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Clinical Cancer Research 13, 5474, September 15, 2007. doi: 10.1158/1078-0432.CCR-07-0928
© 2007 American Association for Cancer Research
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Cancer Susceptibility and Prevention

Multiplicity of Benign Breast Lesions Is a Risk Factor for Progression to Breast Cancer

Maria J. Worsham1, Usha Raju2, Mei Lu3, Alissa Kapke3, Jingfang Cheng1 and Sandra R. Wolman4

Authors' Affiliations: Departments of 1 Otolaryngology/Head and Neck Surgery, 2 Pathology, and 3 Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Michigan; and 4 Department of Pathology, George Washington University, Washington, District of Columbia

Requests for reprints: Maria J. Worsham, Henry Ford Health System, 1 Ford Place, 1D, Detroit, MI 48202. Phone: 313-874-3350; Fax: 313-874-1079; E-mail: mworsha1{at}hfhs.org.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Benign breast disease (BBD) in women encompasses a broad spectrum of histopathologic lesions. Studies on BBD have focused on the risks for subsequent breast cancer associated with three broad categories of lesions, classified as nonproliferative, proliferative, or proliferative with atypia, without addressing the issue of the contribution of concurrent multiple BBD lesions. There is very limited information with regard to the issue of BBD lesion multiplicity and breast cancer risk.

Experimental Design: We evaluated a detailed microscopic spectrum of 18 BBD lesions from fibrosis to atypical hyperplasia in a BBD cohort of 4,544 subjects, within which 4.5% (n = 201) developed breast cancer during an average follow-up period of 10.3 years. Lesions were defined as nonproliferative (8 diagnoses; risk level 1 = no risk or low risk), proliferative without atypical hyperplasia (8 diagnoses; risk level 2 = intermediate risk), and proliferative with atypical hyperplasia (2 diagnoses; risk level 3 = highest risk level). Twenty variables including age (≥50 or <50 years) at the time of BBD diagnosis and race (African American or non–African American) were assessed. A categorical variable, surrogate for lesion type and number, was represented initially by four levels: 1, nonproliferative = 1 (reference); 2, nonproliferative > 1; 3, proliferative = 1; and 4, proliferative > 1.

Results: The majority of BBD subjects in our cohort (almost 70%) had more than one BBD lesion. Concurrent multiple nonproliferative or proliferative BBD lesions with or without atypia in a BBD biopsy and age are significant predictors of risk for progression of BBD to breast cancer. The presence of atypical hyperplasia in a BBD biopsy alone or in conjunction with other lesions without atypia conferred higher risks. Women with fibrosis had a reduced risk for progression to breast cancer. Race was not a significant predictor of progression to breast cancer. The effect of age, fibrosis, and multiple lesions (whether nonproliferative, proliferative, or atypia) on breast cancer progression was not influenced by race.

Conclusion: BBD lesion multiplicity is frequent, and teasing out the heterogeneity of multiple concurrent BBD lesions is warranted to refine and improve risk estimates for progression of breast cancer from BBD.

Benign breast disease (BBD) in women encompasses a spectrum of histopathologic lesions. Of the many types of benign entities found in the human breast, only a few have been shown to have clinically significant premalignant potential. Currently, the best-characterized premalignant lesions are atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ (1). Ductal carcinoma in situ is considered a preinvasive malignant lesion. Many BBD studies (2–7) have focused on the risks for subsequent breast cancer associated with lesions classified into three broad pathologic categories: nonproliferative, proliferative, and proliferative with atypia. When different but concurrent BBD lesions (Table 1 ) are present, the BBD biopsy is usually classified in terms of the most serious of these three outcome categories (highest risk level). Thus, the contribution of lesion multiplicity to breast cancer progression is usually not a consideration and therefore is less well understood.


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  		Table 1. Microscopic spectrum of benign breast lesions

 
We tested the hypothesis that multiplicity of lesions in a BBD biopsy and other BBD characteristics are risk factors for breast cancer. The entire spectrum of microscopic findings of BBD lesions was evaluated in a BBD cohort of 4,465 subjects, within which 4.5% (201) developed breast cancer during an average follow-up period of 10.3 years (8).


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
BBD cohort. Women were eligible for this study if they were 18 years or older, had a breast biopsy done for diagnostic purposes, did not have a history of breast cancer, and were not diagnosed with breast cancer within 6 months of the index BBD diagnosis (8). A cohort of 4,544 women, initially identified using surgical pathology reports of biopsy-proven BBD (8), was studied for determination of BBD risks for subsequent progression to breast cancer. Thirty-seven individuals with no follow-up after the BBD diagnosis and 42 women with needle biopsies were excluded from the analysis for a final cohort of 4,465 women. Subsequent to and more than 6 months after the index biopsy, during an average follow-up period of 10.3 years, 4.5% (201) of these women developed breast cancer. The median time from the original biopsy to the diagnosis of breast cancer was 7.19 years [mean, 7.61 years; 95% confidence interval (95% CI) for mean, 6.98-8.24]. Approximately 20% (40 of 201) of these women had stage 0 or in situ breast cancer at diagnosis, 63% (126 of 201) had stage I or higher stage disease, and for 17% (35 of 201), stage could not be determined from either the Henry Ford Health System tumor registry or from Surveillance Epidemiology and End Results. Bilaterality was observed in 152 (3.4%) women, of whom five progressed to breast cancer.

Determination of breast cancer outcome from BBD was accomplished through examination of the tumor registries of the Henry Ford Health system, the Detroit Surveillance Epidemiology and End Results registry, and the State of Michigan cancer registry.

BBD pathology review. Ascertainment of cohort subjects (before exclusions) was based on retrieval and review (by the primary pathologist) of all reports of biopsies with a BBD diagnosis within the Henry Ford Health system within the period from January 1981 to December 1994 (8). Breast pathologists reviewed the histology for all eligible subjects of the study cohort using a detailed pathology review form designed to capture a broad spectrum of histologic findings. The primary reference pathologist rereviewed a 10% sample to assess intra-rater reliability. For women with more than one BBD biopsy, the earliest biopsy was recorded and multiple lesions were noted based on this first biopsy.

Based on criteria reported elsewhere (9), BBD lesions were divided into three risk categories: nonproliferative (low risk or risk level 1), proliferation without atypia (intermediate risk or risk level 2), and proliferation with atypia (high risk or risk level 3).

The pathology review form for this study was designed to capture every histopathologic lesion present in an individual BBD biopsy. The nonproliferative (risk level 1) lesion category consisted of 8 diagnoses; the proliferative without atypical hyperplasia category (risk level 2) had 8 diagnoses; and the proliferative with atypical hyperplasia (risk level 3) lesion category had 2 diagnoses (Table 1).

Demographic risk factors. Demographic risk factors considered for analysis and assessed at the time of BBD diagnosis were age (≥50 or <50 years) and race (African American or non–African American).

Statistical methods. We used Poisson regression models with a robust error variance (10) and considered the time from BBD diagnosis to follow-up to examine 20 variables (Table 1), including age (≥50 or <50 years) at the time of BBD diagnosis and race (African American or non–African American), and 18 BBD lesions in three risk levels as possible predictors of breast cancer. To account for multiplicity of BBD lesions and risk of breast cancer, we initially created a categorical variable consisting of four levels: 1, nonproliferative = 1 (reference); 2, nonproliferative > 1; 3, proliferative = 1; and 4, proliferative > 1.

The Poisson regression models were done using PROC GENMOD in SAS v 9.1, which assumed the log link and included log time as an offset variable. Analysis began with testing for individual risks (univariate analysis) including testing of individual variables by race interaction, followed by a multivariable modeling process by including variable or variable interactions with P < 0.20 from the individual test. The backward model selection was considered and the final multivariable model retained variables that either had an individual effect at P < 0.05 or a variable interaction effect at P < 0.10.

Risk ratios (RR) and their 95% CIs were calculated for the multivariable model. A RR > 1 and 95% CIs excluding 1 indicate that such individuals were at greater risk for development of breast cancer as compared with those without such risk (reference group). Similarly, a RR < 1 (and 95% CI excluding 1) indicates patients with reduced risk of breast cancer.

To measure the predictive ability of the model, the concordance index (c-index; ref. 11) was calculated. The c-index is a generalization of the C-statistic from the final regression modeling and allows for censoring. A value of 1.0 indicates a perfect fit, whereas a c-index of 0.5 indicates the model is not an improvement over random classification. A value of ≥0.7 is a good fit.


   Results
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 Materials and Methods
 Results
Discussion
 References
 
More than 70% of BBD subjects (n = 3,138; 70.28%) had more than one BBD lesion. Of the 42 excluded BBD needle biopsies, 36% (n = 15) had multiple lesions.

From the univariate Poisson regression analysis of 19 variables, 11 individual risk factors were significant predictors of breast cancer including age, multiplicity (lesion number), atypical hyperplasia, cysts, periductal mastitis/duct ectasia, fibrosis, simple apocrine metaplasia, fibroadenoma, proliferative hyperplasia, sclerosing adenosis, and papilloma (P < 0.2; Table 2 ). There was one marginally significant interaction detected for race and presence of fibrosis (P = 0.077; Table 2). No interaction was detected between race and lesion risk level.


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  		Table 2. Univariate Poisson regression analysis for individual risk effect and the risk by race interaction

 
Multivariable modeling retained age, presence of fibrosis, atypical hyperplasia, and multiplicity of lesions with P < 0.05 (data not shown). Interaction of race and fibrosis did not retain significance in the final model (P = 0.116 for fibrosis by race interaction).

The effect of fibrosis, as part of nonproliferative lesions, was independent of whether nonproliferative lesions were single or multiple (P > 0.55 for multiple lesion by fibrosis interaction). On the other hand, the effects of atypical hyperplasia, as the part of proliferative lesions, varied based on proliferative lesions being single or multiple. These observations on fibrosis and atypical hyperplasia, lesions at the opposite ends of the BBD risk level spectrum, prompted reclassification of the lesion number and presence of atypical hyperplasia into six levels (Table 3 ) to address lesion multiplicity using lesion risk levels (nonproliferative, proliferative, and atypical hyperplasia). No other two-variable or three-variable interaction was detected. The c-index for the predictive measure of the final multivariable model (Table 3) was 0.715.


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  		Table 3. Clinical and histologic predictors of breast cancer

 
In the final model, age ≥50 years was a significant predictor of breast cancer risk. Older women (age >50 years) had a significant risk of progression to breast cancer from BBD (RR, 1.64; 95% CI, 1.24-2.17; P = 0.0005) when compared with younger women (age <50 years).

The presence of fibrosis was protective against breast cancer. Women with fibrosis had an approximately 37% lower risk of breast cancer as compared with women without fibrosis (RR, 0.63; 95% CI, 0.45-0.87; P = 0.005). The latter outcome was independent of whether nonproliferative lesions were single or multiple (P > 0.55).

Women in the multiple nonproliferative lesion group (n = 773) showed increased risk (RR, 1.79; 95% CI, 1.0-3.21, P = 0.051) compared with women with only one nonproliferative lesion (reference group; n = 937). Proliferative lesions, single or multiple in the same biopsy, with or without atypical hyperplasia, were significant risk factors for breast cancer (P < 0.001). Women with a single proliferative lesion without atypical hyperplasia (P = 1; n = 1,453) had a 2-fold risk for breast cancer (RR, 2.06; 95% CI, 1.23-3.43; P = 0.006). Women with multiple proliferative lesions without atypical hyperplasia (P > 1; n = 1,059) had a 2.87-fold risk of breast cancer (RR, 2.87; 95% CI, 1.70-4.83; P < 0.0001). Women with atypical hyperplasia as the sole lesion (n = 65) had the highest risk for breast cancer (RR, 6.26; 95% CI, 2.73-14.32; P = 0.0001) followed by those with atypical hyperplasia and a concurrent proliferative lesion (n = 178; RR, 4.90; 95% CI, 2.60-9.21, P < 0.0001).

Race was not a significant predictor of progression to breast cancer (P = 0.519). The effect of age, fibrosis, and multiple lesions (whether nonproliferative, proliferative, or atypia) for breast cancer progression was not influenced by race.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
BBD is a heterogeneous condition comprising a wide variety of histologic entities that include connective tissue and glandular structures and combinations thereof. These lesions may grow and change cyclically under hormonal regulation (12–15).

Women 50 years and older were more likely to develop breast cancer than women of <50 years of age (Table 3). The cutoff at age 50 years was an attempt to group women as premenopausal (<50 years) or postmenopausal (≥50 years). The importance of age as a predictor of breast cancer risk for older women is supported by other recent studies (8, 16, 17). The current assumption that cancer results from a multistep, progressive accumulation of destabilization events is consistent with an expectation of age-related increase in our cohort (8).

At 5 years of follow-up, no significant difference in risk between women with nonproliferative lesions or those with proliferative lesions without atypia was observed, although the risk was four times higher for women with atypia. At 10 years of follow-up, however, cumulative breast cancer incidence was significant for both women with proliferative lesions without atypia and for women with atypia (8).

The presence of atypical hyperplasia in a BBD biopsy solely or in conjunction with other nonatypical hyperplasia lesions conferred higher risks, which corroborates other studies indicating that the risk of developing breast cancer is directly related to the degree of epithelial atypia (2, 3, 6, 8, 18–20).

The presence of fibrosis was protective for breast cancer. Fibrosis of the breast has been diagnosed variously as focal fibrosis, stromal fibrosis, focal fibrous disease of the breast, fibrous mastopathy, fibrous tumor of the breast, and chronic indurative mastitis (21–24). It is characterized by proliferation of the stromal connective tissue with obliteration of the mammary ducts and lobules. The diagnosis is common in core needle biopsies of clinically occult, mammographically or sonographically detected breast lesions (21–23). The incidence of focal fibrosis ranges from 3.6% to 8.2% of lesions from imaging-guided core biopsy (24, 25). In a series of 1,095 imaging-guided core needle biopsies, the low incidence of missed cancers [2 of 73 (2.7%) patients] suggests that patients with palpable or impalpable stromal fibrosis diagnosed at core biopsy can be managed conservatively with a short-term follow-up imaging protocol (24). Thus, whereas stromal fibrosis seems to be a source of false-positive radiologic diagnoses, the consensus suggests that when fibrosis is the biopsy diagnosis, the appropriate response is conservative (i.e., "watchful waiting"; ref. 21). However, our data are implicitly in opposition to the assumption that stromal growth factors support epithelial proliferation (26).

Several pathologic entities are associated with an enhanced risk of breast cancer (2–4). Epidemiologic studies have shown that women with proliferative epithelial disorders affecting the small ducts and the terminal ductal lobular units of the breast are at increased risk of subsequent breast cancer, particularly when the epithelial proliferation is accompanied by evidence of atypia (5, 6). Risk is increased ~1.5- to 2-fold for those with epithelial proliferation without atypia (5, 6) and 4- to 5-fold for those with proliferative disease with atypia (6, 7). However, most studies on BBD have focused on the risks associated with a few specific BBD lesions (13, 15, 27–29). Jacobs et al. (20) reported that coexistence of radial scar with other proliferative lesions may double the risk of breast cancer.

Our cohort of 4,465 women with biopsy-proven BBD draws from an urban population with nearly 28% of eligible women who are African American. The review of BBD biopsies captured every designation of BBD lesion type encountered in the index biopsy, classifying with great specificity the different lesions in the categories of nonproliferative (8 diagnoses), proliferative without atypia (8 diagnoses), and proliferative with atypia (2 diagnoses).

Information with regard to the issue of lesion multiplicity is very limited. Wang et al. (4) reported that 38% of women with lower-grade BBD (combination of risk level 1 and risk level 2 lesions) contained multiple lesions. In our study, multiplicity was frequent, and women with multiple nonproliferative or proliferative lesions with or without atypia were at an increased risk for breast cancer (Table 3). Significance was retained after adjusting for age in the analysis.

A recent study combined two groups of women, those with proliferative disease without atypia and those with nonproliferative disease (lower category BBD), and found a slight increase in the risk of breast cancer among women >50 years of age (4). However, another more recent large study (6) found an increased risk of breast cancer only among women with proliferative disease. Only those women with nonproliferative lesions and a strong family history of breast cancer were at increased risk. In our study, the risk for women with multiple nonproliferative lesions was 1.8 times (P = 0.05) higher than women with only one nonproliferative lesion, suggesting some effect on risk with nonproliferative > 1. The risk was increased 2.8 times for women with multiple proliferative lesions without atypical hyperplasia and was further increased by 5-fold for women with multiple proliferative lesions with atypical hyperplasia compared with women with a single nonproliferative lesion (P < 0.01).

Race was not a significant predictor of progression to breast cancer. The effect of age, fibrosis, and multiple lesions (whether nonproliferative, proliferative, or atypia) for breast cancer progression was not influenced by race.

The results of this study indicate that BBD lesion multiplicity is frequent, and that teasing out the heterogeneity of multiple concurrent BBD lesions is required to refine and improve risk estimates for progression of breast cancer from BBD.


   Footnotes
 
Grant support: National Cancer Institute grant R01 CA 70923 (M.J. Worsham) and American Cancer Society grant ACS EDT-116 (M.J. Worsham).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/18/07; revised 6/28/07; accepted 7/ 5/07.


   References
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 Abstract
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 Discussion
 References
 

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Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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