Risk Factor Analysis for Breast Cellulitis Complicating Breast Conservation Therapy

Transcription

1 654 MAJOR ARTICLES Risk Factor Analysis for Breast Cellulitis Complicating Breast Conservation Therapy Valerie H. Brewer, Kevin A. Hahn, Barton W. Rohrbach, John L. Bell, and Larry M. Baddour Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee Knoxville, and Departments of Surgery and Medicine, University of Tennessee Medical Center at Knoxville, Knoxville, Tennessee Women who undergo breast conservation therapy for early-stage breast cancer can develop breast cellulitis, a complication for which risk factors are undefined. A matched case-control investigation was conducted to identify risk factors for the development of breast cellulitis among patients who have undergone breast conservation therapy. Patients comprised 17 patients with cases of breast cellulitis diagnosed after partial mastectomies that had been performed from 1992 through 1997 and 34 control patients who were matched to case-patients by date of breast lumpectomy and by primary surgeon. Statistical analyses indicated the following factors were associated with breast cellulitis: drainage of a hematoma ( P p.010); postoperative ecchymosis ( P p.021); lymphedema (odds ratio [OR], ; 95% confidence interval [CI], ); resected breast tissue volume (OR, 1.456; 95% CI, ); and previous number of breast seroma aspirations (OR, 3.445; 95% CI, ). This is the first matched case-control study to identify risk factors for the development of breast cellulitis after breast conservation therapy. Breast conservation therapy includes breast lumpectomy, axillary lymph node dissection, and radiotherapy for the remaining breast for the locoregional treatment of stage I and II breast cancer. This novel form of breast cancer treatment has been shown to have equivalent therapeutic efficacy to that of mastectomy in appropriately selected patients and has been preferred by most patients [1 3]. Unfortunately, a minority of women who undergo breast conservation therapy develop breast cellulitis, often on a recurrent basis [4 9]. This represents a newly described infection syndrome that, through undefined mechanisms, complicates breast conservation therapy [4 6]. As the use of breast conservation therapy for early-stage breast cancer becomes more common, a growing number of breast cellulitis cases will occur. Therefore, it is imperative that we define risk factors for the development of breast cellulitis in an attempt to reduce the occurrence of this complication by incorporating defined preventive measures. We describe a matched case-control study that we performed to statistically identify risk factors in the largest sample of breast cellulitis cases studied to date. Received 25 August 1999; revised 1 December 1999; electronically published 21 September Reprints or correspondence: Dr. Larry M. Baddour, Dept. of Medicine, 1924 Alcoa Highway U-114, Knoxville, TN (lbaddour@mc.utmck.edu). Clinical Infectious Diseases 2000;31: by the Infectious Diseases Society of America. All rights reserved /2000/ $03.00 Methods Study design. In assessing potential risk factors associated with the development of breast cellulitis, a case-control study was the design of choice because of the low incidence of cellulitis [8] and because patient records were readily accessible for review. To date, and to our knowledge, literature that describes the complication of breast cellulitis occurring after breast conservation therapy has been limited to an unmatched study [5] that included 10 cellulitis patients and 4 case series [4, 6 8] that described the syndrome. Case selection. The cases evaluated in this study were patients who developed breast cellulitis after they underwent partial mastectomies performed by 3 surgeons at the University of Tennessee Medical Center, Knoxville (UTMCK). Surgery residents assisted in all cases; no data were collected to analyze the training level of the residents. There was no temporal association between cases of cellulitis and initiation of surgical residency training. UTMCK s database of diagnosis codes, used to classify primary and associated diagnoses of patients discharged from the hospital, was searched for all patients discharged from the hospital from January 1985 through June 1998 with a primary or associated diagnosis of inflammatory breast disease, the general classification group in which breast cellulitis would be found. Because the possibility existed that breast cellulitis could have been listed as erysipelas, medical record numbers were also obtained for all codes that indicated a primary or associated diagnosis of erysipelas. From January 1985 through June 1998, 105 patients were discharged from UTMCK with either a primary or an associated diagnosis of inflammatory breast disease; 22 patients had a primary or associated diagnosis of erysipelas. UTMCK s tumor registry database was searched for all patients who received partial mas-

2 CID 2000;31 (September) Risk Factor Analysis for Breast Cellulitis 655 tectomies from January 1985 through June Nineteen cases had diagnosis codes of inflammatory breast disease or erysipelas after partial mastectomy and were considered as potential cases for inclusion in the study. The medical records and hospital discharge records were reviewed to confirm the occurrence of breast cellulitis in potential cases. Cellulitis was defined as the acute development of erythema, swelling, warmth, and tenderness of the partial mastectomy breast. Systemic toxicity, including fever and chills, was seen in some patients. Bacterial pathogens were infrequently recovered, a finding described in other case series of breast cellulitis [9]. Cellulitis was distinguished from local changes because of the postoperative state and local irradiation; cellulitis signs and symptoms were usually acute at onset and more severe. Seventeen of 19 patients were confirmed to have breast cellulitis after they had breast conservation therapy. All patients diagnosed with breast cellulitis had had a partial mastectomy between 1992 and Control selection. Two control patients were selected for each case patient. Control patients for the study were matched to the case patients by date of partial mastectomy (range, 2 days to 3 months) and primary surgeon. Matched controls were identified as patients who received a partial mastectomy by the same surgeon immediately before and after the partial mastectomy of the case patient. For 1 case patient, both controls identified were patients who had partial mastectomies preceding the case patient s date of partial mastectomy because no later partial mastectomies were performed by the surgeon. Data collection. A list of potential risk factors for the development of cellulitis was generated on the basis of clinical experience and speculations listed in the medical literature (table 1). Because no previous case-control studies had been conducted, all conceivable risk factors were included in this investigation. Medical abstracts, which contained complete summaries of the patients breast conservation therapy and aftercare, were obtained from UTMCK s tumor registry for all case patients and control patients. The abstracts were used to find or verify patient information such as name, medical record number, and the primary surgeon who performed the partial mastectomy. They were also used to gather preliminary information regarding each patient s breast surgery to include date of birth; race; date of partial mastectomy; cancer histology; cancer grade; tumor size; stage of cancer; breast quadrant in which the partial mastectomy was performed; names of surgeons and attending physicians; number of lymph nodes examined; types of treatment administered (radiation, chemotherapy, or hormonal therapy); date of last contact; and survival time (in months) as of the last date of contact. Upon gathering preliminary information from the medical abstracts, a retrospective review of the complete patient record for each of the 17 case patients and 34 control patients was conducted to investigate the potential risk factors presented in table 1. The patients records were maintained by their primary surgeons. Records consisted of office visits, operative and pathology reports, admission and discharge summaries, mammography, ultrasound scan and laboratory reports, treatment (radiation, chemotherapy, etc.), surgery and prescription orders, summaries from other physicians, and any other oncology or general medical correspondence related to the patient. The number of days that lapsed from the time of breast lumpectomy to the initial diagnosis of breast cellulitis was calculated for each patient. Matched control patients were observed for the same amount of time as the case patients and did not develop breast cellulitis during the study period. If a control patient could not be followed for as long as it took their matched case patients to develop cellulitis, or if a control patient had a total mastectomy within this time frame, then the control patient was excluded from the study and a new one was selected. Sixteen control patients were excluded and replaced from the study because data were not available for the required period. Four of the control patients died, 6 had a mastectomy after undergoing breast conservation therapy, and 6 were not followed for a long enough time after undergoing lumpectomy to be included because of a change in address or a change in physician. Statistical analysis. Data obtained from the records of case patients and control patients were entered into a statistical spreadsheet (Epi Info, version 6.04, Centers for Disease Control and Prevention, Atlanta) and converted into a SAS software data file (version 6.12; SAS, Cary, NC). If information relating to a specific risk factor was missing for both matched controls or for a case-patient, the case patient and control patients were excluded from the analysis. Case-control sets were not excluded from the analysis if a case patient and only 1 matched control patient had information pertaining to a specific risk factor. Logistic regression was used to evaluate the association of each of the potential risk factors measured on the interval scale with the occurrence of breast cellulitis. Nominal and ordinal characteristics were associated with breast cellulitis with x 2 test or Fisher s exact test, depending on the expected cell counts in the contingency tables. Because of small sample size and multiple levels of some categorical variables, selected strata were combined. These variables included histopathologic grade, histology, nuclear grade, cancer stage, and quadrant. Attempts to create a multiple logistic regression model were unsuccessful because of limited sample size. For risk factors, P.05 was considered statistically significant, P 1.05 to P.35 was considered possibly associated, and P 1.35 was considered to be unlikely to be associated with breast cellulitis. Results Seventeen women who were found to have breast cellulitis after they had undergone breast conservation therapy and 34 matched control patients were evaluated. The median time from date of partial mastectomy to date of breast cellulitis diagnosis was 190 days (range, days). Two case patients completed chemotherapy in the time between dates of partial mastectomy and diagnosis of breast cellulitis. One patient developed cellulitis 1 day after completion of chemotherapy, whereas the other case patient developed cellulitis 47 days after chemotherapy was completed. Thirteen women completed the planned radiotherapy protocol between dates of partial mastectomy and breast cellulitis diagnosis. The median number of days from end of radiotherapy to diagnosis of cellulitis was 109 days (range, days). The majority of case patients in the study had at least 1 mammogram between the time of surgery and the diagnosis of breast cellulitis. The median number of days between diagnosis of cellulitis and the last mammogram taken before diagnosis of breast cellulitis was 82 days (range, days). Fourteen case patients in the study had at least 1 ultrasound scan between the time of surgery and diagnosis of breast cellulitis. The median

3 Table 1. Risk factor Risk factors analyzed for the development of breast cellulitis diagnosed after breast conservation therapy. Description Additional surgery Additional surgery (ipsilateral breast surgery or axillary dissection) after partial mastectomy Age Years of age at time of partial mastectomy Alcohol consumption Whether patient ever consumed alcohol Allergy desensitization Allergy desensitization by immunization prior to partial mastectomy Antibiotics Receipt of antibiotics within 24 h of partial mastectomy (including perioperative antibiotics) Autoimmune diseases Autoimmune diseases or vasculitis Axillary dissection Axillary dissection as part of breast conservation therapy Bacteria Positive bacterial cultures 6 mo before partial mastectomy at sites other than the ipsilateral breast Brachial plexus palsy Development of brachial plexus palsy because of radiation or prior trauma Central line Insertion of a central line (Porta Cath, Groshong, etc.) Chemotherapy Chemotherapy after partial mastectomy Deep venous thrombosis Development of deep venous thrombosis at site of partial mastectomy or in ipsilateral arm Diabetes Diabetes mellitus Ecchymosis Development of postoperative ecchymosis Estrogen receptor positivity Grade Histopathologic grade: (1) grade I, grade II, or grade III; or (2) grade I vs. all other grades Heart problems Presence of cardiac abnormalities at any time during patient s life (excluding murmurs) Hematoma Development of hematoma in ipsilateral breast after partial mastectomy Hematoma drainage Drainage of hematoma in ipsilateral breast following partial mastectomy Histology Histology of tumor: (1) as listed in pathology report or (2) carcinoma not otherwise specified, ductal, or lobular Hormonal therapy Hormonal therapy (i.e., tamoxifen) after partial mastectomy Injection drug use Whether patient ever used illicit injection drugs Invasive tumor Invasive tumor vs. noninvasive tumor Lymph nodes removed Number of lymph nodes removed Lymphedema Development of lymphedema in ipsilateral upper arm after partial mastectomy per clinical diagnosis by the respective oncologic surgeon Mammograms Number of mammograms from date of partial mastectomy to initial diagnosis of breast cellulitis Mastitis Development of mastitis following partial mastectomy Menopausal status Pre-, post-, or perimenopausal at time of partial mastectomy Necrosis Skin necrosis after partial mastectomy Nipple discharge Nipple discharge in ipsilateral breast any time before the development of breast cellulitis NSAI drug use Regular use of nonsteroidal anti-inflammatory drugs Nuclear grade Nuclear grade of cancer: (1) 1/3, 1-2/3, 2/3, 2-3/3, or 3/3; or (2) 1/3 vs. all other nuclear grades Physical therapy Prescribed physical therapy (beyond routine recommendations) for ipsilateral upper extremity Previous breast biopsies Previous biopsies in ipsilateral breast (yes or no) and prior number of biopsies in ipsilateral breast Previous chest surgery Previous chest surgery in ipsilateral breast Quadrant Quadrant of the breast in which partial mastectomy was performed: (1) upper-inner, upper-outer, lower-inner, lower-outer, or central; (2) central, inner, or outer; or (3) central, upper, or lower Race Radiation dose Total radiation dose, cgy Radiodermatitis Development of radiodermatitis of ipsilateral breast Volume of resected axillary tissue Volume of resected axillary tissue, ml 3 Volume of resected breast tissue Volume of resected breast tissue, ml 3 Seroma Development of seroma in ipsilateral breast following partial mastectomy Seroma aspirations Aspiration of seroma following partial mastectomy (yes or no) and number of breast seroma aspirations after partial mastectomy Shoulder joint problems Ipsilateral shoulder joint problems Side Breast in which partial mastectomy was performed (left or right) Site infection Development of a surgical site infection Skin infections Dermatitis, skin disorders, or other skin infections diagnosed anytime before or after partial mastectomy Smoking history Whether patient ever smoked cigarettes or other tobacco products Stage Cancer stage: (1) 0, I, IIA, or IIB; or (2) stages 0, I, or IIA/IIB Steroids Use of corticosteroids Suture removal Removal of sutures after partial mastectomy Tumor size Size of the tumor, cm Trauma Trauma to the chest wall before or after partial mastectomy Ultrasonography Number of ultrasound scans from date of partial mastectomy to initial diagnosis of breast cellulitis Upper-outer quadrant Whether partial mastectomy was performed in the upper-outer quadrant of the breast Weight Weight of the patient at time of partial mastectomy NOTE. NSAI, nonsteroidal anti-inflammatory.

4 CID 2000;31 (September) Risk Factor Analysis for Breast Cellulitis 657 Table 2. Significant risk factors for the development of breast cellulitis diagnosed after breast conservation therapy ( P.05). Risk factor P a OR 95% CI Hematoma drainage.010 Ecchymosis b.021 Lymphedema Volume of resected breast tissue c No. of previous breast biopsies No. of breast seroma aspirations a Logistic regression test was used in statistical analyses. b A protective association was demonstrated for this factor. c OR is for an increase in a unit of 50 cm 3. number of days between diagnosis of cellulitis and the last ultrasound scan performed before breast cellulitis diagnosis was 73 days (range, days). No instances of cellulitis were seen in the first 7 years ( ) of the survey. There are at least 3 factors that likely accounted for this observation. First, as addressed previously, there was a delay of months to years between the date of surgery and the initial bout of cellulitis for most patients. Second, breast conservation therapy was a new treatment modality in the mid- 1980s for women with early-stage breast cancer, and adoption of the therapy was gradual; only 96 cases of breast lumpectomy were performed at our institution over the first 7 years of the study period. Third, the incidence of breast cellulitis is low, calculated as 0.8% per year in one investigation [8]. Thus, a critical pool size of at-risk patients was needed before cases of breast cellulitis were seen. Risk factors that had a P value.05 are listed in table 2, along with their associated ORs and 95% CIs. These included drainage of a hematoma, postoperative ecchymosis, presence of lymphedema, volume of resected breast tissue, previous number of breast biopsies, and the number of breast seroma aspiration procedures. ORs and CIs could not be obtained for hematoma drainage ( P p.010) or ecchymosis ( P p.021). For the calculation of ORs, there must have been at least 1 case patient and 1 control patient exposed to the risk factor, and this criterion was not met for either hematoma drainage or ecchymosis. Table 3. Results of the analysis of numerical variables considered as potential risk factors for the development of breast cellulitis diagnosed after breast conservation therapy. Risk factor Values for patient height were not available in the medical records; therefore, body-mass index could not be calculated. All 51 patients were white, so race could not be evaluated as a risk factor. The number of mammograms and ultrasound scans performed between the date of partial mastectomy and the onset of breast cellulitis was calculated for case patients and control patients. For each case patient, we counted the number of mammograms and ultrasound scans performed during the period from the date of breast surgery to the diagnosis of cellulitis; for each matched control patient, made the same count for an equal period of time after they underwent surgery. The median number of mammograms and ultrasound scans was similar for case patients and control patients (table 3). Risk factors that were measured dichotomously (i.e., according to a yes/no outcome) are listed in table 4. None of the 51 patients in this study had any known evidence of injection drug use, shoulder joint problems, brachial plexus palsy, skin necrosis, or extended physical therapy; therefore, these potential risk factors could not be analyzed. Categorically measured factors that did not require a yes or no outcome included tumor stage, nuclear grade, histopathologic grade, histology, breast and breast quadrant in which partial mastectomy was performed, and menopausal status. Because some of these categorical risk factors (e.g., histopathologic grade, histology, nuclear grade, cancer stage, and quadrant) had low sample size within various strata, some strata were combined and separate analyses performed. For example, when evaluating the significance of histopathologic grade, the first analysis was performed to determine if a significant difference existed between the individual grades (i.e., grade group I vs. II vs. III), and the second analysis was performed to determine if a significant difference existed between arbitrarily combined strata (i.e., grade group I vs. II/III; table 1). With the exception of histology, for each of the above-mentioned risk factors the P value was.3 when evaluated, regardless of whether strata were combined. When evaluating tumor histology, P was.143; however, when Case patients, median (range) Control patients, median (range) Age, y 53 (33 75) 54.5 (33 78).587 Weight, kg 74.7 ( ) 69.3 ( ).452 Tumor size, cm 1.5 ( ) 1.6 ( ).755 Volume of resected breast tissue, cm ( ) ( ).030 No. of lymph nodes removed 12 (0 31) 10.5 (0 45).520 Volume of resected axillary tissue, cm ( ) ( ).274 Total radiation dose, cgy 6120 (0 6440) 6120 (0 6440).500 No. of previous breast biopsies 1 (0 3) 1 (0 3).031 No. of breast seroma aspirations 0 (0 11) 0 (0 1).035 No. of mammograms 1 (0 6) 1 (0 4).825 No. of ultrasound scans 1 (0 10) 0 (0 4).117 P a a P values were obtained by logistic regression.

5 658 Brewer et al. CID 2000;31 (September) Table 4. Results of the analysis of dichotomous variables considered as potential risk factors for the development of breast cellulitis diagnosed after breast conservation therapy. Risk factors Case patients, n (%) Control patients, n (%) Additional surgery 7 (41.2) 14 (41.2) Alcohol consumption 4 (25.0) 10 (31.3).746 Allergy desensitization 0 (0.0) 1 (2.9) Antibiotics 11 (64.7) 16 (47.1).234 Autoimmune diseases 1 (5.9) 3 (8.8) Axillary dissection 15 (88.2) 26 (76.5).463 Bacteria 3 (17.6) 1 (2.9).102 Brachial plexus palsy 0 (0.0) 0 (0.0) Central line 0 (0.0) 3 (8.8).542 Chemotherapy 2 (11.8) 9 (26.5).297 Deep venous thrombosis 0 (0.0) 1 (2.9) Diabetes mellitus 2 (11.8) 2 (5.9).593 Ecchymosis 0 (0.0) 10 (29.4).021 Estrogen receptor positivity 12 (75.0) 23 (88.5).397 Heart problems 0 (0.0) 6 (17.6).161 Hematoma 8 (47.1) 8 (23.5).088 Hematoma drainage 4 (23.5) 0 (0.0).010 Hormonal therapy 6 (35.3) 14 (41.2).685 Injection drug use 0 (0.0) 0 (0.0) Invasive tumor 16 (94.1) 27 (79.4).242 Lymphedema 4 (23.5) 1 (2.9).023 Mastitis 2 (11.8) 0 (0.0).107 Necrosis 0 (0.0) 0 (0.0) Nipple discharge 1 (5.9) 1 (2.9) NSAI drug use 2 (11.8) 5 (14.7) Physical therapy 0 (0.0) 0 (0.0) Previous biopsies 15 (88.2) 22 (64.7).102 Previous chest surgery 3 (17.6) 4 (11.8).673 Radiodermatitis 0 (0.0) 1 (2.9) Seroma 11 (64.7) 13 (38.2).074 Seroma aspirations 5 (29.4) 3 (8.8).099 Shoulder joint problems 0 (0.0) 0 (0.0) Site infection 2 (11.8) 1 (2.9).255 Skin infections 2 (11.8) 2 (5.9).593 Smoking history 3 (17.6) 8 (23.5).731 Steroids 1 (5.9) 1 (2.9) Suture removal 8 (47.1) 9 (26.5).141 Trauma 1 (5.9) 1 (2.9) Upper-outer quadrant 10 (58.8) 16 (48.5).488 NOTE. NSAI, nonsteroidal anti-inflammatory. a P values obtained with x 2 test or Fisher s exact test, where appropriate. tumor histology was grouped and evaluated according to whether the tumors were carcinoma not otherwise specified, ductal, or lobular, P was.442. Discussion Previous reports [4 8] of breast cellulitis complicating breast conservation therapy described the novel syndrome. In 1 report [5], risk factors were also analyzed, but case patients were not matched to control patients. Thus, our report is the first matched case-control study to statistically associate potential risk factors with the development of breast cellulitis diagnosed after the patient had undergone breast conservation therapy. In the published case series of breast cellulitis [4 8], speculated risk factors included lymphedema, postoperative ecchymosis, breast seroma development, breast seroma aspiration, hematoma P a development, mastitis, unabsorbed suture material, breast tissue trauma, axillary lymph node dissection, diabetes, mammography (as a source of microtrauma), and radiation. We hypothesized that use of perioperative antibiotics, the size of the primary tumor, and histology were not associated with breast cellulitis [4]. The present study evaluated these and other possible risk factors to determine if an association with breast cellulitis existed. This case-control study included 17 women with breast cellulitis and 34 matched control patients without cellulitis. The following 6 factors were identified: drainage of a hematoma; postoperative ecchymosis; presence of lymphedema; volume of resected breast tissue; previous number of biopsies; and the number of breast seroma aspiration procedures. Lymphedema has long been recognized clinically as a risk factor for the development of cellulitis, often on a recurrent basis, in a variety of syndromes [10]. It was the most prominent risk factor for the development of breast cellulitis in our study and to our knowledge, it is the only case-control investigation [11] of lower extremity cellulitis published to date. In a multivariate analysis of risk factors among 129 leg cellulitis cases collected in a multicenter study [11], the OR for lymphedema was Twenty-two (18%) women with cellulitis had underlying lymphedema; in contrast, only 1 (0.4%) of 294 control patients manifested lymphedema. Because of the proclivity of b-hemolytic streptococci to produce cellulitis in the setting of venous and lymphatic compromise [10], it is likely that these organisms commonly cause breast cellulitis. Nevertheless, in only a small minority of cases described to date [9] have pathogens been identified. The mechanisms involved in the predisposition to infection in the setting of venous and lymphatic compromise are largely undefined. Extramammary sites of infection could contribute to the development of breast cellulitis. Manian [12] speculated that an odontogenic source of bacteria produced breast cellulitis in the 2 patients he describes. Our study provides evidence that there is a significant protective association between postoperative ecchymosis and breast cellulitis. Of the 17 women with breast cellulitis, 0 of 17 had postoperative ecchymosis, as compared with 10 of 24 control patients ( P!.03; table 4). We have no explanation for this observation. Breast seroma aspiration was also significantly associated with breast cellulitis. A woman s odds of developing breast cellulitis increased by a factor of 3.4 with every breast seroma aspiration after partial mastectomy. These findings should be interpreted with caution. The median number of aspirations was 0 (mean, 0.9), ranging from 0 to 11 aspirations. The case patient with 11 aspirations was an outlier in this study and may possibly account for a significant association when one does not exist. However, analyzing breast seroma aspirations categorically (i.e., yes or no) produced a P value of.099, indicating a possible association (table 4). This observation deserves further study. Development of seromas and hematomas were not statistically

6 CID 2000;31 (September) Risk Factor Analysis for Breast Cellulitis 659 associated with breast cellulitis. Although the P values for seroma and hematoma development were 1.05 (.074 and.088, respectively), they were small enough to be regarded as potential risk factors. Eleven (64.7%) and 8 (47.1%) of 17 cellulitis patients developed seroma and hematoma, respectively, after breast lumpectomy. This was in contrast to 13 (38.2%) and 8 (23.5%) of 34 control patients who developed postoperative seroma and hematoma, respectively. Mozes et al. [13] noted a statistical association between seroma and hematoma formation and lymphedema among women who had undergone mastectomy. No analysis of drainage procedures was conducted in that study. The current study did not find a significant association between an increased number of mammograms, total radiation dose, or radiodermatitis and the development of breast cellulitis. Previous speculation had included radiotherapy as a breast cellulitis risk factor [7]. It is difficult to explain why there was a statistical difference between case versus control populations for volume of resected breast tissues and not for tumor size or body weight. The mean tumor size and the mean amount of breast tissue resected were analyzed by the surgeons, and no statistical differences were found (data not shown). Although the current study examined the largest sample of women with breast cellulitis to date, sample size was insufficient to create a statistical model. Thus, confounding and interaction among risk factors identified by univariate analysis could not be examined. It is also possible that P values indicating statistically insignificant risk factors were a result of low sample size or lack of adjustment for multiple comparisons, rather than reflecting an insignificant association. For example, only 2 case patients and 2 control patients had diabetes mellitus. Considering the biological and clinical significance of diabetes mellitus as a risk factor for the development of infection, one cannot conclude that it is not associated with breast cellulitis. Nevertheless, a case-control study [11] of risk factors for the development of lower extremity cellulitis found no statistical association between diabetes mellitus and infection. The present study was an exploratory investigation that included an examination of numerous purported risk factors for infection. Inclusion of a relatively large number of risk factors for statistical analysis increases the chance of a type 1 error occurring. Later work should focus on the factors identified as statistically important in this survey for further statistical evaluation. In conclusion, our investigation identified risk factors for the development of breast cellulitis in women who had undergone breast conservation therapy. Six factors were statistically associated with breast cellulitis and included drainage of a hematoma, postoperative ecchymosis, presence of lymphedema, size of resected breast tissue, previous number of biopsies, and number of breast seroma aspirations. These results, if further substantiated by additional investigations, could lead to interventions by physicians to diminish the incidence of infection by identifying patients at increased risk for developing breast cellulitis. Interventions could include manipulation of risk factors, where feasible, and antibiotic prophylaxis if future investigations support these practices. Acknowledgments We thank Mandana Tayidi and Linda Wilhoite for excellent assistance in data collection and review of medical records and Dr. James Schmidhammer for generous advice regarding statistical analysis of data. We also thank Sandy Tallant for expert preparation of the manuscript. References 1. Early Breast Cancer Trialists Collaborative Group. Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials. N Engl J Med 1995;333: Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333: Christian MC, McCabe MS, Korn El, Abrams JS, Kaplan RS, Friedman MA. The National Cancer Institute audit of the National Surgical Adjuvant Breast and Bowel Project Protocol B-06. N Engl J Med 1995;333: Rescigno J, McCormick B, Brown AE, Myskowski PL. Breast cellulitis after conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 1994; 29: Staren ED, Klepac S, Smith AP, et al. The dilemma of delayed cellulitis after breast conservation therapy. Arch Surg 1996;131: Hughes LL, Styblo TM, Thoms WW, et al. Cellulitis of the breast as a complication of breast-conserving surgery and irradiation. Am J Clin Oncol 1997;20: Mertz KR, Baddour LM, Bell JL, Gwin JL. Breast cellulitis following breast conservation therapy: a novel complication of medical progress. Clin Infect Dis 1998;26: Miller SR, Mondry T, Reed JS, Findley A, Johnstone PAS. Delayed cellulitis associated with conservative therapy for breast cancer. J Surg Oncol 1998; 67: Baddour LM. Breast cellulitis complicating breast conservation therapy. J Intern Med 1999;245: Baddour LM, Bisno AL. Non-group A b-hemolytic streptococcal cellulitis. Association with venous and lymphatic compromise. Am J Med 1985; 79: Dupuy A, Benchikhi H, Roujeau J-C, et al. Risk factors for erysipelas of the leg (cellulitis): case-control study. Br Med J 1999;318: Manian FA. Cellulitis associated with an oral source of infection in breast cellulitis patients: report of two cases. Scand J Infect Dis 1997;29: Mozes M, Papa MZ, Karasik A, Reshef A, Adar R. The role of infection in post-mastectomy lymphedema. Surg Annu 1982;14:73 83.