Atypical Ductal Hyperplasia

Etiology

The etiology of atypical ductal hyperplasia is unknown; however, ADH is more prevalent in patients with a strong family history of breast cancer.[2] Hoogerbrugge et al. found that nearly 50% of women undergoing prophylactic mastectomies due to high family risk of breast cancer uncovered high-risk lesions, 39% of which were ADH; this suggests that there is a hereditary component involved, which requires further study.

Additionally, a study from 2009 demonstrated that rates of ADH have declined with the loss of favor of post-menopausal hormonal therapies, suggesting this also may have been a contributing factor.[3]

Epidemiology

Atypical ductal hyperplasia, due to its lack of imaging findings, is, by definition, an incidental pathology finding. Most frequently, this is found on core needle biopsy; however, it can also be discovered on excisional biopsies, breast oncologic surgeries, cosmetic breast reductions, or any other breast surgery resulting in submitting breast tissue to pathology. The prevalence of atypical ductal hyperplasia in biopsies has been in the 3.5 to 5% range and most frequently found on core needle biopsy.[4]

Rates of ADH in a large study from 2009 reviewing nearly 31,000 biopsies demonstrated initially increasing rate of diagnosis with the increase in breast cancer awareness, screening mammographies, prophylactic mastectomies, and use of post-menopausal hormonal therapy - resulting in peak diagnosis of ADH in 1999 (5.5 cases per 10,000 mamograms). Since the loss of favor of post-menopausal hormonal therapy, however, there has been a slight decrease in the diagnosis of ADH over time.[3]

Typical patients are females in their fifth to sixth decade of life, as this is the population most likely to be undergoing breast biopsies. Males are also susceptible to atypical ductal hyperplasia, although diagnosis is less common. One Dutch study analyzing over 5,000 cases of excised breast tissue for gynecomastia in males found a prevalence of 0.4% of atypical ductal hyperplasia.[5]

Pathophysiology

Genetics studies reveal ADH has recurrent alterations involving losses of 16q and 17p and gains of 1q.  These genetic abnormalities are similar to those seen in low grade ductal carcinoma in situ (LGDCIS), implying a precursor-product relationship. [6]

Histopathology

Normal breast ducts terminate into a terminal duct lobular unit (TDLU). The duct ends into lobules made up of small glandular structures called acini. There is a bilayer of cells lining the ductal-lobular systems consisting of inner luminal epithelial cells and outer luminal myoepithelial cells. The majority of breast lesions (benign or malignant) develop in the TDLU.[7]

Atypical ductal hyperplasia is an intraductal clonal epithelial cell proliferation. ADH and LGDCIS involve the TDLU or the interlobular ducts.  ADH and LGDCIS have the same atypical histological features of small, round, monomorphic, non-overlapping cells that are evenly spaced, with uniform nuclei, rare mitosis, and inconspicuous nucleoli.  ADH is differentiated from LGDCIS by size or volume; if the atypical cells involve ≤ 2 mm, ≤ 2 spaces, or a portion of a duct a diagnosis of ADH is made. Although size is helpful there is no universally accepted size criterion for ADH.[8]

ADH has similar architectural features to DCIS, such as arcades, rigid bridges, bars of uniform thickness, a solid growth pattern, and micropapillae (papillae with a broad tip and a slender base and lack fibrovascular cores). ADH commonly grows in the cribriform architecture where cells bridge across and fill the duct, and form pseudo-lumens that appear as punched-out spaces. In ADH the spaces are not as uniform as in DCIS and the bridges may be thin and show streaming cells, versus the polarized cells in DCIS.[9][1]

Benign cell changes may be present such as spindle cells, columnar cell change (some with apical snouts), or cuboidal cells. Benign cellular proliferations like usual ductal hyperplasia can also involve ADH. ADH is often associated with secretory material that fosters the development of microcalcifications, that are commonly identified on mammography. ADH can involve benign lesions such as apocrine metaplasia, papillomas, fibroadenomas, sclerosing adenosis, and gynecomastia. ADH involving a papilloma is termed papilloma with atypia. [10]

Large nuclei with conspicuous nucleoli and frequent mitosis, such as those seen in intermediate or high-grade DCIS, are never present in ADH. If high-grade nuclei are identified, regardless of size, a diagnosis of high-grade DCIS is rendered. 

ADH is typically present as a single focus or involves a small area on a core biopsy. However, ADH is occasionally found in close proximity to DCIS when multiple level sections of the core biopsy are performed (however, this is not routinely done). Patients with a diagnosis of ADH on a core biopsy sometimes have worse lesions on surgical excision (DCIS or invasive carcinoma). For this reason, surgical excision is indicated when a diagnosis of ADH is made on a core biopsy.[11]

The immunohistochemistry staining for ADH and LGDCIS is similar. Both lesions stain negatively for Cytokeratin 5/6 (but it is positive in the myoepithelial cells surrounding the duct or lobule due to the in situ nature of the lesions). ADH is typically diffusely and strongly positive for estrogen receptor (ER).[12][13]

Not all pathologies are consistent when diagnosing ADH or LGDCIS. A diagnosis of ADH is applied only to lesions when LGDCIS is highly considered, but the histological features present or the size is not sufficient for it. In true borderline cases, a diagnosis of ADH is made, and the pathologist should relay the complexity of the case to the treating clinician. [8]

History and Physical

Atypical ductal hyperplasia is most often found after biopsy in the setting of calcifications found on mammography or imaging. ADH can also be found incidentally on other breast tissue that is sent to pathology for any number of reasons, including oncologic resections, plastic surgery resections, excisional biopsies, etc. There are no physical findings on the exam, such as a lump, breast discoloration, or breast distortion grossly.

Evaluation

It is important to know the type of specimen in which the ADH is identified because the lesion's management depends on it. 

If atypical ductal hyperplasia is found on core needle biopsy, additional tissue is necessary by excisional biopsy. A wire or seed localization technique should be used at the time of the core biopsy to later identify the area potentially requiring excision. The reason for re-excision is that with a more extensive tissue specimen, there is a chance the lesion will be upgraded to carcinoma in situ or invasive carcinoma. Studies suggest that 22 to 65% of ADH found on core needle biopsies were upgraded to carcinoma after subsequent excisional biopsy.[14][15] Most upgrades are to DCIS; however, IDC is also sometimes found.

If, however, ADH alone is diagnosed on an excisional biopsy, no additional surgery is required, even if there are positive margins because ADH is a high-risk lesion, but it is not a pre-cancerous or cancerous lesion.[1][14][16]

Treatment / Management

Once identifying atypical ductal hyperplasia as the diagnosis and ruling out breast carcinoma, it is essential to address risk reduction strategies.

One such measure is treating these patients with tamoxifen, as the vast majority of lesions are ER+. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, tamoxifen conferred a risk reduction of 86% in women with ADH.[17] Therefore, we recommend the discussion of tamoxifen in patients diagnosed with ADH. Tamoxifen is known to increase the risk of endometrial cancer, stroke, DVT, and PE - particularly in patients over the age of 50. Therefore the risk-benefit discussion starting tamoxifen would need to include consideration of these risks and the decision to begin tamoxifen be patient dependant.(A1)

Additionally, it is important to increase surveillance and awareness in the patient.[18][19](B3)

Differential Diagnosis

If a core biopsy identifies atypical ductal hyperplasia, it is important to take a larger excisional biopsy to ensure a large enough specimen to rule out carcinoma of the breast. It is also important to note that on biopsy, low-grade DCIS and ADH share many morphologic similarities. Therefore the pathology specimen at hand should be carefully examined to rule out DCIS.[1]

Surgical Oncology

Atypical ductal hyperplasia has a history of surgical overtreatment. If diagnosed on core needle biopsy, a more extensive excisional biopsy is required to rule out breast carcinoma.[20] If, however, ADH and only ADH is found on excisional biopsy, the patient is surgically complete; this includes cases where margins are positive. As ADH is not cancer, there is no need for node sampling nor any role for mastectomy.

Radiation Oncology

There is no role at this time for radiation therapy in a patient diagnosed only with atypical ductal hyperplasia.

Complications

Complications of atypical ductal hyperplasia result from both over and undertreating the diagnosis. There is a risk of missing a breast carcinoma with undertreatment of ADH and not proceeding with additional tissue sampling.[21][20] There is also a risk of overtreating ADH with aggressive surgeries (e.g., mastectomy or excessively large biopsies) in the setting of no malignancy.[18] There is toxicity risk from chemotherapy agents if ADH is misrecognized as a cancerous or precancerous lesion rather than a high-risk lesion. As discussed above, there are known and well-established complications as a result of tamoxifen that should also merit consideration before starting treatment.