Recent Developments in Diagnostic and Therapeutic Approaches to Breast Diseases
Daniel W. Visscher, M.D.
Carol Reynolds, M.D.
Case 1A -
Atypical ductal hyperplasia with associated calcifications
This stereotactic core needle biopsy specimen is from a 57-year old woman with
mammographically-detected microcalcifications. Is an open biopsy necessary?
Atypical ductal hyperplasia with associated calcifications. Recommendation: Open
Image guided core needle biopsy has been increasingly utilized for the diagnosis of
mammographically detected non-palpable breast lesions. The purpose of core needle biopsy is to identify
patients with mammographic abnormalities who have histologic abnormalities that require surgical
intervention. The finding of ductal carcinoma in situ or invasive carcinoma on core needle biopsy allows
for appropriate surgical therapy, whereas lesions characterized by normal breast parenchyma or
proliferative changes do not require open biopsy. However, breast core needle biopsy specimens can
present with diagnostic problems and pitfalls primarily related to small sample size. In addition, there
are several breast lesions diagnosed on core needle biopsy that can have drastically different clinical
and management implications when the same diagnosis is rendered on an open biopsy specimen. A thorough
understanding of the limitations of sampling and histopathologic issues affecting lesion management is
critical to a successful breast intervention practice. Equally important is understanding what
constitutes an acceptable histopathologic result given the mammographic or sonographic appearance of the
lesion. It is imperative when dealing with core needle biopsy specimens that there is a close
collaboration between the pathologist, radiologist, and clinician to make certain the surgical pathology
report reflects the mammographic and clinical findings.
The finding of atypical ductal hyperplasia in an open biopsy specimen is a predictor of an increased
risk for developing subsequent carcinoma. While this still applies to atypical ductal hyperplasia found
on core needle biopsy, the prevalence of carcinoma after a diagnosis of atypical ductal hyperplasia on
core needle biopsy has been well documented in the literature and ranges from 11% to 87%. Many of these
cases prove to be either ductal carcinoma in situ (majority) or invasive mammary carcinoma. The
underestimation rate of malignancy has decreased (0-38%) with the advent of better sampling techniques,
such as the vacuum-assisted device. The likelihood of finding malignancy at surgical excision has
contributed to the recommendation that all patients with atypical ductal hyperplasia on core needle
biopsy undergo open biopsy.
However, several studies have looked at the question whether surgical excision is necessary for
atypical ductal hyperplasia diagnosed on core needle biopsy. In 2000, O'Hea and Tornos retrospectively
reviewed breast core needle biopsy specimens that were diagnosed as atypical with the aim to identify a
select group of patients who did not need surgical excision. Nineteen patients were assigned to 3 groups
according to the severity of the atypia. Group 1 (8 cases) was characterized as mild atypia, not meeting
the criteria of atypical ductal hyperplasia, Group 2 (6 cases) was "true" atypical ductal hyperplasia,
and Group 3 (5 cases) was severe atypical ductal hyperplasia/borderline ductal carcinoma in situ.
Surgical excision yielded carcinoma in 6 of 19 patients, and no patient in Group 1 was shown to have
carcinoma at open biopsy. They concluded that surgical excision could be avoided in patients with only
"mild atypia" on core needle biopsy.
O'Hea et al. Surgery 128:738-743, 2000
|Core biopsy ||Surgical Excisional Biopsy|
|1 - mild atypia ||8 ||0|
|2 - "true" atypia ||4 ||2|
|3 - severe atypia/DCIS ||1 ||4|
Another study performed by Adrales et al. showed that mild atypical ductal hyperplasia identified on
core needle biopsy may not need surgical excision. Similar to O'Hea's study evaluating the degree of
cytologic and architectural atypia found on core needle biopsy, they evaluated multiple variables
predicting malignancy (age, parity, hormone replacement therapy, personal history of contralateral breast
cancer, and family history of breast cancer) and the extent of removal of calcifications by core needle
biopsy. Sixty-two patients comprised the study with 9 (15%) patients yielding malignancy at surgical
excision. All 9 patients diagnosed with cancer had at least one of the following variables: previous
contralateral breast cancer, a first- or second-degree relative with breast cancer, or marked atypia on
core needle biopsy. Additionally, all 9 patients had incomplete removal of calcifications at core needle
biopsy. They concluded that patients diagnosed with "mild" atypical ductal hyperplasia on core needle
biopsy and without associated personal or family history of breast cancer might not need excision if all
calcifications have been removed.
Ely and colleagues assessed whether there were certain histopathologic features of atypical ductal
hyperplasia in the core needle biopsy that were predictive of open biopsy outcomes. Forty-seven cases
formed the basis of their study. The extent of involvement determined by evaluating the number of large
ducts and/or terminal lobular units involved by atypical ductal hyperplasia were counted. This
information was then assigned to 3 groups (Group 1 – 1 or 2 foci of ADH, Group 2 – 3 foci, Group 3 -
> 4 foci). Other data recorded at the time of examination were needle gauge, histologic
pattern of atypical ductal hyperplasia (e.g., cribriform, solid, or micropapillary), number of tissue
cores, and presence of calcifications. At surgical excision, 14 cases yielded benign findings, 3 cases
atypical lobular hyperplasia, 13 cases residual atypical ductal hyperplasia, 15 cases ductal carcinoma in
situ, and invasive mammary carcinoma in 2 cases.
Ely et al. AJSP 25:1017-1021, 2001
|Core Biopsy ||Surgical Excisional Biopsy|
|Benign ||ADH ||ALH ||DCIS ||Inv CA|
|< 2 ADH foci ||14 ||7 ||3 ||0 ||0|
|3 ADH foci ||0 ||4 ||0 ||3 ||1|
|> 4 ADH foci ||0 ||2 ||0 ||12 ||1|
They found that atypical ductal hyperplasia limited to 1 or 2 foci resulted in no worse lesion (14
benign, 3 ALH, 7 ADH), whereas atypical ductal hyperplasia involving 4 or more foci was a strong
predictor of a more significant lesion (12 DCIS, 1 invasive carcinoma). Atypical ductal hyperplasia
limited to 3 foci had an equal likelihood of being associated with atypical ductal hyperplasia as finding
a more significant risk lesion at open biopsy. Most importantly, when the atypical proliferation had
micropapillary architecture, this finding was strongly correlated with concomitant malignancy. They
concluded that all patients with greater than 4 foci of atypical ductal hyperplasia and any
micropapillary histologic pattern, regardless of the extent, be surgically excised. Those patients with
limited atypical ductal hyperplasia (less than or equal to 2 foci) may not need further surgical
intervention, especially if the mammographic abnormality has been removed.
Most recently, Sneige et al. retrospectively studied whether they could identify features within a
core needle biopsy diagnosed as atypical ductal hyperplasia with microcalcifications that would help
predict which lesions should go on to open biopsy. All samples were removed by directional,
vacuum-assisted biopsy technique using an 11- or 14-gauge needle. Their review included the mammographic
characteristics of the lesions, the extent of atypical ductal hyperplasia on core biopsy using criteria
established by Ely et al., the percentage of the lesion removed, and the open biopsy findings.
Sneige et al. AJCP 119:248-253, 2003
|Core Biopsy ||Surgical Excisional Biopsy|
|Benign ||ADH ||DCIS/Inv CA|
| 1 ADH foci ||14 ||7 ||0|
| 2 ADH foci ||2 ||5 ||0|
| 3 ADH foci ||3 ||1 ||1|
|> 4 ADH foci ||5 ||2 ||2 (1 with Inv CA)|
Their study reports one of the lowest overall rates (7%) with which DCIS and invasive carcinoma were
underestimated using the directional, vacuum assisted biopsy device. Similar to Ely et al., atypical
ductal hyperplasia confined to 2 or fewer lobular units correlated with surgical findings free of a
higher-risk lesion. However, this is in contrast to a recent abstract by Dalton et al. that showed that
the number of lobular units containing atypical ductal hyperplasia did not correlate with carcinoma at
open biopsy. Twenty-two percent (8/36) of women with 2 or fewer lobular units containing atypical ductal
hyperplasia had in situ or invasive carcinoma at surgical excision. Sneige et al. also stated that if
all microcalcifications have been removed, the lesion may be considered to have been adequately
represented with no risk of atypical ductal hyperplasia underestimation. Based on their findings, they
suggested that information about the percentage of microcalcifications removed and the extent of lobular
involvement by atypical ductal hyperplasia be used in the selection of patients for open biopsy.
More recently, Bonnett et al. examined what factors, both pathologic and clinical, contribute to the
underdiagnosis of ductal carcinoma in situ and invasive carcinoma among patients diagnosed with atypia on
core needle biopsy. They found three factors that imply a greater likelihood for malignancy at open
biopsy: (1) more severe atypical ductal hyperplasia, especially if accompanied by cytologic atypia, (2)
the number of foci (> four foci) involved by atypical ductal hyperplasia, similar to past
studies performed by Ely et al. and Sneige et al., and (3) patients with significant nuclear atypia, the
size of microcalcification span on mammogram. They reported that if the span of microcalcifications on
mammogram is < 2 cm in extent, this rules out approximately 75% of ductal carcinoma in situ cases.
A variety of studies have investigated the role of cytokeratin expression as an adjunct to
problematic intraductal proliferations of the breast. High molecular weight cytokeratins, cytokeratin
5/6 and 34ßE12, have been the most commonly used monoclonal antibodies. These studies have shown that
cytokeratin 5/6 and 34ßE12 is strongly expressed in florid epithelial intraductal proliferations, while
there is lack or only focal reactivity of this antigen in malignant intraductal proliferations (i.e.,
ductal carcinoma in situ). Furthermore, the cytokeratin immunohistochemical profile of atypical ductal
proliferations is similar to that seen in ductal carcinoma in situ. In a recent abstract, Carlo et al.
showed that high molecular weight keratin expression could not be used to help define atypia in columnar
cell lesions in contrast to non-columnar cell proliferative lesions. As a word of caution, it is
important to remember that immunohistochemistry in no way should replace conventional H&E morphology.
The consensus on how to best manage patients with atypical ductal hyperplasia diagnosed on core
needle biopsy still remains open biopsy. However, this appears to be changing and whether we recommend
an open biopsy for every patient with atypical ductal hyperplasia diagnosed on core needle biopsy will
depend on future outcome studies.
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- Brem RF, Behrndt VS, Sanow L, Gatewood OMB. Atypical ductal hyperplasia: Histologic underestimation of carcinoma in tissue harvested from impalpable breast lesions using 11-gauge stereotactically guided directional vacuum-assisted biopsy. AJR 1999; 172:1405-1407.
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