When a patient’s breast mass is detected by breast ultrasound or breast palpation, a clinical biopsy of the breast mass is often used to evaluate the nature of the mass and, of course, most are ultimately confirmed to be benign. More than one million breast biopsies within the United States each year end up with a benign mass. Depending on the tissue type of the mass, women with benign biopsy pathology can be stratified differently based on their potential risk of developing breast cancer. Among these, atypical hyperplasia is a high-risk benign disease, with roughly 10% of benign nodules being associated with this pathology. We detect such lesions because they are important in predicting breast cancer development. Two types of atypical hyperplasia have been found to exist, which are distinguished by what is seen microscopically: atypical ductal hyperplasia and atypical lobular hyperplasia. These two types of atypical hyperplasia occur with similar frequency and have the same risk of developing into breast cancer. Therefore, through this article, we will refer to both types of atypical hyperplasia as “atypical hyperplasia”. In atypical hyperplasia, there is an abnormal proliferation of a single mass of epithelial cells, which includes some clonal subpopulations. In the breast cancer model, atypical hyperplasia occupies the area of transition from benign to malignant disease and is considered a precancerous lesion because it contains some of the characteristics necessary for tumor cells. In studies with long-term follow-up, atypical hyperplasia has shown the potential to develop into breast cancer. Although these risk-related statistics have been accepted for decades, only recently have studies shown the exact percentage of risk of developing cancer from atypical hyperplasia, i.e., a 30% risk of developing cancer after 25 years of follow-up from atypical hyperplasia. Because of the high incidence of atypical hyperplasia, its high risk profile, and the availability of many preventive tools for breast cancer, atypical hyperplasia is receiving increasing attention from clinicians. In this report, we describe the histologic and molecular biology of atypical hyperplasia, the current treatment status, the latest data on the risk of developing breast cancer, and the current guidelines and recommendations for screening and prevention. Risk: Overall Risk of Atypical Hyperplasia In a study of the risk of progression of atypical hyperplasia to breast cancer, women with atypical hyperplasia had a 4.4% risk of developing invasive breast cancer. Other researchers have used cohort studies or case-control studies to confirm that the risk of atypical ductal hyperplasia and atypical lobular hyperplasia leading to breast cancer is approximately 4%. The most recent data comes from the Mayo Clinic, where the percentage of patients who underwent a breast biopsy to confirm atypical hyperplasia that progressed to breast cancer (in situ or invasive cancer) after 25 years of follow-up was 30%. Data from the Nashville Breast Cancer Center is similar at 27.5% (unpublished data). 2. Characteristics of breast cancer Recent staging and staging methods for breast cancers that develop from atypical hyperplasia have been contributed by the Mayo Clinic. Of the 698 patients with atypical hyperplasia, 143 presented with breast cancer (81% with invasive carcinoma and 19% with carcinoma in situ). Of the patients with atypical ductal hyperplasia who subsequently developed breast cancer, 78% had ductal carcinoma and 22% had lobular or other types of tumors. Among patients with atypical lobular hyperplasia that developed into breast cancer, 77% had ductal carcinoma and 23% had lobular carcinoma or other types. Of the 95 women with invasive carcinoma and known lymph node metastasis status, 75% had tumors without lymph node metastasis and 25% had lymph node metastasis. A total of 88% of the breast cancers were estrogen receptor positive. The risk of breast cancer tends to increase linearly with the duration of atypical hyperplasia. 3. Clinical measures With the common use of percutaneous aspiration biopsy methods, when atypical hyperplastic lesions are detected, it is likely that the true tumor will be missed due to sampling errors. Therefore, NCCN recommends that excisional biopsy may be performed for patients with atypical hyperplasia findings. In patients with atypical hyperplasia, excisional biopsy can detect breast cancer (escalation) in 15-30% or more of patients. Thus, excisional biopsy has become the standard of care after the detection of atypical hyperplasia. However, studies are currently being conducted to identify patients who can avoid unnecessary excisional procedures. In cases of atypical lobular hyperplasia, this “escalation” has been reported in the literature as 0-67%. However, three recent studies suggest that in patients with atypical lobular hyperplasia, resection may be avoided (0-6% risk of escalation), assuming that the finding is incidental and that there are no signs of malignancy on imaging or pathology. Assuming that resection is not performed, then patients are recommended for close clinical and imaging follow-up. 4. Screening The current NCCN screening guidelines for women at high risk of breast cancer are annual mammograms, 6-monthly breast exams, and self-examination of the breast for women older than 35 years of age with a 5-year risk of cancer greater than 1.7%. For women with a lifetime risk of breast cancer greater than 20%, the NCCN guidelines recommend annual MRI screening. Especially for women with atypical hyperplasia, they indicate that there is no clear evidence for or against MRI screening. 5. Risk-reducing drug therapy Several randomized clinical trials have evaluated selective estrogen receptor modulators (SERMs) as well as aromatase inhibitors (AIs) in the prevention of breast cancer. A series of studies showed clinical trials designed with breast cancer prevention as the primary study endpoint, while others were originally designed with bone mineral density as well as osteoporosis, etc., and breast cancer development as a secondary study endpoint. All of these studies have shown a decrease in the incidence of breast cancer after 5-7 years of treatment. A recent meta-analysis showed a 38% reduction in breast cancer incidence in all subjects participating in the SERM trial, with a 31% reduction in ductal carcinoma incidence. Four placebo-controlled studies focused on atypical hyperplasia as a subgroup. A total of 2009 women with atypical hyperplasia were randomly assigned to two groups, those receiving active drug therapy and those receiving placebo. The risk reduction in the atypical hyperplasia subgroup ranged from 41-79%, suggesting that this group of patients would benefit more from this type of treatment than the overall patient population. In addition, the side effects of this type of drug therapy are also of interest. In order to quantitatively assess the adverse effects of this drug, we obtained the incidence of adverse drug reactions per 1,000 population in the comparison drug treatment group and the placebo group. The major adverse effect was venous thromboembolism, but the incidence was not high, increasing by only 5.5 per 1,000 compared to the control group. Although the risk-benefit ratio was still skewed toward the benefits of prophylaxis, only 0.03% of people were treated with a drug such as tamoxifen for breast cancer prophylaxis. Based on the current status of preventive drug therapy, the American Society of Clinical Oncology guidelines only recommend exploring the use of such drugs for patients with an absolute 5-year risk of breast cancer greater than 1.7%. The U.S. Prevention Panel notes that the higher the risk of breast cancer (3% or higher) the more likely it is to benefit from preventive medications. The NCCN guidelines recommend that prophylactic bilateral mastectomy be recommended only for women who are at risk for breast cancer, such as those who have received chest radiation therapy before age 30 or have a family history of lobular breast cancer. The Society for Surgical Oncology considers atypical hyperplasia to be treatable only, but not a routine indication for double mastectomy. In a small retrospective study, 24% of patients with atypical hyperplasia underwent double mastectomy. Summary and Recommendations For optimal treatment at this time, physicians need to be aware that atypical hyperplasia can expose patients to a 30% risk of cancer at 25 years of follow-up. For women at high risk, screening MRI should be performed as a test in addition to mammography. Randomized controlled studies have shown that women with atypical hyperplasia can benefit from prophylactic breast cancer medications, although those currently receiving such treatment are still in the minority. Further health education should be provided on the use of preventive medications, including the absolute risk of breast cancer, the ability of the medication to reduce the risk, and the possible side effects of the medication.