calcifications, callback rate, and biopsy recommendation rates were compared to determine whether breast calcifications in renal patients led to excessive workups. Results: Overall, breast calcifications in the renal group were statistically significantly increased compared with controls, mostly because of several benign-appearing morphological characteristics. No statistically significant difference was present between the 2 groups with respect to callback rates. However, incidences of malignancy-associated calcification and hence biopsy recommendation rate were slightly greater for the renal group. Conclusion: Renal patients have an increase in breast calcification, mostly caused by several benign calcifications. The callback rate is no greater than that in the general population. However, there is a slightly greater incidence of malignancy-associated calcifications; hence, once called back, they have a greater probability of being recommended for biopsy. Am J Kidney Dis 48: by the National Kidney Foundation, Inc. INDEX WORDS: Breast calcification; end-stage renal disease (ESRD); chronic kidney disease (CKD); screening mammography. CURRENTLY IN THE United States, 431,284 patients are being treated for end-stage renal disease (ESRD). Females account for about 43%, with the majority older than 45 years. 1,2 According to current recommendations for breast cancer screening, most of these patients are in the age range in which patients are encouraged to undergo screening mammography. Breast calcification is an important finding on screening mammography; the appearance and pattern may be specific, reflecting a benign, malignant, or indeterminate pattern. Patterns of breast calcification in renal dialysis patients are of particular interest because there is an increased incidence of breast calcification in patients with renal disease There were attempts in the past to describe patterns of breast calcifications in renal patients, but these included only 2 old small studies 5,11 and a few scattered case reports, 4,9,12 significantly limited by the poor quality of mammogram resolution of that period. Data for morphological characteristics of breast calcification associated with renal disease, incidence of benign versus malignant calcifications, and their clinical consequences clearly are limited, although thousands of women with ESRD are eligible for mammogram screening. This data is important to aid in management and avoid unnecessary costly erroneous workups and psychological stress for the patient. In this study, we compare mammograms of women with ESRD on long-term dialysis therapy with those of women with normal renal function. We describe morphological characteristics of breast calcifications in each group and compare From the Departments of Medicine and Radiology, Staten Island University Hospital; and Regional Radiology, St Vincent s Medical Center of Richmond, Staten Island, NY. Received October 21, 2005; accepted in revised form May 4, Originally published online as doi: /j.ajkd on June 30, Support: None. Potential conflicts of interest: None. Address reprint requests to Mario Castellanos, MD, Director of Medical Women s Health Division, Associate Director of Research, Department of Medicine, 401 Seaview Ave, Staten Island, NY mario_castellanos@ siuh.edu 2006 by the National Kidney Foundation, Inc /06/ $32.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 48, No 2 (August), 2006: pp

2 302 callback rates, incidences of benign and malignant calcifications, diagnostic workups for suspicious calcifications, and biopsy recommendation rates for each group. METHODS Study Population We performed a retrospective case-control study in After institutional review board approval, medical records from 3 dialysis units from a university-affiliated medical center were reviewed. All women who were on hemodialysis therapy were considered. From this cohort, patients who had a previous mammogram performed at the medical center were assigned to the study group. Women attending the institution s medical clinics who had normal renal function were randomly selected to form the control group. Patients with normal renal function were obtained by randomly selecting patients with normal creatinine clearance and serum calcium levels. Patients were screened to ensure that each had a mammogram at the institution. Patients in the control group were age matched to the renal group to create a similar age distribution to the study group because the incidence of breast calcification is influenced by age. 5 Figure 1 shows the age distribution of renal patients. Mammography Mammograms of patients from both the renal and control groups were reviewed. Mammograms were obtained by using a standard 4-view examination with Lorad MIII mammography units (Trex Medical, Danbury, CT). Three experienced mammographers reviewed the films (S.-J.G., D.D., and C.R.). They were blinded to patient renal function and reexamined the mammograms independently (Fig 2). Calcifications were described, categorized, and reported according to the American College of Radiology Breast Imaging Reporting and Data Systems (BIRADS) 13 (Table 1). A component of the BIRADS is that it gives standard terminology for describing findings seen on mammography that are used to provide consistency among radiologists. Using this CASTELLANOS ET AL system, breast calcifications can be grouped as being associated with benign (9 calcification patterns), malignant (3 calcification patterns), and indeterminate breast pathological states (2 calcification patterns). The final diagnosis of mammograms was reported by using the BIRADS final assessment categories. Negative/ normal studies are placed into category 1; benign lesions, category 2; probably benign lesions, category 3; suspicious lesions, category 4; and highly suspicious lesions, category 5. Incomplete screening that requires additional workup is placed in category 0. BIRADS 1, 2, and 3 were regarded as negative studies and BIRADS 4 and 5 were regarded as positive studies for malignancy. Follow-Up Patients were called back for abnormal findings on initial screening mammogram, such as a mass, asymmetric densities, and suspicious breast calcifications. The callback rate, a standard mammography measure, was examined in both groups. The callback rate is the number of cases called back after initial screening mammography of the total number of patients screened. Additional workup included magnification views of the breast with or without breast ultrasound, as needed. Patients who had a final BIRADS description after the additional workup consistent with suspicious calcifications for malignancy were recommended to undergo a biopsy. Biopsy recommendation rates were calculated as total number of patients recommended for biopsy in each group against the total number of patients screened. Statistical Analyses Nonparametric statistics were used. Chi-square and Fisher exact tests were performed as appropriate, with Fisher exact used in all instances in which cell sizes were less than 5. RESULTS Forty-five renal patients from the 3 dialysis units had mammograms at the medical center. Controls consisted of 86 age-matched patients. Fig 1. Age distribution of renal patients.

3 BREAST CALCIFICATIONS IN RENAL DISEASE 303 Fig 2. Mammogram showing vascular calcifications. From the renal group, 38 of 45 patients (84.4%) had calcifications on their mammograms. Conversely, 51 of 86 controls (59.3%) had calcifications on their mammograms. The incidence of Table 1. Abbreviations of Breast Calcification Categories Pattern Malignant association Interrupted, fine, linear, or branching Pleomorphic heterogeneous Amorphous Benign association Skin Vascular Large rod-like Eggshell Spherical or lucent center Suture Dystrophic Punctate ( 0.5 mm) Milk of calcium Indeterminate Coarse Round (0.5-1 mm) Abbreviation IC HC AC SC VC LG EC OC SC1 DC PC MC CC RC calcifications in the renal group versus the control group was statistically significant (P 0.003; Table 2). The frequency of each category is listed in Table 3. Most of the increase in incidence of calcifications in the renal group appears to be caused by several benign calcification patterns (Fig 3; Table 3). Comparing categories of benign calcifications, vascular calcification was the most common pattern seen in both groups, with no statistical difference between groups (P 0.46). The benign pattern that differed between groups was parenchymal spherical or lucent calcification pattern. Renal patients were significantly more likely to have this calcification pattern than controls (P ; Table 3). Comparing only incidence of calcifications commonly considered to be associated with malignancy (BIRADS 4 and 5), amorphous, pleomorphic heterogeneous, and interrupted, fine, linear, or branching, no statistically significant difference was identified between the renal and control groups for the incidence of each indi-

4 304 CASTELLANOS ET AL Table 2. Results of Mammogram Review Renal Patients Controls P No. of patients No. of cases with calcifications 38 (84.4) 51 (59.3) Callback rate for suspicious calcifications 4/45 (8.8) 3/86 (3.48) 0.23 Final BIRADS description consistent with malignancy-associated calcification and cases sent for biopsy 4/45 (8.8) 1/86 (1.16) 0.047* NOTE. Values expressed as number (percent). *As a group, malignancy-associated calcifications were significantly greater in the renal group (8.8%) versus controls (1.16%), and biopsy recommendation rates were significantly different (P 0.047). vidual calcification (Table 3). However, as a group, the final diagnosis of malignancy-associated calcifications provoking a biopsy recommendation was significantly greater in the renal group (4 of 45 patients) versus controls (1 of 86 patients; P 0.047; Tables 2 and 4). On initial screening mammography, there were 4 cases with suspicious calcifications in the renal group of 45 patients screened and 3 cases with suspicious calcifications in the control group of 86 patients screened (Table 2). Therefore, callback rates for abnormal calcifications were 8.8% for the renal group versus 3.48% for controls. This was not statistically significant (P 0.23). Upon further workup of patients called back for suspicious calcifications, all 4 cases in the renal group, but only 1 case of the 3 callback cases in the control group, had a final BIRADS description consistent with a malignancy-associated calcification pattern, and biopsy was recommended. Therefore, the incidence of final radiological diagnosis of malignant-associated calcifications, reflecting the biopsy recommendation rate, was calculated as the total number of patients recommended for biopsy of the total number of patients screened in each group. In the renal group, this was 8.8%, and in controls, 1.16% (P 0.047, which is statistically significant; Tables 2 and 4). Table 3. Frequencies of Morphological Characteristics of Calcifications on Mammograms of the Renal and Control Groups Morphological Characteristics of Calcification Abbreviation Frequency of Calcification Pattern in the Renal Group (%) Frequency of Calcification Pattern in the Control Group (%) P Malignant Interrupted, fine, linear, or branching IC Pleomorphic heterogeneous HC Amorphous AC Benign Skin SC Vascular VC Large rod-like LG Eggshell EC Spherical or lucent center OC * Suture SC Dystrophic DC Punctate ( 0.5 mm) PC Milk of calcium MC Benign or malignant Coarse CC Round (0.5-1 mm) RC NOTE. As a group, malignancy-associated calcifications were significantly greater in the renal group (4 of 45 patients) versus controls (1 of 86 patients; P 0.047). Vascular calcification was the most common pattern seen in both groups, with no statistical difference between groups. *Categories are statistically significant.

5 BREAST CALCIFICATIONS IN RENAL DISEASE 305 Fig 3. Frequencies of benign and malignant calcifications on mammograms of the renal and control groups. The frequency of spherical or lucent (OC) calcification pattern was more common in the renal group, P DISCUSSION Thousands of patients with ESRD are eligible for breast cancer screening with mammography. However, there is a concern that mammographic interpretation in this population may be difficult because of the increased incidence of breast tissue calcification. Metastatic soft-tissue calcification as a result of secondary hyperparathyroidism in patients with chronic renal disease is well described. 5,7,8,10 In 1987, Sommer et al 5 described breast calcifications in 68% of patients undergoing dialysis. Since then, there have been several reports describing breast calcifications in patients with renal disease. 3,4,6,9 There is concern that the increased incidence of breast calcifications in patients on dialysis therapy may pose a diagnostic dilemma. Despite this possibility, only 2 old studies 5,11 attempted to describe and categorize morphological characteristics of breast calcifications in dialysis patients. These studies were small and significantly limited by the unavailability of current highresolution mammography techniques. Furthermore, investigators of these studies 5,11 and previous case reports 4,9,12 did not have uniform terminology available for categorizing and reporting breast calcifications because they were done before institution of the American College of Radiology BIRADS. Sommer et al 5 compared mammograms of 15 patients with compensated renal insufficiency, 22 on hemodialysis therapy and 14 who had renal transplants, with a control group of 100 who had normal kidney function. Frequency, size, structure, and location of calcific lesions were assessed. Patients with renal disease had significantly more calcifications than those with normal kidney function. Parenchymal calcifications (61% versus 27%) were the most frequent, followed by vascular (45% versus 8%) and ductal (29% versus 9%). Parenchymal calcifications were categorized as small, round, or oval; scattered; and not associated with a mass. This appears to correspond to punctate and round calcifications in the BIRADS groups. Ductal calcifications, large rod-like in current terms, usually were found behind the areola and also could be seen in other areas of the breast in the typical orientation toward the nipple. No calcification looked like malignant calcification of the breast, according to the investigators. Evans et al 11 studied mammograms of 16 women on renal dialysis therapy and compared them with a control group of 32 women attending for routine mammographic screening. They categorized calcifications as vascular, parenchymal, and ductal. Parenchymal calcifications were grouped as punctate, teacup, or pearl shaped. Using the current BIRADS lexicon, these terms probably would represent dystrophic, milk of calcium, and round, respectively. They categorized ductal calcifica-

6 306 tions as granular, casting, or linear, which, in BIRADS terms, describes large rod-like calcifications. They found a significant increase in parenchymal, followed by vascular, calcifications in women on renal dialysis therapy. Ductal calcifications were no more prevalent in patients on dialysis therapy compared with the control group, and in no case did calcifications simulate malignancy. These 2 studies correctly concluded that there was an increased incidence of breast calcifications on mammograms of renal patients, and most of these calcifications did not simulate malignancy with the available imaging resolution. However, they did not compare the incidence of malignant calcifications as a group, clinical consequences of increased calcifications, or callback and biopsy recommendation rates. In our study, breast calcifications were more common in patients on long-term dialysis therapy (84.4%) compared with age-matched control patients (59%), and the increased incidence was caused mostly by calcifications associated with benign morphological characteristics categorized according to the current standard BIRADS. This is reflected by the similar callback rates and is consistent with results of the 2 previously reported studies and case reports. 5,7,8,10 However, compared with the control group, the incidence of malignancy-associated calcifications as a group was slightly greater in the renal group, as was the biopsy recommendation rate (P 0.047). Therefore, it appears that renal patients, once called back, were more likely to be recommended for biopsy compared with the general population. However, an increase in cancer rates in renal patients remains uncertain at this time because the study is not designed to clarify this question. Bias related to interval length between mammogram screenings may exist, leading to group differences. Therefore, what can be concluded from this study is that the greater frequency of breast calcifications leads to a greater rate of breast calcifications of indeterminate behavior warranting biopsies. The callback rate at our institution for the entire year of 2005 was about 10%. The renal group in the study had a similar rate of 8.8%. The biopsy rate at the institution is 1.5%, similar to that of controls at 1.16%. However, this is much lower than the 8.8% biopsy rate for the renal group in the study. CASTELLANOS ET AL Additional studies with a larger sample size are recommended to confirm this new finding and determine the positive predictive value of indeterminate calcifications and determine cancer rates in the hemodialysis population. Therefore, at this time, every woman on dialysis therapy should be referred for screening mammography, and the physician taking care of these patients should be aware of the slightly increased risk for workup and possibly resultant psychological stress after screening in dialysis patients. Mammography is an important screening tool and should be offered to all dialysis patients according to standard health care guidelines of the general population. REFERENCES 1. US Renal Data System: Excerpts from the USRDS 2004 Annual Data Report. Am J Kidney Dis 45:S1-S280, 2005 (suppl 1) 2. US Renal Data System: Annual Report. Incidence and prevalence of ESRD. Am J Kidney Dis 34:S40-S50, 1999 (suppl 1) 3. Sarah Rovno HD, Feig SA, Hughes JS, Hurford MT, Karasick D, Filippone E: Breast imaging case of the day. Radiographics 18: , Cooper RA, Berman S: Extensive breast calcification in renal failure. J Thorac Imaging 3:81-82, Sommer G, Kopsa H, Zazgornik J, Salomonowitz E: Breast calcifications in renal hyperparathyroidism. AJR Am J Roentgenol 148: , McDougal BA, Lukert BP: Resolution of breast pain and calcification with renal transplantation. Arch Intern Med 137: , Conger JD, Hammond WS, Alfrey AC, Contiguglia SR, Stanford RE, Huffer WE: Pulmonary calcification in chronic dialysis patients: Clinical and pathologic studies. Ann Intern Med 83: , Parfitt AM: Soft tissue calcification in uremia. Arch Intern Med 124: , Han SY, Witten DM: Diffuse calcification of the breast in chronic renal failure. AJR Am J Roentgenol 129: , Massry SG, Coburn JW, Popovtzer MM, Shinaberger JH, Maxwell MH, Kleeman CR: Secondary hyperparathyroidism in chronic renal failure: The clinical spectrum in uremia, during hemodialysis, and after renal transplantation. Arch Intern Med 124: , Evans AJ, Cohen MEL, Cohen GF: Patterns of breast calcification in patients on renal dialysis. Clin Radiol 45: , Evans SE, Whitehouse GH: Extensive calcification in the breast in chronic renal failure. Br J Radiol 64: , American College of Radiology: Breast Imaging Reporting and Data Systems (BIRADS) (ed 4). Reston, VA, American College of Radiology, 2003