Tissue type and molecular features
The criteria for the diagnosis of atypical ductal hyperplasia and atypical lobular hyperplasia were published by Professor David Page and others and adopted by the College of American Pathologists in 1985. Atypical ductal hyperplasia is characterized by a single ductal epithelium with many complex patterns of structures, including sieve-like secondary lumen or micropapillary structures.
In atypical lobular hyperplasia, the follicles of the lobular units are swollen and filled with a single small round or polygonal cell, and lack cell junctions and lumens. Lobular carcinoma in situ, although very similar to lobular hyperplasia, has a higher potential for extended growth and is therefore more likely to develop into breast cancer. Similarly, atypical ductal hyperplasia and low-grade ductal carcinoma in situ share the same histologic features, but ductal carcinoma in situ is more aggressive and thus more likely to develop into breast cancer.
Because the difference between carcinoma in situ and atypical hyperplasia is primarily the invasive ability of the lesion, some studies have also shown inconsistency in identifying atypical hyperplasia as well as carcinoma in situ of the breast. However, other studies have shown that when pathologists use a standardized diagnostic process, consistency can still be assured.
Molecular biology studies can help pathologists better identify atypical hyperplasia. In an early consensus gene expression study on breast cancer development, Prof. Ma et al. found similar transforming factors and epithelial changes in invasive breast cancer, carcinoma in situ, and atypical hyperplasia, which additionally supports the fact that atypical hyperplasia is a precursor to breast cancer.
A feature that distinguishes lobular atypical hyperplasia from lobular carcinoma in situ and invasive lobular carcinoma is the absence of the cell-to-cell linker E calcineurin.
Mutant expression of E calcineurin can be detected by immunohistochemical methods and can be used to diagnose and differentiate between lobular and ductal subtypes. In a large study of estrogen receptor expression, 97% of atypical ductal hyperplastic lesions and 88% of atypical lobular hyperplastic lesions were found to have at least 10% estrogen staining. Notably, the percentage of positive cells and the intensity of staining were higher in ductal lesions.
Risk
Risks of atypical hyperplasia overall
The landmark longitudinal cohort study of the risk of progression of atypical hyperplasia to breast cancer was described by David Page and William Dupont in 1985. In that study, which included 3,303 women who underwent breast biopsy for confirmed benign masses, the authors defined a number of categories for the presence of breast cancer risk. The cohort included 232 women who had atypical hyperplasia with a 4.4% risk of developing invasive breast cancer.
Following the publication of this article, 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% (Table 1). The most recent data are from the Mayo Clinic, where the percentage of patients who underwent breast biopsy to confirm atypical hyperplasia who developed breast cancer (in situ or invasive cancer) after 25 years of follow-up was 30%. The data from the Nashville Breast Cancer Center is similar at 27.5% (unpublished data).
Risk in different conditions
By clinical and epidemiological factors
The younger the patient is at the time of atypical hyperplasia diagnosis, the higher the risk of developing breast cancer. And family history of breast cancer is currently controversial for the risk of atypical hyperplasia transformation. The first study by Dupont and Page et al. found that a group of 39 women with a family history of breast cancer and atypical hyperplasia had an 8.9 risk of progression to breast cancer, compared with a 3.5 risk for 193 women with no family history of progression to breast cancer.
However, subsequent data published in the Nursing Health Study showed that family history had no significant effect on women with atypical growths. However, since many patients with atypical hyperplasia have a family history of breast cancer, it is likely that atypical hyperplasia is a tissue type that is at inherent risk.
Histologic factors
Two histologic features are associated with the risk of atypical hyperplasia, the number of independent foci of atypical hyperplasia (the more independent foci the higher the risk) and the degree of regression of normal background lobular units, the greater the degree of regression the lower the risk. This pattern is the same in other types of benign breast disease.
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 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, while 22% had lobular carcinoma or other types of tumors.
Among patients with atypical lobular hyperplasia that progressed to 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.
Clinical measures
Excisional biopsy after fine needle aspiration diagnosis of atypical hyperplasia
With the widespread use of percutaneous fine needle aspiration methods, when an atypical hyperplastic lesion is detected, it is likely that the true tumor will be missed due to sampling errors. Therefore, the NCCN recommends excisional biopsy for patients with atypical hyperplasia. 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 to undergo close clinical and imaging follow-up.
Risk prevention
For women with atypical hyperplasia, the current approach is to assess them using the Breast Cancer Risk Assessment Tool (BCRAT) or the International Breast Cancer Intervention Study (IBIS) model. Both models claim to include parameters that adjust for the risk of atypical hyperplasia. However, these models were ultimately found to be inappropriate for women with atypical hyperplasia. In fact, in one study, researchers scored 331 women on the BCRAT and used long-term follow-up to assess their risk of progression to breast cancer.
The BCRAT significantly underestimated the risk of breast cancer in women with atypical hyperplasia, while the IBIS model overestimated this risk. IBIS model overestimated this risk.
Since both models performed poorly, we believe it is more appropriate to use the cumulative risk data, which is the previously mentioned presence of a certain percentage of cancer risk for atypical hyperplasia beyond a certain number of years. If we know the number of small foci of atypical hyperplasia in a patient, then the risk can be assessed in more detail.
Screening
Current breast cancer screening for women at high risk, including guidelines from the NCCN guidelines, the American Cancer Society (ACS) guidelines, and the American College of Radiology, focus on women at genetic risk. The ACS guidelines state that most risk assessment models are based on family history.
The ACS states that there is currently insufficient evidence to recommend MRI screening in the population of patients with atypical hyperplasia. However, the literature they cite suggests that this subset of patients with lobular atypical hyperplasia has only a 10-20% lifetime risk of developing breast cancer. the ACS does not provide a cumulative risk assessment for patients with atypical ductal hyperplasia.
To our knowledge, the only literature on the need for MRI screening for atypical hyperplasia was contributed by the ACS, a retrospective study that included 47 patients with atypical hyperplasia who underwent MRI (as recommended by their physicians) and an additional 79 patients who had atypical hyperplasia but were not screened as controls.
Among the women who were screened, one MRI-negative patient developed breast cancer, while there were two cases of breast cancer among women who were not screened. The authors concluded that there was no additional survival benefit from MRI screening in this study, but the number of cases in this study was indeed too small. The American College of Radiology found that women with atypical hyperplasia have a 15-20% risk of breast cancer, and concluded that the use of MRI for screening “remains controversial.
The NCCN’s recommended screening guidelines for women older than 35 years with a 5-year risk of cancer greater than 1.7% are annual mammograms, breast exams every 6 months to 6 months, and consistent breast self-exams. 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 suggest that there is no clear evidence for or against MRI screening.
To date, there are no prospective data on the value of MRI screening in women with atypical hyperplasia. These women should undergo prospective clinical studies when new imaging techniques become available in the future. For the inclusion of MRI in routine screening programs, rather than just the use of mammograms may be the way forward for future guideline updates.
Risk-reducing drug therapy
Several randomized clinical trials have evaluated the use of selective estrogen receptor modulators (SERMs) as well as aromatase inhibitors (AIs) in the prevention of breast cancer. A series of studies, as shown in Table 2, were 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 occurrence 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 main adverse effect was venous thromboembolism, but the incidence was not high and only increased by 5.5 per 1,000 compared to the control group.
Although the risk-benefit ratio was still skewed in favor of the benefits of prophylaxis, only 0.03% of the population was treated with drugs 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 developing breast cancer (3% or higher) the more likely it is to benefit from preventive medications.
Using surgery to reduce breast cancer risk
The NCCN guidelines recommend prophylactic bilateral mastectomy only for women who are at risk for breast cancer, such as those who have received radiation therapy to the chest before age 30 or have a family history of lobular breast cancer. The Society for Surgical Oncology considers atypical hyperplasia to be only treatable but not a routine indication for double mastectomy. In a small retrospective study, 24% of patients with atypical hyperplasia underwent double mastectomy.
Of course, not much has been written in this area, and there are numerous medications available for prevention, so prophylactic bilateral mastectomy is not recommended for women with atypical hyperplasia.
Summary and recommendations
Currently, for optimal treatment, physicians need to know that atypical hyperplasia can expose patients to a 30% risk of cancer at 25 years of follow-up. The use of risk prediction models does not accurately assess the risk of cancer in women with atypical hyperplasia. Absolute risk values should be used to assess the risk of breast cancer in this group of women. The guidelines for women at high risk should be revised and updated for the subgroup of women with atypical hyperplasia.
This group of women should receive screening MRI 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 they 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.
Further research is needed in the management of atypical hyperplasia. First, accurate diagnosis is essential, and quality control studies are needed to ensure the dissemination of standardized pathological diagnosis. When new diagnostic tools become available in the future, it is recommended that women with atypical hyperplasia be included in the trials. Molecular biology is also an important field that will allow us to better risk stratify patients with atypical hyperplasia, develop new diagnostic tools, etc.
It is important to know that patients should be informed not only about the risk of breast cancer, but also about the risk from other diseases, since only a small percentage of patients with atypical hyperplasia will develop breast cancer, and the risk of other diseases is higher at this age.