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Magnitude and laterality of breast cancer risk according to histologic type of atypical hyperplasia
Results from the Nurses' Health Study
Version of Record online: 7 DEC 2006
Copyright © 2006 American Cancer Society
Volume 109, Issue 2, pages 180–187, 15 January 2007
How to Cite
Collins, L. C., Baer, H. J., Tamimi, R. M., Connolly, J. L., Colditz, G. A. and Schnitt, S. J. (2007), Magnitude and laterality of breast cancer risk according to histologic type of atypical hyperplasia. Cancer, 109: 180–187. doi: 10.1002/cncr.22408
- Issue online: 8 JAN 2007
- Version of Record online: 7 DEC 2006
- Manuscript Accepted: 24 OCT 2006
- Manuscript Revised: 20 OCT 2006
- Manuscript Received: 29 AUG 2006
- Public Health Service. Grant Numbers: CA087969, CA046475, CA050385
- National Cancer Institute
- National Institutes of Health
- Department of Health and Human Services
- breast cancer;
- atypical hyperplasia;
- atypical ductal hyperplasia;
- atypical lobular hyperplasia
Atypical hyperplasia (AH) in a benign breast biopsy is associated with an increased breast cancer risk. However, the influence of the histologic type of AH on the magnitude and laterality of breast cancer risk is poorly defined.
The authors conducted a case-control study of benign breast disease and breast cancer risk nested within the Nurses' Health Study (395 cases, 1610 controls). Benign breast biopsy slides were reviewed and categorized as showing nonproliferative lesions, proliferative lesions without atypia, or AH. Slides that showed AH were categorized further as atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH).
The odds ratio (OR) for breast cancer among all women with AH was 4.1 (95% confidence interval [95% CI], 2.9–5.8). However, among premenopausal women, breast cancer risk was higher for women with ALH (OR, 7.3; 95% CI, 3.8–14.2) than for women with ADH (OR, 3.1; 95% CI, 2.0–4.8). Overall, 58.9% of invasive breast cancers that developed in women with AH were in the ipsilateral breast, and the frequency of ipsilateral breast cancer was similar for women with ALH (61.3%) and women with ADH (55.9%; P = .66).
Women with AH in a benign breast biopsy were at a substantially increased risk for the development of breast cancer. Among premenopausal women, the risk appeared to be greater for those with ALH than those with ADH. Because only ≈60% of cancers that develop in women with AH occur in the ipsilateral breast, for the purposes of clinical management, these lesions are viewed best as markers of a generalized (bilateral) increase in breast cancer risk. Cancer 2007. © 2006 American Cancer Society.
Previous clinical and epidemiologic studies of women with benign breast disease (BBD) have established a relation between histologic category of BBD and risk of subsequent breast cancer.1–13 Arguably the most clinically important finding that has emerged from those studies is that, among women with biopsy-confirmed BBD, those with atypical hyperplasia (AH) have the highest breast cancer risk.1–15 In particular, several large studies that used the same histologic criteria for the diagnosis of AH have shown that the level of risk associated with these lesions is from 3 to 5 times that for women with nonproliferative lesions or without BBD2, 6, 9, 11, 13 and that this risk may be even higher in certain subgroups of women with AH.6, 11, 13, 16
AH was uncommon in the premammographic era, when most breast biopsies were performed because of a palpable mass. For example, in 2 large, retrospective reviews of women who underwent benign breast biopsies primarily before the widespread use of screening mammography, only ≈4% of the biopsies in each study showed AH.2, 13 In contrast, the increased use of mammographic screening has resulted in a dramatic increase in the detection of AH. Among women who have undergone a breast biopsy because of mammographic microcalcifications, AH has been identified in from 15% to 20% of biopsies.17–19
The term atypical hyperplasia encompasses 2 histologically distinct lesions: atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). In most prior studies that have examined the relation between biopsy-confirmed BBD and the risk of breast cancer, ADH and ALH were combined into a single group for the purposes of analysis because of the relative infrequency of these lesions. However, combining these 2 types of AH into 1 group may obscure potentially important biologic and clinical differences between them. Given the increasing frequency with which AH is being encountered in clinical practice, a better understanding of the relation between these 2 types of AH and the risk of breast cancer clearly would be of value to assist in risk assessment and clinical management. Thus, the objective of the current study was to define further the relation between AH and subsequent breast cancer, particularly with regard to the magnitude and laterality of breast cancer risk according to the histologic type of AH.
MATERIALS AND METHODS
The Nurses' Health Study (NHS) is an ongoing, prospective cohort study that began in 1976, when 121,700 women who were registered nurses between ages 30 years and 55 years completed a mailed, self-administered questionnaire about their health behaviors, lifestyle factors, and medical histories. Follow-up questionnaires have been sent to participants every 2 years to obtain updated information, and the follow-up rate for each 2-year cycle has been >90%. The biennial questionnaires have assessed a variety of known and suspected risk factors for breast cancer, including history of BBD. On the 1976, 1978, and 1980 questionnaires, participants were asked whether they ever had been diagnosed with fibrocystic or other BBD and whether this diagnosis had required hospitalization; from 1982 onward, the questionnaires have inquired specifically about BBD confirmed by biopsy. Deaths are reported by family members and the postal service, and regular searches of the computerized National Death Index also are conducted.20 The NHS II is a separate cohort study consisting of 116,671 women who are registered nurses and were between ages 25 years and 42 years when the study began in 1989. The follow-up methods used in this cohort are very similar to those used for the original NHS.21 On each biennial questionnaire, participants have been asked whether they ever have been diagnosed with BBD and, if so, whether the diagnosis was confirmed by biopsy or aspiration.
Design of Nested Case-Control Study
We conducted a nested case-control study of BBD and breast cancer risk among participants in the NHS and NHS II who had reported a previous diagnosis of BBD that either required hospitalization or was confirmed by biopsy. Within this subcohort, eligible cases were women who reported a first diagnosis of breast cancer between 1976 and return of the 1996 questionnaire (NHS) or between 1989 and return of the 1995 questionnaire (NHS II). Self-reported breast cancers were confirmed by review of medical records, and both invasive breast cancer and carcinoma in situ were included in the study. Eligible controls were women who were free from breast cancer at the time the case was diagnosed and who also had a previous diagnosis of biopsy-confirmed BBD; they were matched to cases on year of birth and exact year of diagnosis of BBD. We attempted to identify 4 matched controls for each case, but this was not always possible for logistical reasons. The study was approved by the Human Research Committee of Brigham and Women's Hospital (Boston, MA).
Collection and Review of Benign Breast Biopsy Specimens
Cases and controls were contacted for permission to obtain their BBD pathology records and biopsy specimens. Greater than 70% of the 1310 cases and 5273 controls who originally were identified for the study confirmed the diagnosis and granted permission, and histologic specimens subsequently were obtained for 52% of those who had granted their permission (465 cases and 1939 controls). The primary reason given by hospital pathology departments for not sending specimens was that they had been destroyed or were no longer available (35%). Approximately 98% of pathology specimens that were obtained were considered to be of good quality and were evaluated by the study pathologists (431 cases and 1869 controls). An additional 262 participants were excluded, because they reported bilateral BBD, but the specimen did not identify the laterality of the benign breast biopsy (n = 2 women), the specimen did not contain breast tissue (n = 76 women), the breast cancer diagnosis was prior to the beginning of the study or after the 1996 or 1995 follow-up cycle (n = 10 women), or the date of BBD diagnosis was within 6 months of the date of the breast cancer diagnosis or index date for controls (n = 174 women).
Biopsy slides were reviewed independently by 1 of 2 pathologists (S.J.S. or J.L.C.) who were blinded to the participants' case or control status. The pathologists completed a detailed worksheet with information on the morphologic features of each specimen; then, lesions were classified into 1 of 3 main histologic categories of BBD, according to the criteria developed by Page et al.,15 as nonproliferative, proliferative without atypia, or AH. AH also was categorized further as ADH or ALH by using the criteria of Page et al.15 All biopsies, including bilateral biopsies, were classified according to the most severe changes present, and specimens with possible or definite AH were reviewed jointly by both pathologists. During the pathology review, 33 women who had an original diagnosis of BBD were identified with evidence of carcinoma in situ (n = 27 women) or invasive carcinoma (n = 6 women). These women were excluded from further analyses, which left 395 breast cancer cases and 1610 controls who had available benign pathology specimens for the current study.
We examined the distribution of breast cancer risk factors among controls according to histologic type of BBD and AH. Unconditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk according to histologic type of BBD, including ADH and ALH, with nonproliferative disease as the reference group. Unconditional rather than conditional logistic regression was used, because this analytic approach allowed us to use all cases and controls for whom we had histologic information. First, we adjusted only for the matching factors, which were age at breast cancer diagnosis or index date (ages <45 years, 45–49 years, 50–54 years, 55–59 years, or ≥60 years), year of benign breast biopsy (<1970, 1970–1979, 1980–1989, or ≥1990), and the length of follow-up (years from BBD diagnosis to breast cancer diagnosis or index date). Adjustments were then made for potential confounding factors, classifying women according to their responses for the questionnaire cycle prior to the breast cancer diagnosis or index date. In addition to the matching factors and follow-up, the following factors were included in the multivariate models: first-degree family history of breast cancer (yes or no), age at menarche (age <12 years, 12 years, 13 years, or ≥14 years), parity/age at first birth (nulliparous, 1 or 2 children with age at first birth <25 years, 1 or 2 children with age at first birth from 25 years to 29 years, 1 or 2 children with age at first birth ≥30 years, ≥3 children with age at first birth <25 years, or ≥3 children with age at first birth ≥25 years), body mass index (<21 kg/m2, 21–22.9 kg/m2, 23–24.9 kg/m2, 25–29.9 kg/m2, or >30 kg/m2), menopausal status/type of menopause (premenopausal, natural menopause, bilateral oophorectomy, or other or unknown type of menopause), and status/duration of postmenopausal hormone use (never, past, current <5 years, or current ≥5 years). Indicator variables were created to represent categories of the matching factors and other covariates, and the length of follow-up was modeled as a continuous variable.
We examined whether the magnitude of breast cancer risk associated with AH varied according to menopausal status at the time of the benign breast biopsy or the number of years since the benign breast biopsy by computing ORs and 95% CIs for histologic types of BBD, stratifying on these factors. We also assessed whether there were significant interactions by conducting likelihood ratio tests to compare models that included only the main effects with models that included jointly classified variables. Finally, we examined the association of AH with laterality of subsequent breast cancers by computing the proportion of ipsilateral cases (ie, breast cancer in the same breast as the original benign breast lesion) according to histologic type of BBD. All statistical analyses were performed using the SAS software package (version 8.2; SAS Institute, Cary, NC).
The mean age at benign breast biopsy was 43.5 years for cases (range, 17–68 years) and 43.8 years for controls (range, 15–71 years), and the median time since benign biopsy was 9.1 years for cases and 8.0 years for controls. Descriptive characteristics of controls according to histologic category of BBD are presented in Table 1. Women with ADH and ALH were older at the time of the benign biopsy, were less likely to be premenopausal at benign biopsy, and were less likely to be nulliparous compared with women who had either nonproliferative lesions or proliferative lesions without atypia. Women with ADH had a slightly higher alcohol intake and were slightly more likely to have undergone a bilateral oophorectomy and to have used postmenopausal hormones for ≥5 years than women in the other BBD categories. Women with ALH were more likely to have had a first-degree family history of breast cancer than the women in the other BBD categories.
|Characteristic||Nonproliferative||Proliferative without atypia||Atypical ductal hyperplasia||Atypical lobular hyperplasia|
|No. of controls (%)||611 (38.0)||839 (52.1)||103 (6.4)||42 (2.6)|
|Age at benign biopsy, y||42.5||43.7||49.2||49.7|
|Year of benign biopsy†||1979||1980||1982||1982|
|Time since benign biopsy, y†||8.6||8.2||6||7|
|Age at menarche, y||12.6||12.6||12.8||13|
|Age at menopause, y‡||49.1||48.5||48.4||50|
|Body mass index, kg/m2||25||24.6||24.4||25.2|
|Alcohol intake, g/d||4.8||5.4||6.8||5.7|
|Age at first birth, y§||24.9||24.8||25.2||25.6|
|First-degree family history of breast cancer||17.4||17.4||13.6||35.7|
|Premenopausal at benign biopsy||72.3||71.4||59.2||50|
|Current postmenopausal hormone use ≥5 y‖||16.8||20.3||26.1||17.2|
Compared with women who had nonproliferative lesions, the multivariate OR for the development of breast cancer (either invasive or in situ) among women who had proliferative lesions without atypia was 1.52 (95% CI, 1.17–1.99), and the OR for women who had AH was 4.11 (95% CI, 2.90–5.83) (Table 2). These ORs were very similar when the development of invasive breast cancer only was used as an endpoint; therefore, unless otherwise specified, the ORs reported below for the subsequent analyses are those for both invasive and in situ breast carcinoma cases combined.
|Histologic subtype||Controls||All breast cancer (N = 395 women)||Invasive breast cancer (N = 316 women)|
|Cases||OR (95% CI)||Cases||OR (95% CI)|
|Nonproliferative||611||99||1.0 (Ref)||1.0 (Ref)||77||1.0 (Ref)||1.0 (Ref)|
|Proliferative with no atypia||839||200||1.50 (1.15–1.95)||1.52 (1.17–1.99)||164||1.58 (1.18–2.12)||1.62 (1.21–2.18)|
|Atypical hyperplasia||160||96||4.09 (2.90–5.76)||4.11 (2.90–5.83)||75||4.04 (2.78–5.87)||4.04 (2.76–5.92)|
|Ductal||103||45||2.99 (1.97–4.55)||3.09 (2.01–4.75)||33||2.77 (1.74–4.42)||2.82 (1.75–4.55)|
|Lobular||42||36||5.78 (3.49–9.55)||5.49 (3.29–9.18)||28||5.72 (3.32–9.84)||5.46 (3.12–9.53)|
|Ductal and lobular||15||15||6.95 (3.26–14.85)||6.94 (3.19–15.09)||14||8.24 (3.78–17.93)||8.32 (3.75–18.46)|
The risk of breast cancer varied according to the histologic type of AH (Table 2). Women with ALH had a greater breast cancer risk than women with ADH. When all breast cancers (invasive and in situ) were considered as the endpoint, the OR for women with ALH was 5.49 (95% CI, 3.29–9.18), whereas the OR for women with ADH was 3.09 (95% CI, 2.01–4.75); this difference approached statistical significance (P = .09). Among the small subset of women who had benign biopsies that showed both ADH and ALH, the OR for breast cancer was 6.94 (95% CI, 3.19–15.09), although there were only 15 cases in this subgroup.
The breast cancer risk for women with AH according to their menopausal status at the time of benign breast biopsy is presented in Table 3. Overall, for all women with AH, the risk for the development of breast cancer was similar for premenopausal and postmenopausal women. However, among women who were premenopausal at the time of their benign breast biopsy, the breast cancer risk associated with ALH (OR, 7.30; 95% CI, 3.47–14.23) was significantly greater than that associated with ADH (OR, 2.72; 95% CI, 1.58–4.69; P = .02). In contrast, among women who were postmenopausal at the time of their benign breast biopsy, the breast cancer risk was similar for women with ALH and women with ADH. However, there was no statistically significant interaction between the histologic type of BBD and menopausal status at the time of benign breast biopsy (P = .25).
|Histologic subtype||Premenopausal at benign biopsy (N = 277 women)||Postmenopausal at benign biopsy (N = 73 women)|
|Cases||Controls||Adjusted OR (95% CI)†||Cases||Controls||Adjusted OR (95% CI)†|
|Nonproliferative||80||442||1.0 (Ref)||14||117||1.0 (Ref)|
|Proliferative with no atypia||145||599||1.39 (1.02–1.90)||39||177||1.89 (0.94–3.77)|
|Atypical hyperplasia||52||82||3.89 (2.47–6.12)||20||49||3.83 (1.72–8.52)|
|Ductal||27||61||2.72 (1.58–4.69)||14||34||4.04 (1.67–9.77)|
|Lobular||25||21||7.30 (3.74–14.23)||6||15||3.41 (1.08–10.76)|
The risk of breast cancer in women with AH varied with the time since the benign breast biopsy (Table 4). Overall, the OR for the development of breast cancer ≥10 years after the benign breast biopsy was 5.15 (95% CI, 2.81–9.43), whereas the risk of developing breast cancer <10 years after the benign biopsy was 3.31 (95% CI, 2.05–5.33). It is noteworthy that ALH was associated more strongly with the development of breast cancer within 10 years (OR, 5.57; 95% CI, 2.90–10.71) compared with ADH (OR, 2.40; 95% CI, 1.36–4.24; P = .06). In contrast, the risk of breast cancer ≥10 years after the benign biopsy was similar for women with ALH (OR, 5.80; 95% CI, 2.38–14.12) and women with ADH (OR, 4.82; 95% CI, 2.38–9.75). However, there was no statistically significant interaction between the histologic type of BBD and the time since benign biopsy (P = .73).
|Histologic subtype||Breast cancer <10 years after benign biopsy (N = 203 women)||Breast cancer ≥10 years after benign biopsy (N = 177 women)|
|Cases||Controls||Adjusted OR (95% CI)†||Cases||Controls||Adjusted OR (95% CI)†|
|Nonproliferative||49||335||1.0 (Ref)||50||276||1.0 (Ref)|
|Proliferative with no atypia||106||487||1.43 (0.98–2.08)||94||352||1.58 (1.07–2.35)|
|Atypical hyperplasia||48||102||3.31 (2.05–5.33)||33||43||5.15 (2.81–9.43)|
|Ductal||25||73||2.40 (1.36–4.24)||20||30||4.82 (2.38–9.75)|
|Lobular||23||29||5.57 (2.90–10.71)||13||13||5.80 (2.38–14.12)|
Overall, 58.9% of breast cancers (and 58.9% of the invasive breast cancers) that developed in women with AH were in the ipsilateral breast (Table 5). This was not statistically different from the frequency of ipsilateral cancers among women who had nonproliferative lesions (51.7%) and women who had proliferative lesions without atypia (50.3%). Although the risk of ipsilateral breast cancer was somewhat greater among women with ALH than among women with ADH (61.3% vs 55.9%), this difference was not statistically significant (P = .66).
|Histologic subtype||All breast cancer (N = 278 women)||Ipsilateral breast cancer||Proportion with ipsilateral breast cancer (95% CI)|
|Proliferative with no atypia||145||73||50.3 (41.9–58.8)|
|Atypical hyperplasia||73||43||58.9 (46.8–70.3)|
|Ductal and lobular||8||5||62.5 (24.5–91.5)|
There is consensus that, among women who have had a benign breast biopsy, the subsequent breast cancer risk varies according to the histologic category of BBD, with a moderately increased risk among women who have proliferative lesions without atypia and a substantially increased risk among women who have AH.1–15 The results presented here provide an update of data from the NHS that originally were reported by Marshall et al in 1997.11 However, the current results were based on an analysis of a substantially larger population (ie, more than twice as many cases and controls than in the prior report). In keeping with the results from our prior study and from other previous studies,1–15 the current results continue to indicate that women with AH are at a substantially increased risk of breast cancer (approximately 4-fold compared with women who have nonproliferative lesions).
In almost all prior studies of benign breast disease and breast cancer risk, ADH and ALH were combined into a single AH category to strengthen the statistical power of the analyses, because both are relatively uncommon lesions. However, combining these 2 histologically distinct patterns of AH into a single group potentially may obscure important differences between them. The results of our study suggest that there well may be important biologic and clinical differences between ADH and ALH.
Aside from the previous report from the NHS,11 few prior studies have evaluated the influence of the histologic category of AH on the risk of breast cancer.4, 15, 22 Page et al initially reported relative risks of 5.8 (95% CI, 3.0–11) and 4.7 (95% CI, 2.5–8.9) for women who had ALH and ADH, respectively, compared with women who had nonproliferative lesions.15 Those investigators subsequently observed that the breast cancer risk among women with ALH was even greater when the lesion involved both lobules and ducts (relative risk, 6.8; 95% CI, 3.6–13).22 Most recently, the same group reported a lower relative risk for women with ALH compared with the risk reported in their prior studies. In their most recent analysis of 252 women with ALH who were identified from among >17,000 benign breast biopsies, the relative risk of breast cancer was 3.1 (95% CI, 2.3–4.3) for all women who had ALH and 3.5 (95% CI, 2.2–5.5) for women who had ALH that involved both lobules and ducts compared with women who had nonproliferative breast lesions.23 The magnitude of risk among women with ALH in our current study (multivariate OR for women with ALH, 5.49; 95% CI, 3.29–9.18) was similar to that reported initially by Page et al.15 but higher than that reported by the same group in their most recent update.23 However, the relative risk of 3.1 reported recently for women with ALH by Page et al.23 is quite similar to the level of risk we observed for women with ALH who were postmenopausal at the time of benign biopsy (OR, 3.41; 95% CI, 1.08–10.76). Thus, it is possible that any differences in the risk estimates for women with ALH between our study and the Nashville study may be explained, at least in part, by differences in the study populations with regard to the menopausal status of participants at the time of benign breast biopsy. Although the risk among women with ADH in our study (OR, 3.09) is somewhat lower than the risk reported for women with ADH by Page et al (relative risk, 4.7),15 these risk estimates are within the 95% CIs of each other.
In keeping with the results reported initially by Marshall et al.,11 we observed that menopausal status at the time of benign breast biopsy appeared to influence the magnitude of subsequent breast cancer risk among women with AH (Table 3). In particular, among women who were premenopausal at the time of their benign breast biopsy, the risk of breast cancer was significantly greater among women with ALH (OR, 7.3) than among women with ADH (OR, 2.72). In contrast, among women who were postmenopausal at the time of benign breast biopsy, the risk was similar for women with ALH and women with ADH.
The influence of time since benign biopsy on breast cancer risk among women with AH is not understood well. Dupont and Page reported that the risk of developing subsequent cancer was 9.8 within the first 10 years after a diagnosis of AH and decreased to 3.6 after 10 years.16 In contrast, we observed that among, all women with AH, the risk of breast cancer was somewhat greater ≥10 years after the benign breast biopsy (OR, 5.15) than within the first 10 years (OR, 3.21) (Table 4). Moreover, we observed that the risk of breast cancer was fairly constant over time for women with ALH but that the risk increased over time for women with ADH, although this difference was not statistically significant.
With regard to the laterality of breast cancer risk, among all women with AH who developed breast cancer, 59% of cancers occurred in the same breast as the benign biopsy that revealed AH. In addition, the proportion of breast cancers that developed in the ipsilateral breast among women with AH remained constant over time (data not shown). Among women with ADH who developed breast cancer, 56% of cancers occurred in the ipsilateral breast. Similarly, Page et al reported that 56% of cancers that developed in women with ADH occurred in the breast ipsilateral to the breast in which a benign biopsy showed ADH.15 Tavassoli and Norris reported that 75% of cancers that developed in women with ADH in their series occurred in the ipsilateral breast.4 However, those authors acknowledged that 7 lesions that they classified as ADH would have been classified as ductal carcinoma in situ according to the criteria of Page et al.15 This may account for the greater proportion of ipsilateral cancers in their study compared with our study and the study by Page et al.,15 because virtually all invasive cancers that develop in patients with ductal carcinoma in situ who undergo biopsy alone occur in the ipsilateral breast.24–26 Among the women in our study with ALH, 61% of subsequent cancers occurred in the ipsilateral breast, whereas a somewhat greater proportion of cancers were noted in the ipsilateral breast among women with ALH in the most recent update from the Nashville group (70%).23
A few potential limitations of our study should be noted. First, we were unable to obtain pathology material for review on a proportion of eligible cases and controls who had given permission. However, the primary reason for not being able to obtain specimens was the routine disposal of biopsy material by the hospitals; therefore, it is unlikely that this introduced selection bias. Second, some of the subgroups that were analyzed in this study were small, resulting in fairly broad 95% CIs for some of the risk estimates. We believe that analysis of these subgroups is important to help define potentially clinically meaningful differences between ADH and ALH, particularly because these lesions are being encountered increasingly in biopsies performed because of mammographic abnormalities. However, we recognize that some of these risk estimates may change with the addition of more cases and controls to our study, a process that currently is ongoing.
In summary, the results of the current study indicate that all women with AH in a benign breast biopsy are at a substantially increased risk for the development of breast cancer. Among premenopausal women, the risk appears to be greater for those with ALH than for those with ADH. Furthermore, only ≈60% of the subsequent breast cancers in women with AH occur in the ipsilateral breast, and this frequency of ipsilateral cancers is similar for ADH and ALH. Therefore, for the purposes of risk assessment and clinical management, ADH and ALH are viewed best as markers of a generalized (bilateral) increase in breast cancer risk.
Supported by Public Health Service Grants CA087969, CA046475, and CA050385 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
- 14Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 consensus statement. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med. 1998; 122: 1053-1–55., , .
- 21The Nurses' Health Study: findings during 10 years of follow-up of a cohort of U.S. women. Curr Probl Obstet Gynecol Fertil. 1990; 13: 129–174..