Nonneoplastic Alterations of the Mammary Epithelium
Can Mimic Atypia
Melissa Murray, DO
● Context.—The pathologist evaluating breast biopsy spec-
imens sometimes encounters nonneoplastic alterations of
the mammary epithelium that raise the differential diag-
nosis of atypia. Because the identification of atypical duc-
tal hyperplasia of the breast has significant clinical impli-
cations, it is important to correctly recognize its nonneo-
plastic morphologic mimics.
Objective.—To highlight a spectrum of physiologic and
treatment-related changes that can occur in the mammary
epithelium and to discuss the differential diagnosis with
true atypia.
Data Sources.—A comprehensive review of the pub-
H istologic examination of tissue biopsy specimens re-
mains the cornerstone for the diagnosis of breast
diseases and it is essential for the pathologist to be famil-
iar with the spectrum of ‘‘normal’’ histologic alterations
of the mammary epithelium. The breast is a hormone-reg-
ulated organ and its morphology is greatly affected by
reproductive hormones. In addition to physiologic chang-
es, therapeutic interventions, such as chemotherapy and/
or radiation, also produce morphologic alterations. As
more patients with breast cancer undergo breast conser-
vation therapy and survival after breast cancer treatment
increases, pathologists will encounter treatment-related
changes of the breast. Knowledge of the histologic spec-
trum of both physiologic and treatment-induced alter-
ations of the breast is of foremost importance to avoid
diagnostic pitfalls. This review highlights some of the non-
neoplastic alterations of the mammary epithelium in the
differential diagnosis of true atypia.
PHYSIOLOGIC CHANGES
The breast undergoes physiologic changes during pu-
berty, pregnancy and lactation, menopause, and postmen-
opausal age. Furthermore, the cells of the mature mam-
mary lobules (myoepithelium and luminal/ductal cells)
Accepted for publication January 8, 2009.
From the Department of Pathology, Memorial Sloan-Kettering Cancer
Center, New York, New York.
The author has no relevant financial interest in the products or com-
panies described in this article.
Presented in part at the Surgical Pathology of Neoplastic Diseases
course, Memorial Sloan-Kettering Cancer Center, New York, New York,
May 12–16, 2008.
Reprints: Melissa Murray, DO, Department of Pathology, Memorial
Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065
(e-mail: murraym@mskcc.org).
722 Arch Pathol Lab Med—Vol 133, May 2009
lished English literature on physiologic and treatment-re-
lated changes of the breast epithelium was performed.
Conclusions.—Among physiologic alterations of the duc-
tal epithelium, luteal-phase changes and secretory changes
can sometimes be overinterpreted as atypical. Treatment-
related changes, secondary to chemotherapy and radiation,
can pose a major diagnostic challenge and their misinter-
pretation as neoplastic carries major clinical consequenc-
es. Familiarity with the morphology of both physiologic
and treatment-related alterations of the mammary epithe-
lium is essential to avoid misdiagnosis.
(Arch Pathol Lab Med. 2009;133:722–728)
undergo physiologic changes associated with the menstru-
al cycle.
During the follicular phase of the menstrual cycle, the
lobules are relatively small, and the acini are tightly clus-
tered. The specialized intralobular stroma is hypocellular
and appears slightly fibrotic. The luminal cells lining the
acini are small and polygonal, have pale cytoplasm and
dark, round, centrally located nuclei. These cells appear
crowded and nearly flattened and the acini show small or
collapsed lumina. No mitotic activity occurs in the normal
epithelium during this phase. The myoepithelial cells are
inconspicuous, often barely discernible on close inspec-
tion. As the menstrual cycle progresses, the myoepithe-
lium becomes more apparent and acquires vacuolated cy-
toplasm. Eosinophilic secretions also begin to appear
within the acinar lumen (Figure 1).
In the luteal phase, the lobules appear increased in size
compared with the proliferative phase. The specialized in-
tralobular stroma responds to progesterone stimulation by
becoming loose and edematous and is infiltrated by lym-
phocytes. The cytoplasm of the luminal cells usually ac-
quires a distinctive basophilic hue and shows polarized
morphology, with basally located nuclei and more prom-
inent apical cytoplasm. The nuclei are enlarged and prom-
inent, with conspicuous nucleoli. The acinar lumina are
open and contain secretions. Mitotic figures are frequent
in the luminal layer, as well as focal apoptosis (Figure 2).
In this phase of the menstrual cycle, the myoepithelial cells
also become more prominent and show abundant, vacu-
olated cytoplasm and small, round, centrally located nu-
clei.1,2 In some instances, the enlarged myoepithelial cells
with clear cytoplasm can mimic classical lobular carcino-
ma in situ, undermining normal luminal epithelium. In
this setting, however, the lobules are not expanded and
do not show increased cellularity and the acinar lumina
Nonneoplastic Epithelial Changes in the Breast—Murray
Figure 1. Follicular phase of the menstrual cycle. A lobule shows tightly clustered acini lined by polygonal cells with scant pale cytoplasm and
dark round nuclei (hematoxylin-eosin, original magnification ⫻400).
Figure 2. Luteal phase of the menstrual cycle. The luminal cells show enlarged nuclei with prominent nucleoli. Mitotic figures are commonly
seen. The intralobular stroma is loose and edematous (hematoxylin-eosin, original magnification ⫻600).
Figure 3. Secretory (pregnancy-like) changes. The acini are dilated and lined by a single layer of cuboidal cells with abundant clear cytoplasm.
The lobule resembles those of pregnancy or lactation (hematoxylin-eosin, original magnification ⫻400).
Figure 4. Cystic hypersecretory hyperplasia. Dilated cysts are filled with homogenous, eosinophilic secretion of colloidlike material. The cysts
are lined by a single layer of cuboidal or columnar cells (hematoxylin-eosin, original magnification ⫻400).

are patent and lined by polarized cells, also showing lu-
teal phase changes.
Presence of mitoses, focal apoptosis, nuclear enlarge-
ment, and prominent nucleoli can be worrisome findings
on high-power examination. In these cases, the diffuse na-
ture of the epithelial changes, the prominent edema of the
intralobular stroma, and the finding of a continuous layer
of vacuolated myoepithelial cells are useful clues to the
diagnosis. Luteal phase changes mimicking atypia should
always be in the differential diagnosis when examining a
specimen from young to premenopausal women.
The postmenopausal breast consists for the most part of
fibrous and adipose tissue with few scattered residual
ducts, acini, and vessels. Atrophy of the glandular com-
ponent is normal with increasing age and is characterized
by loss of the glandular epithelium and increasing thick-
ness of the basement membranes, leading to progressive
obliteration of the acini. Cystification of the acini may oc-
Arch Pathol Lab Med—Vol 133, May 2009
cur, but it is not considered part of fibrocystic disease.
Exogenous hormones reduce the atrophic changes and can
result in epithelial hyperplasia, with appreciable mitotic
activity.3
Secretory (Pregnancy-like) Changes
Secretory (pregnancy-like) changes (SC) can occur in
the breast independent of pregnancy status. These secre-
tory changes have also been reported in men taking ex-
ogenous estrogen. The etiology of these changes is un-
known and association with medications has been sug-
gested.
The lobules with SC resemble those of late pregnancy
and lactation, but the alteration is usually limited to only
1 or 2 lobules. The affected acini are dilated and lined by
a single layer of cuboidal to columnar cells with abundant
pale to clear cytoplasm, finely granular or vacuolated. The
nuclei are typically small, round, and darkly stained (Fig-
Nonneoplastic Epithelial Changes in the Breast—Murray 723
Figure 5. A, Lobule with clear cell change. The cells have abundant clear cytoplasm and small dark nuclei (hematoxylin-eosin). B, Clear cell
change. The myoepithelial cells are maintained, as highlighted by positive stain for calponin (immunoperoxidase stain) (original magnifications
⫻200 [A] and ⫻100 [B]).
ure 3). Sometimes the nuclei protrude into the gland lu-
men and impart a hobnail appearance to the cells. The
epithelium in the lobules usually consists of 2 cell layers
but the myoepithelium is inconspicuous; rarely, hyperpla-
sia can occur and is not worrisome. Secretory material is
often present within the distended lumina and can be-
come calcified, resulting in mammographically detectable
deposits. No further treatment is necessary if secretory
changes are present in a core biopsy specimen and the
findings are concordant with the imaging.
Coexistence of SC and cystic hypersecretory hyperplasia
has been reported by Shin and Rosen,4 and is discussed
in the next section.
Cystic Hypersecretory Hyperplasia
Cystic hypersecretory hyperplasia (CHH) is regarded as
a benign proliferative lesion. Dilated cysts filled with ho-
mogenous, eosinophilic, colloidlike secretions constitute
its hallmark feature. The characteristic secretions are usu-
ally acellular and often retract from the surrounding epi-
thelium, with a smooth or scalloped margin; they rarely
undergo calcification and seldom contain histiocytes. The
cysts of CHH are lined by a single layer of flat, cuboidal,
or columnar cells with eosinophilic cytoplasm; myoepi-
thelial cells are inconspicuous. The epithelial cells have
round to oval, monotonous, and bland nuclei (Figure 4).
Necrosis and mitoses are not found in CHH.5
The differential diagnosis of CHH includes CHH with
atypia and cystic hypersecretory carcinoma in situ (CH-
CIS), as well as clear cell ductal carcinoma in situ. Some
morphologic overlap exists in the spectrum of the cystic
hypersecretory lesions of the mammary epithelium. The
term cystic hypersecretory hyperplasia applies only to cysts
lined by monostratified, cytologically bland epithelial cells
with low nuclear to cytoplasmic ratio. Increase in nuclear
to cytoplasmic ratio, mitotic figures, nuclear pleomor-
phism, and/or prominent large nucleoli are features in-
dicative of cytologic atypia. Architectural atypia is typi-
cally seen in the form of micropapillary growth. Greater
extents of architectural complexity (solid, cribriform, and
micropapillary growth) together with cytologic atypia are
required for the diagnosis of CH-CIS. The latter may not
724 Arch Pathol Lab Med—Vol 133, May 2009
show the typical colloidlike secretions, and necrosis and
mitoses can be seen. In contrast to CH-CIS, clear cell duc-
tal carcinoma in situ is typically solid with associated ne-
crosis, and the cells have clear but nonvacuolated cyto-
plasm; nuclei are hyperchromatic with clumped chromatin
and prominent nucleoli.
Recently, Shin and Rosen4 showed a close relationship
between SC and CHH. The authors reviewed 12 biopsy
specimens with SC and found coexisting CHH in 5 (42%).
Secretory changes histologically merged with CHH in 4
cases. Four biopsy specimens also showed cytologic atyp-
ia, but no carcinoma in situ was identified.4
The same authors have also reported a series of 9 cases
of SC and/or CHH adjacent to carcinoma in situ (7 CH-
CIS and 2 low-grade micropapillary ductal carcinomas in
situ, 1 of which was associated with invasive ductal car-
cinoma). In this series, the breast biopsies were performed
for calcifications (6 cases), mass (2 cases), and nipple dis-
charge (1 case). Secretory changes merged with CHH in
5 cases and were geographically distinct from it in 3, and
1 case showed SC only. All but 3 cases showed atypia in
SC, CHH, or both. Six patients underwent mastectomy (2
bilateral) and 2 underwent excision; 1 patient had incom-
plete surgical history. The patient with invasive carcinoma
had micrometastatic nodal disease, whereas no metastases
were found in 4 patients who underwent lymph node
staging. None of the patients had evidence of disease on
follow-up (range, 10 to 69 months).6 The authors conclud-
ed that complete excision of the lesion is prudent when-
ever CHH is seen on a core biopsy specimen to rule out
the possibility of focal carcinoma.4,6
Clear Cell Change
The descriptive term clear cell change applies to an al-
teration of the epithelium of the terminal duct lobular unit
characterized by cytoplasmic clearing. No specific etiology
has been reported for this alteration.
The cells usually have abundant cytoplasm, small dark
nuclei, and no nucleoli. The myoepithelial cells are main-
tained. Clear cell change usually constitutes an incidental
finding, limited to a lobule or only part of it, and rarely
associates with calcifications (Figure 5, A and B). Clear cell
Nonneoplastic Epithelial Changes in the Breast—Murray
change is easily distinguished from clear cell carcinoma,
as the latter is usually more extensive and shows mark-
edly atypical, enlarged, and hyperchromatic nuclei.
Occasionally, it is the myoepithelium that shows a
prominent clear cell change, but it can be recognized be-
cause of its location between luminal epithelium and base-
ment membrane.
A lobule involved by clear cell changes can mimic atyp-
ical lobular hyperplasia or focal lobular carcinoma in situ.
The polygonal clear cells, though, are cytologically benign
and tightly cohesive, with sharply defined cell borders,
and the acinar lumen is typically preserved. Positive mem-
branous immunoreactivity for E-cadherin will decorate
the cells with clear changes, but not lobular carcinoma in
situ.
TREATMENT-RELATED CHANGES
Estimates had indicated that more than 182 000 new cas-
es of invasive breast cancer and an additional 67 000 cases
of carcinoma in situ would require diagnosis and treat-
ment in 2008.7 In the modern day and age, treatment of
breast carcinoma usually consists of breast-conserving
therapy (BCT), including tumor excision and radiotherapy
of the affected breast to eradicate any residual disease.
Studies have demonstrated that the outcome of BCT is
comparable to that of mastectomy.8,9
Both radiation and chemotherapy can induce morpho-
logic alterations in the breast epithelium; with the in-
creased survival of patients with breast carcinoma, the pa-
thologist must be familiar with the histologic changes in-
troduced by these therapies. Frequently, patients who un-
dergo prior BCT will require a posttreatment biopsy
because of new clinically or radiologically detected lesions
within the breast. This is the most common setting in
which the pathologist will encounter nonneoplastic epi-
thelial atypia secondary to treatment effect.
Chemotherapy
Cytotoxic chemotherapy primarily affects the carcinoma
but it also alters the nonneoplastic breast parenchyma, re-
sulting in subtle changes. Following chemotherapy, the
nonneoplastic breast parenchyma undergoes diffuse atro-
phy, with reduced number of lobules and a decrease in
size of those remaining3,10 (Figure 6). Lobular atrophy con-
sists of a spectrum of changes ranging from concentric
thickening of the basement membrane to almost complete
fibrous obliteration and sclerosis of the acini. The residual
glands are lined by flattened epithelium, but cytomor-
phologic alterations may sometimes occur and mimic
atypia. The epithelial cells are often enlarged and appear
less uniform. The cytoplasm can be vacuolated, granular,
clear, or eosinophilic and, occasionally, the degree of vac-
uolization can mimic that seen in histiocytes.11,12 Morpho-
logic alterations in the epithelial cells include nucleome-
galy, multinucleation, and prominent nucleoli10 (Figure 7).
Marked epithelial atypia is not a common finding and one
should be cautious about interpreting any severe epithelial
alteration as secondary to chemotherapy effect in nonneo-
plastic epithelium. Morphologic comparison with the un-
treated carcinoma is particularly helpful in this situation.
Radiation
The pathologist is often challenged with the difficult
task of evaluating a breast biopsy specimen for a patient
who has previously received radiation therapy. Care is
Arch Pathol Lab Med—Vol 133, May 2009
necessary to avoid overcalling radiation-induced changes
as carcinoma because this will result in mastectomy. On
the other hand, underdiagnosis of recurrent carcinoma as
radiation-induced changes will delay appropriate treat-
ment of a potentially curable disease.
In the course of radiation for BCT, both neoplastic and
nonneoplastic breast tissue receive the same level of ex-
posure. Radiation-induced changes are most apparent in
the terminal-duct lobular unit and less pronounced in the
larger ducts.3,13,14 The alterations include fibrosis, lobular
atrophy, collagenization of the intralobular stroma, and
thickening of the basement membrane. The epithelial cells
of lobules and terminal ducts show cytologic alterations
that can mimic atypia, including increased cell size, large
pleomorphic nuclei, and often, prominent but small nucle-
oli (Figure 8). Irradiated nuclei are sometimes hyperchro-
matic but most often show uniform chromatin.15 In radi-
ation changes, the cells with enlarged nuclei are scattered
and admixed with benign epithelium. The lobules are
atrophic and mitotic activity is absent. Finding of mitotic
activity is suggestive of recurrent malignant disease. The
myoepithelial cells lining the acini tend to be preserved
to a greater extent than the luminal cells and may be rel-
atively prominent (Figure 9).
Occasionally, fibrosis distorts the terminal-duct lobular
unit and obscures the myoepithelium. In lobules severely
affected by radiation treatment, fibrosis may distort the
acini, resulting in a pseudoinfiltrative pattern13 (Figure
10). Close attention to the presence of myoepithelial cells,
atrophic epithelial changes, and lack of proliferative activ-
ity help the pathologist to distinguish this pseudoinfiltra-
tive pattern from invasive carcinoma.
Atypical stromal fibroblasts are commonly encountered
in irradiated breast (Figure 11). Nonspecific vascular
changes, such as intimal and myointimal proliferation of
small arteries and arterioles, mural hyalinization, and
prominence of capillary endothelial cells have also been
described.13,15 Fat necrosis and squamous metaplasia are
also frequently encountered in postradiation biopsy spec-
imens14 (Figure 12).
The aforementioned changes are typically described in
breast biopsy specimens obtained long after radiotherapy,
but occasionally a breast biopsy specimen is obtained in
the course of radiation or shortly after its completion be-
cause of suspicious radiologic findings (eg, new or resid-
ual calcifications). The epithelial atypia present in early
posttreatment tends to be severe and diffusely involves the
breast epithelium (Figure 13). Severity and extent of the
changes make interpretation of these findings even more
challenging. A very important point to remember is that
the epithelial changes secondary to radiation do not in-
clude mitotic activity. In situ carcinoma persisting after
radiation treatment remains largely intact and the mor-
phology of neoplastic cells in lobules or ducts is not sub-
stantially different from that of the untreated tumor.3,16 Re-
current carcinoma in irradiated breast has a similar nucle-
ar grade as that of the untreated tumor in 84% of cases16
(Figure 14). Therefore, in cases of suspected recurrent or
persistent carcinoma after BCT, comparison of the pre-
treatment and posttreatment tissue sample is extremely
helpful.
Local recurrence tends to appear later in women treated
with BCT than in those treated with mastectomy. In one
report, for example, the actuarial incidence of local recur-
rence was 7%, 14%, and 20% at 5, 10, and 20 years, re-
Nonneoplastic Epithelial Changes in the Breast—Murray 725
Figure 6. Chemotherapy-related changes. Atrophy of lobules with decreased number of acini and concentric thickening of the basement mem-
brane (hematoxylin-eosin, original magnification ⫻100).
Figure 7. Chemotherapy-related changes. Isolated epithelial cells show enlarged nuclei. Thickening of the basement membrane is evident (he-
matoxylin-eosin, original magnification ⫻200).
Figure 8. Radiation-induced changes. The epithelial cells have enlarged hyperchromatic nuclei. No mitoses are seen. The myoepithelium is
maintained (hematoxylin-eosin, original magnification ⫻400).
Figure 9. Radiation-induced changes. Atrophy of epithelial cells and cytoplasmic clearing in the myoepithelium. A thickened basement membrane
surrounds the acini (hematoxylin-eosin, original magnification ⫻400).
Figure 10. Radiation-induced changes. Marked fibrosis induced by radiation can distort a lobule, resulting in a pseudoinfiltrative appearance
(hematoxylin-eosin, original magnification ⫻100).
Figure 11. Radiation-induced changes. Atypical stromal cells in irradiated breast tissue (hematoxylin-eosin, original magnification ⫻400).

726 Arch Pathol Lab Med—Vol 133, May 2009 Nonneoplastic Epithelial Changes in the Breast—Murray
Figure 12. Radiation-induced changes. Squamous metaplasia in ir- Figure 14. Recurrent carcinoma in an irradiated breast. Ductal car-
radiated breast tissue (hematoxylin-eosin, original magnification cinoma in situ arising in irradiated breast shows no radiation-induced
⫻200). changes (hematoxylin-eosin, original magnification ⫻200).

spectively, after BCT.17 Changes secondary to radiation SUMMARY

have been seen up to 20 years after treatment. One study
showed that the histologic changes induced in the non-
neoplastic breast tissue by radiation therapy showed no
significant progression or improvement during time inter-
vals as great as 229 months.13,14 Therefore, the pathologist
needs to be familiar with and watch for radiation-induced
changes in the nonneoplastic breast tissue even many
years after treatment.
When faced with epithelial atypia, which may be post-
treatment-related, it is necessary to inquire about possible
prior history of BCT; unfortunately, information regarding
prior radiation therapy, though extremely important, is not
always provided. Careful search for histologic evidence of
treatment effect in nonepithelial cells can help suggest a
prior breast radiation and avoid the overdiagnosing of ep-
ithelial changes as ductal carcinoma in situ, even though
stromal fibrosis alone has been shown to be a poor cor-
relate of evidence of treatment-related changes when com-
pared with biopsy specimens from nontreated patients.
The histomorphology of the breast parenchyma varies
with age and is under hormonal influence. Knowledge of
the physiologic changes that occur in the breast is essential
to distinguish them from pathologic alterations. Treat-
ment-related changes secondary to chemotherapy and/or
radiation may pose a major diagnostic challenge and their
misdiagnosis as neoplastic has serious clinical consequenc-
es. Because of the success of BCT, pathologists will see
increasing numbers of postradiation and/or chemothera-
py biopsy specimens. Familiarity with the morphologic al-
terations of the breast epithelium secondary to treatment
effect is thus extremely important to avoid misdiagnosis
of treatment-induced nonneoplastic changes, which can
persist many years after treatment.
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Figure 13. Early radiation-induced changes. A and B, Breast biopsy taken within 6 months of radiation treatment. Marked epithelial atypia is
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