Diagnosis and Management of Specific Breast Abnormalities

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AHRQ Evidence Reports, 

Numbers 1-60

33. Diagnosis and Management 

of Specific Breast Abnormalities

Chapter 1. Introduction 

Chapter 2. Methodology 

Chapter 3. Results 

Chapter 4. Conclusions 

Chapter 5. Recommendations for 

Future Research 

Evidence Tables

Appendices

Figures

AHRQ Evidence reports and summaries AHRQ Evidence Reports, Numbers 1-60

33. Diagnosis and Management of Specific Breast Abnormalities

Evidence Report/Technology Assessment

Number 33 

Prepared for: 

Agency for Healthcare Research and Quality 

Department of Health and Human Services 

2101 East Jefferson Street 

Rockville, MD 20852

http://www.ahrq.gov/ 

Contract No. 290-97-0016 

Prepared by: 

MetaWorks, Inc., Boston, MA 

Cindy Levine, MD 

Katrina Armstrong, MD 

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Diagnosis and Management of Specific Breast Abnormalities

References

Bibliography

Sameer Chopra, MA 

Rhonda Estok, RN, BSN 

Shuhuan Zhang, MS 

Susan Ross, MD 

AHRQ Publication No. 01-E046 

September 2001

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was 

reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to 

continue its research on the cost, quality, and outcomes of health care, and expands its role to improve patient safety 

and address medical errors.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other 

quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of 

Health and Human Services endorsement of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, 

reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors 

and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and 

access. The information helps health care decisionmakers -- patients and clinicians, health system leaders, and 

policymakers -- make more informed decisions and improve the quality of health care services.

Preface

The Agency for Healthcare Research and Quality (AHRQ, formerly the Agency for Health Care Policy and 

Research, AHCPR), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence 

reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations with comprehensive, 

science-based information on common, costly medical conditions and new health care technologies. The EPCs 

systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional 

analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, 

AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research 

organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology 

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Diagnosis and Management of Specific Breast Abnormalities

assessments they produce will become building blocks for health care quality improvement projects throughout the 

Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, 

providers, and purchasers as well as the health care system as a whole by providing important information to help 

improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and 

Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, 

MD 20852.

Robert Graham, M.D. John M. Eisenberg, M.D.

Director, Center for Practice Director, Agency for Healthcare

And Technology Assessment Research and Quality 

The authors of this report are responsible for its content. Statements in the report should not be construed as 

endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human 

Services of a particular drug, device, test, treatment, or other clinical service.

Acknowledgments

We are grateful to the following individuals for their diverse contributions throughout the course of developing this 

report: Elenie Chadbourne, Rebecca Cintron, Janet Connelly, Matthew Guldin, Veronica Ludensky, Luba Nalysnyk, 

Christopher Schmid, Sandy Schwartz, Marya Zilberberg, members of the TEP, peer reviewers, representatives from 

Kaiser, and representatives from AHRQ.

Structured Abstract

Objective.

Over 170,000 women are diagnosed with breast cancer yearly in the United States, incurring enormous individual 

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and societal costs. The objective of this systematic review is to assess the quantity and quality of published evidence 

regarding specific current issues of diagnosis and management of women with breast disease.

Search Strategy.

Literature published from January 1, 1994 to September 15, 1999 was searched using Medline and Current 

Contents databases. These searches were supplemented by manually reviewing bibliographies of all accepted 

studies and review articles.

Selection Criteria.

Accepted studies included observational studies, randomized controlled trials (RCTs), non-randomized controlled 

trials (nRCTs), and uncontrolled case series (UCSs). All accepted publications were required to address the 

prospectively identified areas of interest and have a total sample size of at least 10 patients. Only English language 

studies were accepted.

Data Collection and Analysis.

Pertinent data were extracted from accepted studies by one researcher, and reviewed by a second. Studies were 

evaluated for quality and level of evidence. The data were summarized and synthesized qualitatively. A panel of 

multidisciplinary clinical experts provided recommendations throughout the project.

Main Results.

The database includes 51 studies (30,178 patients) regarding breast symptoms and risk factors, 20 studies (3,501 

patients) pertinent to lobular carcinoma in situ (LCIS) or atypical hyperplasia (AH), and 39 studies (5,900 patients) 

regarding sentinel node biopsy.

Incomplete reporting of outcomes in patients with different risk factors precludes assessment of the relationship 

between risk factors, breast symptoms, and cancer incidence.

When managed by observation alone, LCIS was associated with a 4.2-9.3 percent incidence of cancer within 5 years 

and 7.7-26.3 percent incidence in studies that followed patients for at least 5 years. AH was associated with a 3.7-

19.3 percent incidence of cancer within 5 years, and 13.6-33.6 percent incidence in longer-term studies. Selective 

estrogen receptor modulator (SERM) therapy with Tamoxifen markedly decreased the incidence of breast cancer 

following a diagnosis of LCIS or AH. After excisional biopsy was done, approximately half of the atypical ductal 

hyperplasias (ADHs) diagnosed by stereotactic core needle biopsy (SCBX) were changed, usually to a more 

worrisome diagnosis.

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Regardless of tumor location, size, or history of breast surgery, sentinel node biopsy had a false negative rate of 1.9 

to 3.3 percent. Sentinel nodes were positive for metastatic disease in approximately one third of cases.

Conclusions.

The best available evidence suggests that breast symptoms are evaluated initially by clinical breast exam and 

imaging study, with supplemental studies when the diagnosis is unclear. There is no evidence to support modifying 

the work-up of breast symptoms or mammographic abnormalities based on risk factors other than age. Strong 

evidence supports the necessity of performing excisional biopsy following SCBX diagnosis of ADH, as excisional 

biopsy often leads to a change in diagnosis. Preliminary evidence strongly suggests that Tamoxifen therapy 

markedly decreases the incidence of cancer following a diagnosis of LCIS or AH, but it is associated with increased 

risk of endometrial cancer, thromboembolic disease, and other complications. While studies to date strongly suggest 

that sentinel node biopsy is successful in most breast cancer patients, long-term cancer outcomes and survival data 

are required before sentinel node biopsy could be considered the standard of care.

This document is in the public domain and may be used and reprinted without permission except those copyrighted 

materials noted for which further reproduction is prohibited without the specific permission of copyright 

holders.

Suggested Citation:

Levine C, Armstrong K, Chopra S, et al. Diagnosis and management of specific breast abnormalities. Evidence 

Report/Technology Assessment No. 33 (Prepared by MetaWorks, Inc., Boston, MA under Contract No. 290-97-

0016). AHRQ Publication No. 01-E046. Rockville, MD: Agency for Healthcare Research and Quality. September 

2001.

Summary

Overview

Each year, more than 170,000 women are diagnosed with breast cancer in the United States alone, and it is the most 

common form of cancer found in women worldwide. The average lifetime risk of breast cancer in a female infant 

born in the United States in the year 2000 is 12 percent, or one in eight. The most common cause of malpractice 

litigation is the missed or delayed diagnosis of breast cancer. Clearly, breast disease is a major concern for women, 

and it has a substantial effect on both individual and societal health care resources.

When a woman presents to her health care provider with a breast symptom, the initial management will nearly 

always include, at a minimum, a clinical breast exam (CBE) and mammogram or ultrasound, depending on the age 

of the patient. Controversies abound concerning the appropriate steps after the initial imaging study. It is unclear 

whether further management should be influenced by patients' risk factors for breast cancer. Other areas of 

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controversy include management of abnormal mammograms, management of certain pathological diagnoses, and 

whether all women with breast cancer require a full axillary lymph node dissection (ALND).

These are but a few of the numerous unresolved issues regarding the diagnosis and management of breast disease. 

In an effort to answer some of these questions, the Agency for Healthcare Research and Quality (AHRQ) directed 

MetaWorks, Inc., Boston, MA, to undertake a systematic review of the English-language literature since 1994 

pertinent to women with breast disease. This topic was nominated for review by Kaiser Permanente.

This review focuses on women with breast signs, symptoms, or mammographic abnormalities for whom specific 

risk factors for breast cancer are reported. Additional areas of interest include specific biopsy findings and initial 

management after breast cancer diagnosis.

The MetaWorks investigators have assembled an evidence base that should be useful to health care providers in 

developing evidence-based strategies to guide breast disease management. It also will be useful to investigators 

planning new clinical trials and others making regulatory decisions. This synthesis of the best available and most 

recent evidence is intended to serve as an information resource for local decisionmakers and developers of practice 

guidelines and recommendations. It focuses attention on gaps in the literature and areas that warrant future 

research.

Reporting the Evidence

This report presents the results of a systematic review of published studies of adult patients who were evaluated for 

breast symptoms. The following key questions guided this review: 

1. What are the recommendations for evaluation of breast symptoms, mammographic findings and other 

suspicious findings based on menstrual status, use of hormone replacement therapy (HRT), pregnancy, age, 

and family history? 

2. How are lobular carcinoma in situ (LCIS) and atypical hyperplasia (AH) managed? 

3. How are nonpalpable lesions and calcifications managed? 

4. What are the indications for sentinel node biopsy? 

5. What costs are associated with diagnosis and management of breast disease as outlined above? 

Methodology

MetaWorks investigators applied methods derived from the evolving science of review research. The review 

followed a work plan that had been developed and shared with AHRQ, Kaiser Permanente, and a technical expert 

panel (TEP) that included gynecologists, family practitioners, internists, medical and surgical oncologists, 

radiologists, and a consumer representative who is a breast cancer survivor.

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The work plan outlined the methods to be used for the literature search, study eligibility criteria, data elements for 

extraction, and methodological strategies employed both to minimize bias and maximize precision during the 

process of data collection and synthesis.

The published English-language literature was searched from January 1, 1994 to September 15, 1999, and the 

retrieval cutoff date was March 15, 2000. Different Medline search strategies were employed for each question. 

● Question 1 (management of symptomatic breast disease and suspicious findings): "breast neoplasms" AND 

"diagnosis. " 

● Question 2 (management of LCIS and AH): "breast neoplasms" AND ("diagnosis" OR "pathology" AND 

("carcinoma in situ" OR "carcinoma, infiltrating duct" OR "carcinoma, intraductal, noninfiltrating" OR 

"carcinoma, lobular" OR "hyperplasia". 

● Question 3 (management of nonpalpable lesions and calcifications): "breast neoplasm" AND ("diagnosis" 

OR "pathology" OR "radiology" AND "mammography" OR "nonpalpable" OR "calcifications" OR 

"microcalcifications". 

● Question 4 (indications for sentinel node biopsy): "breast neoplasm" AND "lymph nodes" AND "pathology. 

" 

● Question 5 (costs): "breast neoplasms" AND ("costs" OR "cost analysis" OR "economic"). 

The Current Contents CD-ROM database was searched (breast cancer and diagnosis) to the same cutoff date. These 

electronic searches were supplemented by a manual search of the reference lists of all accepted articles, review 

articles from 1999, and relevant Internet sites.

Abstracts were screened using predefined exclusion criteria, then full papers were reviewed and assessed for fit with 

inclusion criteria. Only English-language studies involving a minimum of 10 patients were eligible for inclusion. 

Only randomized controlled trials (RCTs), nonrandomized controlled trials, uncontrolled case series (UCSs), and 

observational studies were accepted.

After initial screening of abstracts, it became clear that the inclusion criteria needed to be refined in order to develop 

evidence that addressed the specific questions that had been posed. Questions 1 and 3 are actually facets of the same 

question; namely, what is the management of patients with risk factors for breast cancer who present with abnormal 

clinical or mammographic findings? Thus, the refined inclusion criteria for questions 1 and 3 included: 

● Reporting of risk factors (age, menstrual status, pregnancy history, HRT use, or family history). 

● Description of suspicious findings (palpable lesion, nipple discharge, or mammographic findings). 

● Diagnosis of cancer at time of presentation and/or subsequently. 

The inclusion criteria for question 2 included: 

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● Diagnosis of LCIS and/or AH. 

● Management options (observation, excisional biopsy, magnetic resonance imaging [MRI], selective estrogen 

receptor modulator [SERM] therapy, bilateral mastectomy). 

● Diagnosis of cancer at time of presentation and/or subsequently. 

Initially, the review of AH was limited to atypical lobular hyperplasia (ALH). All studies that involved only atypical 

ductal hyperplasia (ADH) were rejected. Because of the scant literature available regarding ALH, the focus of this 

review was expanded to include both ALH and ADH.

Inclusion criteria for question 4 included: 

● Indication for sentinel node biopsy (tumor size, tumor location, absence of palpable axillary nodes, no 

history of breast surgery). 

● Method of sentinel node identification (vital blue dye, radiocolloid mapping, or both). 

● Results of biopsy and comparison with gold standard (axillary node dissection). 

The only criteria for acceptance for question 5 were: 

● Acceptance of study for one of the other questions. 

● Discussion of costs, in U.S. dollars. 

Studies that involved only screening populations were rejected because the questions for this review were focused 

on patients with clinical or mammographic abnormalities in addition to risk factors. Populations of interest would 

not be represented in screening studies, which by definition consist of asymptomatic patients.

For questions 1 and 3, studies that involved only cancer patients were rejected because the questions for this review 

aimed to determine the incidence of cancer in patients with specific findings, not to determine the prevalence of 

specific findings in cancer patients.

For question 2, studies of patients who had cancer concurrently with LCIS or AH were rejected, as it would be 

impossible to determine whether these patients' outcomes were related to their cancer or their LCIS/AH.

Rejection of studies with cancer populations obviously did not apply to question 4, as sentinel node biopsy would be 

done only in patients with a diagnosis of cancer.

Relevant data from all accepted studies were entered onto data extraction forms (DEFs) designed specifically for 

this project. Results that required extrapolation from graphs or derivations from figures were not captured due to 

concerns about accuracy. All data elements were extracted by one investigator and reviewed by a second 

investigator; 100 hundred percent agreement between the two reviewers was required prior to entry of data elements 

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into the database. At least one physician reviewed all data elements extracted from every study.

All accepted studies were evaluated for quality by using the previously published methods of Level of Evidence and 

the Jadad Quality Score Assessment.

The elements extracted from each study varied, depending on the question. In general, the information captured 

included date of publication, location and type of study, primary objective of study, number of patients with various 

risk factors and clinical or mammographic findings, management of the abnormal findings, number of patients 

diagnosed with cancer, and any statistical measures reported. No quantitative analyses were performed beyond 

descriptive statistics to summarize findings.

A group of 11 peer reviewers, drawn from consumer groups and professional organizations, was assembled to 

review and provide suggestions for the draft final report of this project. Their comments, in addition to those of the 

TEP, were incorporated into the final report.

Findings

● 109 studies (k) plus 11 kinship studies. 

● 39,560 patients (n). 

● Study designs: interventional 69 (UCS [k=66], nRCT [k=2], RCT [k=1]); observational 40 (retrospective 

[k=33], prospective [k=6], cross-sectional [k=1]). 

● Study location: North America (k=69), Europe (k=33), other (k=7). 

Questions 1 and 3 (Risk factors, abnormal clinical or mammographic findings): 

● Risk factors were commonly reported, but age was the only risk factor consistently reported in association 

with symptoms and cancer diagnosis. 

● There was no evidence to support modifying the workup based on risk factors other than age. 

● The only age-related modification reported was ultrasound for younger women (specific age not reported) 

and mammogram for older women. 

Question 2 (LCIS and AH): 

● Within 5 years after LCIS diagnosis, 4.2-9.3 percent of patients were diagnosed with breast cancer (k=5, 

n=1,014 [of which 53 were diagnosed with cancer], overall incidence = 5.2 percent). In studies that followed 

patients for greater than 5 years, the incidence of cancer was 7.7-26.3 percent (k=3, n=421 [of which 77 were 

diagnosed with cancer], overall incidence = 22.3 percent). 

● Within 5 years after AH diagnosis, 3.7-19.3 percent of patients were reported to have developed breast 

cancer (k=3, n=752 [of which 48 were diagnosed with cancer], overall incidence = 6.4 percent). In studies 

that followed patients for greater than 5 years, the incidence of cancer was 13.6-33.6 percent (k=3, n=425 [of 

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which 83 were diagnosed with cancer], overall incidence = 19.5 percent). 

● When the diagnosis of ADH was made by stereotactic core biopsy (SCBX), it generally was followed by 

open surgical biopsy to confirm the diagnosis and rule out concurrent carcinoma, LCIS, or ductal carcinoma 

in situ (DCIS). Forty-two percent of the ADH diagnoses were changed as a result of excisional biopsy. Most 

changes were to DCIS or invasive cancer, although approximately 20 percent changed to more benign 

diagnoses. Only one study reported the incidence of diagnosis change after ALH (in one of four patients, the 

diagnosis of ALH was changed to LCIS). 

● Although data are available from only one study of 13,175 patients, those patients with LCIS or AH who 

received tamoxifen therapy had a markedly decreased subsequent incidence of cancer, compared with 

patients who were treated by observation alone (1.9 percent vs. 4.4 percent in LCIS, 0.5 percent vs. 3.7 

percent in AH). However, the risks associated with tamoxifen therapy must be considered, including an 

increased risk of endometrial cancer and thromboembolic disease. 

Question 4 (sentinel node biopsy): 

● Sentinel node biopsy had a false negative rate of 1.9-3.3 percent. 

● While both methods of sentinel node detection were effective, the combination of vital blue dye and 

radiocolloid mapping was more sensitive than either method alone. 

● Successful sentinel node detection was independent of tumor location, tumor size, and history of breast 

surgery. 

● Approximately one-third of sentinel lymph nodes were positive for metastatic disease. These patients 

required full axillary lymph node dissection (ALND) to determine the extent of metastatic disease. The 

remaining two-thirds of patients, however, could have been spared this invasive procedure at a cost of 

missing metastatic disease in 2 to 3 percent of women with cancer. 

● Long-term studies regarding the efficacy and safety of sentinel node biopsy are lacking. 

Question 5 (cost): 

● Only six of the accepted studies addressed cost. 

● Information was too disparate to draw any conclusions regarding the actual costs of various interventions and/

or the long-term cost savings resulting from their use. 

Future Research

Additional research is needed to more thoroughly examine risk factors and breast symptoms and how they relate to 

cancer diagnoses. Standardization of reporting results is essential, particularly with regard to reporting numbers of 

patients and not just numbers of lesions. Investigators should report baseline risk factors, presenting symptoms, and 

followup data pertaining to which patients developed cancer.

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Future research also should be undertaken to identify additional or new risk factors. If all of this information were 

available, a comprehensive assessment of risk could be calculated. This, in turn, could lead to development of a risk 

model that could be used by doctors and patients to assess breast cancer risk. Such a model could be an adjunct to 

models (such as the Gail model) that currently are in use, and it could include not only risk factors but also breast 

symptoms and mammographic findings.

Further studies should be done to confirm and extend the promising initial data that supports prophylactic SERM 

therapy for patients with AH or LCIS. Although sentinel node biopsy reportedly is effective in most patients, future 

studies should attempt to identify differences in sensitivities based on tumor size, location, and history of breast 

surgeries. Additionally, variations in success rates may depend on the experience of the surgeon performing the 

procedure and the extent of the pathological investigation. These factors should be addressed in future studies. Longterm cancer outcomes and survival data are required before sentinel node biopsy can be recommended for breast 

cancer patients.

The management of breast disease is changing, with important new developments in genetic susceptibility and 

promising new imaging techniques. These changes will have a major impact on the diagnosis and management of 

breast disease in the future.

Copyright and Disclaimer

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