Recent Developments in Diagnostic and Therapeutic Approaches to Breast Diseases
Daniel W. Visscher, M.D.
Carol Reynolds, M.D.
Case 1D -
This core needle biopsy specimen was performed in a 52 year old woman with a subareolar
mass. Ultrasound showed a solid, homogenously hypoechoic mass. What is your diagnosis? What is your
Intraductal papilloma. Recommendation: If histopathologic findings and imaging
concordant and the patient is asymptomatic, then it may be appropriate to follow the patient and
recommend six month follow up.
Papillary lesions of the breast represent a spectrum of entities, both benign and
malignant, with different clinical presentations and imaging appearances. The prognosis depends on the
number of lesions and the presence of epithelial proliferation. There is little or no evidence that
women with single, central papillomas have a significant increased risk of developing breast carcinoma.
However, multiple papillomas may be associated with concurrent atypical ductal hyperplasia and in situ
carcinoma, thereby carrying an increased risk of subsequent malignancy.
The most common papillary lesion is the solitary intraductal papilloma. This benign neoplasm arises
in the major ducts in the periareolar or subareolar region and a common cause of clinically significant
nipple discharge. Microscopically, papillomas are composed of well-defined fibrovascular cores covered
by the usual two population of cells, although many times, the myoepithelium is not easily seen.
Apocrine metaplasia is often present as well as areas of fibrosis and sclerosis. The breast imaging
features of papillary cancer can overlap with those of the benign more common solid, central intraductal
The term intracystic papillary carcinoma, encysted noninvasive papillary carcinoma and in situ
papillary carcinoma are synonymous terms referring to malignant lesions with an underlying structure of a
papilloma. These tumors comprise approximately 1-2% of all breast carcinomas and are more common in the
older population. Grossly, intracystic papillary carcinomas are usually well circumscribed, encapsulated
and larger than benign intraductal papillomas. Microscopically, the tumor is well defined with a dense
collagenous fibrous capsule. The underlying tumor has a microscopic growth pattern that is predominantly
frond forming, but in some cases, the papillary structures may not be evident and the tumor may exhibit a
more solid papillary pattern. The distinction between a benign intraductal papilloma and papillary
carcinoma is determined by uniform cytology of the cells and architectural growth pattern. However, with
that said, papillary carcinoma arising in a papilloma is quite challenging diagnostically. These tumors
tend to retain areas of benign papilloma and contain a spectrum of epithelial proliferation from atypical
hyperplasia to carcinoma. Wide local excision is probably adequate therapy if no extension of in situ
carcinoma is beyond the main lesion. Invasive papillary carcinoma occurs infrequently and often is only
a small focus of stromal invasion. Solitary masses may be seen mammographically, sometimes with
satellite nodules. Mammographic distinction between invasive and intracystic carcinoma is difficult
because the small focus of invasion either is not detected or cannot be differentiated from the focal
irregular margin of some intracystic tumors.
The diagnosis of a papillary lesion on core needle biopsy ranges from 1.5-3.0%. Similar to the
finding of atypical lobular hyperplasia, lobular carcinoma in situ, and radial scar at core needle
biopsy, there is minimal data on clinical outcome when papillary lesions are diagnosed on core needle
biopsy. At present, there are only a few published studies and multiple abstracts that have addressed
this question. The studies correlating core needle biopsy and open biopsy have been contradictory and
most believe that the diagnosis of a papillary lesion by core needle biopsy is an indication for surgical
excision until more data is available.
In 1999, Liberman et al. retrospectively reviewed 1,077 consecutive core needle biopsies.
Thirty-four (3%) cases were diagnosed as a papillary lesion. Follow up was available in 26 (76.4%) of 34
cases. Twenty-two cases had surgical correlation and 4 cases had a minimum of two years mammographic
follow up. The histologic findings of the core needle biopsies of these 26 lesions were benign in 9
(34.6%), atypical in 10 (38.4%), and malignant in 7 (27%). Of the 9 lesions diagnosed benign, 7 were
papillomas and 2 showed papillomatosis. No carcinoma was identified at open surgical biopsy in the 7
lesions yielding benign papilloma at core needle biopsy. However, one (50%) of two cases diagnosed as
papillomatosis at core needle biopsy revealed ductal carcinoma in situ at excisional biopsy. Surgical
biopsy was recommended in this case due to the mammographic-histologic discordance. The 10 papillary
lesions with atypical hyperplasia, open surgical biopsy revealed atypical ductal hyperplasia in 5 (50%)
cases, benign findings without atypia in 2 (20%) cases, and intraductal carcinoma in 3 (30%) cases. Of
the 7 lesions yielding ductal carcinoma in situ at core needle biopsy, all cases had ductal carcinoma in
situ at open surgical biopsy with 3 (43%) cases also having invasive carcinoma. The diagnosis of large
benign papilloma from a noninvasive papillary carcinoma by core needle biopsy may on occasion cause
diagnostic difficulties. Nonetheless, the authors suggest that core needle biopsy can provide adequate
samples to differentiate between a papilloma and papillary carcinoma and that the diagnosis of a benign
papillary lesion can be reliable when concordant with the mammographic findings.
Ioffe et al. also examined the reliability of core needle biopsy in accurately diagnosing papillary
lesions. They identified 37 (2.8%) papillary lesions in 1,327 consecutive core needle biopsies. Of the
37 papillary lesions, 28 (75.6%) cases rendered a benign diagnosis, 4 (10.8%) cases revealed atypia, and
5 (13.5%) cases were malignant. Excisional biopsy was available in 8 of the 28 cases with a diagnosis of
a benign intraductal papilloma. Five (17.9%) of these 8 lesions were underestimated at core needle
biopsy. In situ carcinoma was identified in 3 cases and atypical ductal hyperplasia in 2 cases. Three
of the four lesions diagnosed at core needle biopsy as atypical went to open biopsy and all three were
underestimated at core needle biopsy. One case was ductal carcinoma in situ and 2 cases were invasive
carcinoma at open surgical biopsy. All 5 malignant lesions remained malignant at excisional biopsy. Due
to the high incidence of malignant or atypical lesions at excision of benign papillary lesion at core
needle biopsy, the authors suggested a more aggressive approach should be taken in the management of
A study at Mayo Clinic was undertaken to determine if it is justified to perform surgical excision on
all papillary lesions or whether there are morphologic features found at the time of core needle biopsy
that could be useful in determining which lesions should undergo surgical excision. Fifty-eight (2.8%)
papillary lesions were identified in 2,067 consecutive core needle biopsies. Surgical correlation was
available in 24 cases and a minimum of one year mammographic follow up was available in 30 cases, for a
total of 54 (93.1%) papillary lesions with surgical or mammographic follow up. Histologic review was
available in all 58 cases. Multiple morphologic features were assessed in the breast core biopsy and
included apocrine change, calcifications, sclerosis, hemosiderin deposition, necrosis and mitotic
activity. When present, the surrounding uninvolved breast tissue was evaluated. The surgical excisional
biopsy was evaluated for the presence or absence of a papillary lesion, presence or absence of a biopsy
site, lesion size, and similar histologic features assessed in the breast core needle biopsy.
The histology of the core needle biopsy revealed benign findings in 48 (82.8%) cases, atypical in 7
(12.1%) cases, and malignant in 3 (5.2%) cases. Of the 48 cases with a benign diagnosis at core needle
biopsy, 14 cases confirmed a benign process at open biopsy and 30 cases had mammographic follow up with
no change. Of the 10 cases diagnosed as atypical or malignant on core breast biopsy, all underwent
surgical excision. Eight cases showed ductal carcinoma in situ and two cases revealed invasive
carcinoma; no cases rendered an atypical or benign diagnosis. Of the morphologic features assessed,
sclerosis was significantly associated (p=0.0384) with a benign diagnosis at core needle biopsy. In
contrast, hemosiderin deposition and large lesion size was statistically significant (p=0.008) for
predicting malignancy. It is our opinion, that when concordant with imaging findings, the histology of
the breast core biopsy proves to be accurate in diagnosing a benign papillary lesion. The presence of
certain histologic features, such as sclerosis or hemosiderin deposition, may aid in the characterization
of the papillary lesion.
Ivan et al. recently reported that cellular monotony, lack of myoepithelial cells, and cytologic
atypia are the most precise histologic features that may help in predicting carcinoma and atypical
papillomas (p<0.0001) than mitotic activity. Overall and similar to previous studies, when the core
needle biopsy reveals atypical or malignant histologic findings, surgical excision is indicated. Most
importantly, all benign lesions with or without excisional biopsy were still benign at last study follow
up. This finding is similar to studies designed by Rosen et al. and Ivan et al. that reported when the
histologic diagnosis is benign and there is imaging-histologic concordance, these lesions may be safely
managed with imaging follow-up rather than with surgical excision. Lawton and Agoff in the recent USCAP
abstracts looked at 28 papillary lesions diagnosed on core needle biopsy. Their conclusion was that
benign papillary lesions can be accurately diagnosed on core needle biopsy. No benign papillary lesion
diagnosed on core needle biopsy was atypical or malignant at excisional biopsy or in long-term
clinical/imaging follow up. However, additional long-term studies are still required to evaluate the
clinical course of benign papillary lesions that are not excised after breast core needle biopsy.
As mentioned before, papillary lesions are problematic because studies correlating core needle biopsy
with open biopsy is contradictory. Below is a summary of all results of papillary lesions diagnosed on
core needle biopsy and surgical biopsy findings and/or mammographic follow up.
Summary of Surgical Biopsy Findings and Mammographic Follow Up in Women with Papillary Lesion at Core Needle Biopsy*
|Core Bx ||No. Excised/Mammo FU ||Excisional Biopsy|
|Benign ||Atypical ||Malignant|
|Benign ||162 ||148 (92%) ||7 (4%) ||7 (4%)|
|Atypical ||72 ||14 (20%) ||24 (33%) ||34 (47%)|
|Malignant ||35 ||0 ||1 (3%) ||34 (97%)|
*Liberman (1999), Ioffe (2000), Philpotts (2000), Bazzochia (2001), Mercado (2001), Rajendiran
(2001), Lawton (2004), Mayo Clinic (unpublished)
As you can see, the majority of papillary lesions diagnosed as benign remain benign at open biopsy or
mammographic follow up. However, there is a 8% chance of finding atypia or malignancy at open biopsy.
On the other hand, the finding of malignant papillary lesion at core needle biopsy is confirmed at open
biopsy. More importantly, it is strongly recommended that those papillary lesions diagnosed as atypical
be excised, since 80% will be found to have in situ or invasive carcinoma at open biopsy. Clinical
history including the age of patient and whether the patient is symptomatic together with imaging studies
as to the size of the lesion may prove to be helpful in management of papillary lesions diagnosed on core
needle biopsy. However, until more data becomes available, many studies recommend excision for all
papillary lesions even the papillary lesions with completely benign features on core needle biopsy.
A variety of studies have investigated the role of immunohistochemistry (p63 and cytokeratin 5/6) to
help improve accuracy of papillary lesions on core needle biopsy. Ali et al. examined the role of p63, a
nuclear transcription factor which is expressed in mammary myoepithelial cells, assess whether this
ancillary study could help in the diagnosis of papillary lesions on core needle biopsy. It was their
opinion that the amount of p63 immunostaining allowed a more confident distinction between benign and
atypical/malignant papillary lesions, but a potential for sampling error in benign papillomas remained.
Their final recommendation was to excise when there is focal epithelial proliferation in a papilloma with
decreased/absent p63 staining. In the recent USCAP abstracts, Nawgiri and colleagues studied the use of
cytokeratin 5/6 in papillary lesions. Thirty papillary lesions were diagnosed on core needle biopsy.
Cytokeratin 5/6 was evaluated in the luminal epithelial component and the myoepithelial component. Their
results shows that all (12/12) benign papillary lesions showed positive immunoreactivity with cytokeratin
5/6. In contrast, 70% of papillary lesions with atypia (7/10) and all cases (8/8) papillary carcinoma in
situ lacked cytokeratin 5/6 immunoexpression in the luminal epithelial component (p<0.001). However,
there was variable cytokeratin 5/6 expression in the myoepithelial component ranging from absent to
strong staining in the papillary lesions with atypia and carcinoma in situ. Overall, they claim there
might be some usefulness in applying cytokeratin 5/6 to papillary lesions on core needle biopsy to help
distinguish benign papillary lesions form atypical/in situ lesions. As with all ancillary tests used in
making a diagnosis, immunohistochemistry should not replace standard H&E morphology.
- Agoff SN and Lawton TJ. Papillary lesions of the breast with and without atypical ductal hyperplasia. Can we accurately predict benign behavior from core needle biopsy? AJCP 2004; 1222:440-443.
- Bazzocchi M, Berra I, Francescutti GE, Del Frate C, Zuiani C, Puglisi F, Di Loreto C. Papillary lesions of the breast: Diagnostic imaging and contribution of percutaneous needle biopsy with 14-gauge needle. Radiol Med 2001; 101:424-431.
- Berg WA, Hruban RH, Kumar D, Singh HR, Brem RF, Gatewood OMB. Lessons from mammographic-histopathologic correlation of large core needle breast biopsy. Radiographics 1996; 16:1111-1130.
- Dennis MA, Parker S, Kaske TI, Stavros AT, Camp J. Incidental treatment of nipple discharge caused by benign intraductal papilloma through diagnostic mammotome biopsy. AJR 2000; 174:1263-1268.
- Ioffe OB , Berg WA, Silverberg SG, Simsir A. Analysis of papillary lesions diagnosed on core needle biopsy of the breast: Management implications. Modern Pathology 2000; 13:23A.
- Ivan D, Selinko V, Sahin AA, Sneige N, Middleton LP. Accuracy of core needle biopsy diagnosis in assessing papillary breast lesions: Histologic predictors of malignancy. Mod Pathol 2003;16:34A.
- Jacobs TW, Connolly JL, Schnitt SJ. Nonmalignant lesions in breast core needle biopsies. To excise or not to excise? AJSP 2002; 26:1095-1110.
- Liberman L, Bracero N, Vuolo MA, Dershaw DD, Morris EA, Abramson AF, Rosen PP. Percutaneous large core biopsy of papillary lesions. AJR 1999; 172:331-337.
- Mercado CL, Hamele-Bena D, Singer C, Koenigsberg T, Pile-Spellman E, Higgins H, Smith SJ. Papillary lesions of the breast: Evaluation with stereotactic directional vacuum-assisted biopsy. Radiology 2001; 221:650-655.
- Nawgiri RS, Shepard-arry A, Naber S, Sharifi S. The value of cytokeratin 5/6 expression as a differentiating marker in the spectrum of papillary lesions of the breast. Modern Pathology 2004; 17:170(a).
- Philpotts LE, Shaheen NA, Jain KS , Carter D, Lee CH. Uncommon high risk lesions of the breast diagnosed at stereotactic core needle biopsy: Clinical importance. Radiology 2000; 216:831-837.
- Rajendiran S, Gupta D, Sumkin J, Johnson R, Nath M. Correlation of image guided core and excision biopsy in papillary lesions of the breast. Modern Pathology 2001; 14:34A.
- Renshaw AA, Derhagopian RP, Tizol-Blanco DM, Gould EW. Papillomas and atypical papillomas in breast core needle biopsy specimens. AJCP 2004; 122:217-221
- Reynolds HE. Core needle biopsy of challenging benign breast conditions: A comprehensive literature review. AJR 2000; 174:1245-1250.
- Rosen EL, Bentley RC, Baker JA, Soo MS. Imaging-guided core needle biopsy of papillary lesions of the breast. AJR 2002; 179:1185-1192.
- Siddiqui MT, Saboorian MH, Gokaslan ST, Peters G, Ashfaq. Pitfalls associated with a diagnosis of intraductal papilloma on needle core biopsy of the breast. Modern Pathology 2002; 15:52A.