Atypical hyperplasia of the breast refers to abnormal epithelial proliferative lesions of the breast which are not qualitatively or quantitatively abnormal enough to be classified as carcinoma in situ. These lesions can occur in both male and female breast tissue, but they are a rare, incidental finding in male gynecomastia specimens. This article will focus on atypical hyperplasia of both ductal and lobular type of the female breast. Both of these lesions are considered pre-malignant or high-risk lesions for development of more advanced neoplasia.
Atypical ductal hyperplasia (ADH) is a relatively common lesion reported to be found in about 5% to 20% of breast biopsies. Although not carcinoma, it is classified as a high-risk precursor lesion due to its association with, and potential to progress to ductal carcinoma in situ (DCIS) as well as invasive carcinoma.
Atypical lobular hyperplasia (ALH), like ADH, is another high-risk breast lesion that has been associated with a four-fold to five-fold increased lifetime risk of developing breast cancer in either the ipsilateral or contralateral breast.
Atypical lobular and ductal hyperplasias are considered high-risk, pre-cursor or pre-malignant lesions associated with either progression to advanced neoplasms or a marker for the development of metachronous or synchronous breast cancer. Molecular studies have demonstrated that genomic changes occur in normal breast tissue. These changes lead to an increased proliferative capacity. A genomic change from the damaging effects of carcinogens is one of the leading theories behind the development of atypical proliferative lesions and breast cancer.
One of the leading players in initiating this genomic change is estrogen. Estrogen and its metabolites have been associated with multiple DNA-damaging effects leading to defective growth control, especially of luminal progenitor cells. Women are exposed to estrogen at differing levels throughout their life, especially beginning at menarche and throughout the remainder of their lives. This life-long exposure to estrogen possibly represents a continued accumulation of genomic changes and damage which may lead to the development of atypical proliferative lesions of the breast.
Molecular studies have discovered shared molecular characteristics between atypical proliferative lesions such as ADH and low-grade DCIS. This leads many to believe that ADH will continue on a spectrum to develop into low-grade DCIS. ALH, on the other hand, is not necessarily considered a pre-cursor for malignancy, but a high-risk indicator. When ADH or ALH is identified in a breast biopsy, the risk of developing DCIS or invasive breast cancer is increased by four to five times with a 2:1 predilection for the ipsilateral breast versus contralateral. It is unclear if a precursor lesion exists for high-grade DCIS or invasive carcinoma; however, breast cancer relative risk is increased by four times when atypical hyperplasia is identified on breast biopsy. The lifetime risk of developing breast cancer in patients with ADH or ALH on biopsy is 15% to 20%.
Molecular studies have identified important agents related to un-checked proliferation, including cyclin D1 overexpression, p16 inactivation, HOXA inactivation, and activation of telomerase. These changes can lead to inhibition of cell death and development of malignancy. The sequence and interplay of these changes are not well understood, but further studies in their relation to each other and development of atypical proliferative lesions and breast cancer could shed light on accurate risk stratification, prognosis, and early predictors of advanced neoplasia.
Approximately 10% of female breast biopsies will contain an atypical proliferative lesion, with the majority of these lesions found in women in their 40s.
Atypical hyperplasia can also be found in males undergoing reduction mammoplasty for gynecomastia, although it is exceedingly rare. The reported incidence in one cohort of over 5000 specimens is reported to be less than 1%.
Both atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are characterized by the criteria put forth by Page et al.
ADH is characterized by an atypical monomorphic epithelial population of luminal origin within the breast that is between normal/usual hyperplasia and low-grade ductal carcinoma in situ (DCIS) on the spectrum of intraductal proliferative lesions. ADH will share some of the features of DCIS without meeting the full criteria for low-grade DCIS. The architectural features of low-grade DCIS include cribriform spaces with polarized lumens composed of highly monotonous cells with fine chromatin in a solid, cribriform, or micropapillary pattern.
When the above architectural and cytologic criteria are met, size can be used to distinguish ADH from low-grade DCIS, where low-grade DCIS requires the full involvement of two or more ductal units and the lesion is greater than 0.2 cm in size. DCIS, like ADH and ALH, will retain myoepithelial cells, as evidenced by positive immunohistochemical staining (e.g., with p63).
ALH is characterized by an intraductal over-proliferative epithelial population within the acini of terminal duct lobular units. These proliferations consist of small, round uniform cells which do not overlap, appear more dyshesive and have increased nuclear to cytoplasmic ratio. Nuclear atypia should be minimal. Loss of E-cadherin staining is characteristic for ALH and is also seen in more advanced lesions such as lobular carcinoma in situ or invasive lobular carcinoma. The distinction between ALH and lobular carcinoma in situ is that with ALH there should be less than 50% involvement of the acini in the TDLU.
Atypical hyperplasia lesions are usually discovered incidentally on routine screening mammograms, often during breast biopsies performed for evidence of calcifications on imaging or in conjunction with other lesions, both benign and malignant. As atypical hyperplasia is a high-risk but non-malignant lesion, it is important to discuss risk-factors for breast cancer such as estrogen exposure and family history of breast cancer.
General physical exam to include focused breast exam is vital to the patient evaluation, although atypical hyperplasia itself is very unlikely to be appreciated on the physical exam due to its small size, as a solitary focus of ADH that is larger than 0.2 cm is more likely to be designated as DCIS.
Atypical hyperplasia cannot be identified on imaging but can be found on histopathologic examination of breast biopsy or excisions performed for other mammographic findings such as calcifications, or other worrisome lesions seen on imaging. Atypical hyperplasia is less likely to be the primary finding on histopathologic examination if a biopsy is performed for a large symptomatic or palpable breast mass or lesion. Women should be encouraged to undergo mammogram screening evaluation and breast exams at the currently recommended intervals according to their risk stratification.
Atypical hyperplasia lesions are pre-malignant, and so if found on breast biopsy, many authorities believe the patient should undergo complete surgical excision to exclude malignancy and prevent the development of advanced neoplasia. Surgical excision for core biopsies that show ADH is considered standard of care. However, ALH may be an incidental finding in small biopsies, and standard surgical resection of these lesions is more controversial. In general, excision is usually recommended in high-risk patients. In carefully selected lower risk patients such as those without a family or personal history of breast cancer, without BRCA1 or BRCA2 mutations, solitary lesions, or lower BI-RADS score, surveillance, and/or medical therapy such as estrogen receptor modulators are possible management options. Short-term follow up with increased mammography frequency should be recommended for patients in whom surgical resection is not performed.
ADH is considered a pre-malignant, high-risk lesion and ALH only a high-risk lesion, and either can be found in association with or at the periphery of a more advanced lesion; therefore it is important to remember that atypical hyperplasia found on a biopsy may not accurately represent the greater lesion. Upgrade on surgical excision after atypical hyperplasia is found on biopsy varies from 10% to as high as 30%, with cases of atypical hyperplasia suspicious for DCIS having a higher rate of an upgrade after undergoing excision. Studies have failed to show reliable independent indicators of which atypical hyperplasia lesions are associated with more aggressive entities such as high-grade DCIS or invasive cancer.
It is important to note that while surgical excision after identifying atypical hyperplasia in a core biopsy is generally considered appropriate, some disagreement persists regarding the management of high-risk lesions in certain cases. Proper management will depend on discussing all factors with the patient, and this includes a review of current treatment modalities and recommendations, patient risk factors, careful radiologic/pathologic correlation, and the overall clinical picture.
Important differential diagnostic entities to consider when viewing possible ADH or ALH include usual ductal hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ, and flat epithelial atypia, with the most important distinguisher being whether a lesion is ADH or low-grade DCIS. These distinctions can be made on the histologic features as outlined above, noting that there are also difficult cases where particularly problematic borderline lesions may be diagnosed as “ADH bordering on DCIS” or “ADH suspicious for DCIS.”