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Diagnosis and Management of Specific Breast Abnormalities


Evidence Report/Technology Assessment: Number 33

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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.

Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of the Full Report

Authors: Levine C, Armstrong K, Chopra S, Estok R, Zhang S, Ross S.


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 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.

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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?

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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.

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 (nRCTs), 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: 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 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.

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  • 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 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 1 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 their 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.

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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.

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. Long-term 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.

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Availability of the Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality by MetaWorks®, Inc., Boston, MA, under contract 290-97-0016. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 1-800-358-9295. Please request Evidence Report/Technology Assessment No. 33, Diagnosis and Management of Specific Breast Abnormalities (AHRQ Publication No. 01-E046).

The Evidence Report is also online on the National Library of Medicine Bookshelf.

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AHRQ Publication Number 01-E045
Current as of April 2001


The information on this page is archived and provided for reference purposes only.


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