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● Context.—The pathologist evaluating breast biopsy spec- lished English literature on physiologic and treatment-re-
imens sometimes encounters nonneoplastic alterations of lated changes of the breast epithelium was performed.
the mammary epithelium that raise the differential diag- Conclusions.—Among physiologic alterations of the duc-
nosis of atypia. Because the identification of atypical duc- tal epithelium, luteal-phase changes and secretory changes
tal hyperplasia of the breast has significant clinical impli- can sometimes be overinterpreted as atypical. Treatment-
cations, it is important to correctly recognize its nonneo- related changes, secondary to chemotherapy and radiation,
plastic morphologic mimics. can pose a major diagnostic challenge and their misinter-
Objective.—To highlight a spectrum of physiologic and pretation as neoplastic carries major clinical consequenc-
treatment-related changes that can occur in the mammary es. Familiarity with the morphology of both physiologic
epithelium and to discuss the differential diagnosis with and treatment-related alterations of the mammary epithe-
true atypia. lium is essential to avoid misdiagnosis.
Data Sources.—A comprehensive review of the pub- (Arch Pathol Lab Med. 2009;133:722–728)
are patent and lined by polarized cells, also showing lu- cur, but it is not considered part of fibrocystic disease.
teal phase changes. Exogenous hormones reduce the atrophic changes and can
Presence of mitoses, focal apoptosis, nuclear enlarge- result in epithelial hyperplasia, with appreciable mitotic
ment, and prominent nucleoli can be worrisome findings activity.3
on high-power examination. In these cases, the diffuse na-
ture of the epithelial changes, the prominent edema of the Secretory (Pregnancy-like) Changes
intralobular stroma, and the finding of a continuous layer Secretory (pregnancy-like) changes (SC) can occur in
of vacuolated myoepithelial cells are useful clues to the the breast independent of pregnancy status. These secre-
diagnosis. Luteal phase changes mimicking atypia should tory changes have also been reported in men taking ex-
always be in the differential diagnosis when examining a ogenous estrogen. The etiology of these changes is un-
specimen from young to premenopausal women. known and association with medications has been sug-
The postmenopausal breast consists for the most part of gested.
fibrous and adipose tissue with few scattered residual The lobules with SC resemble those of late pregnancy
ducts, acini, and vessels. Atrophy of the glandular com- and lactation, but the alteration is usually limited to only
ponent is normal with increasing age and is characterized 1 or 2 lobules. The affected acini are dilated and lined by
by loss of the glandular epithelium and increasing thick- a single layer of cuboidal to columnar cells with abundant
ness of the basement membranes, leading to progressive pale to clear cytoplasm, finely granular or vacuolated. The
obliteration of the acini. Cystification of the acini may oc- nuclei are typically small, round, and darkly stained (Fig-
Arch Pathol Lab Med—Vol 133, May 2009 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- show the typical colloidlike secretions, and necrosis and
men and impart a hobnail appearance to the cells. The mitoses can be seen. In contrast to CH-CIS, clear cell duc-
epithelium in the lobules usually consists of 2 cell layers tal carcinoma in situ is typically solid with associated ne-
but the myoepithelium is inconspicuous; rarely, hyperpla- crosis, and the cells have clear but nonvacuolated cyto-
sia can occur and is not worrisome. Secretory material is plasm; nuclei are hyperchromatic with clumped chromatin
often present within the distended lumina and can be- and prominent nucleoli.
come calcified, resulting in mammographically detectable Recently, Shin and Rosen4 showed a close relationship
deposits. No further treatment is necessary if secretory between SC and CHH. The authors reviewed 12 biopsy
changes are present in a core biopsy specimen and the specimens with SC and found coexisting CHH in 5 (42%).
findings are concordant with the imaging. Secretory changes histologically merged with CHH in 4
Coexistence of SC and cystic hypersecretory hyperplasia cases. Four biopsy specimens also showed cytologic atyp-
has been reported by Shin and Rosen,4 and is discussed ia, but no carcinoma in situ was identified.4
in the next section. The same authors have also reported a series of 9 cases
of SC and/or CHH adjacent to carcinoma in situ (7 CH-
Cystic Hypersecretory Hyperplasia CIS and 2 low-grade micropapillary ductal carcinomas in
Cystic hypersecretory hyperplasia (CHH) is regarded as situ, 1 of which was associated with invasive ductal car-
a benign proliferative lesion. Dilated cysts filled with ho- cinoma). In this series, the breast biopsies were performed
mogenous, eosinophilic, colloidlike secretions constitute for calcifications (6 cases), mass (2 cases), and nipple dis-
its hallmark feature. The characteristic secretions are usu- charge (1 case). Secretory changes merged with CHH in
ally acellular and often retract from the surrounding epi- 5 cases and were geographically distinct from it in 3, and
thelium, with a smooth or scalloped margin; they rarely 1 case showed SC only. All but 3 cases showed atypia in
undergo calcification and seldom contain histiocytes. The SC, CHH, or both. Six patients underwent mastectomy (2
cysts of CHH are lined by a single layer of flat, cuboidal, bilateral) and 2 underwent excision; 1 patient had incom-
or columnar cells with eosinophilic cytoplasm; myoepi- plete surgical history. The patient with invasive carcinoma
thelial cells are inconspicuous. The epithelial cells have had micrometastatic nodal disease, whereas no metastases
round to oval, monotonous, and bland nuclei (Figure 4). were found in 4 patients who underwent lymph node
Necrosis and mitoses are not found in CHH.5 staging. None of the patients had evidence of disease on
The differential diagnosis of CHH includes CHH with follow-up (range, 10 to 69 months).6 The authors conclud-
atypia and cystic hypersecretory carcinoma in situ (CH- ed that complete excision of the lesion is prudent when-
CIS), as well as clear cell ductal carcinoma in situ. Some ever CHH is seen on a core biopsy specimen to rule out
morphologic overlap exists in the spectrum of the cystic the possibility of focal carcinoma.4,6
hypersecretory lesions of the mammary epithelium. The
term cystic hypersecretory hyperplasia applies only to cysts Clear Cell Change
lined by monostratified, cytologically bland epithelial cells The descriptive term clear cell change applies to an al-
with low nuclear to cytoplasmic ratio. Increase in nuclear teration of the epithelium of the terminal duct lobular unit
to cytoplasmic ratio, mitotic figures, nuclear pleomor- characterized by cytoplasmic clearing. No specific etiology
phism, and/or prominent large nucleoli are features in- has been reported for this alteration.
dicative of cytologic atypia. Architectural atypia is typi- The cells usually have abundant cytoplasm, small dark
cally seen in the form of micropapillary growth. Greater nuclei, and no nucleoli. The myoepithelial cells are main-
extents of architectural complexity (solid, cribriform, and tained. Clear cell change usually constitutes an incidental
micropapillary growth) together with cytologic atypia are finding, limited to a lobule or only part of it, and rarely
required for the diagnosis of CH-CIS. The latter may not associates with calcifications (Figure 5, A and B). Clear cell
724 Arch Pathol Lab Med—Vol 133, May 2009 Nonneoplastic Epithelial Changes in the Breast—Murray
change is easily distinguished from clear cell carcinoma, necessary to avoid overcalling radiation-induced changes
as the latter is usually more extensive and shows mark- as carcinoma because this will result in mastectomy. On
edly atypical, enlarged, and hyperchromatic nuclei. the other hand, underdiagnosis of recurrent carcinoma as
Occasionally, it is the myoepithelium that shows a radiation-induced changes will delay appropriate treat-
prominent clear cell change, but it can be recognized be- ment of a potentially curable disease.
cause of its location between luminal epithelium and base- In the course of radiation for BCT, both neoplastic and
ment membrane. nonneoplastic breast tissue receive the same level of ex-
A lobule involved by clear cell changes can mimic atyp- posure. Radiation-induced changes are most apparent in
ical lobular hyperplasia or focal lobular carcinoma in situ. the terminal-duct lobular unit and less pronounced in the
The polygonal clear cells, though, are cytologically benign larger ducts.3,13,14 The alterations include fibrosis, lobular
and tightly cohesive, with sharply defined cell borders, atrophy, collagenization of the intralobular stroma, and
and the acinar lumen is typically preserved. Positive mem- thickening of the basement membrane. The epithelial cells
branous immunoreactivity for E-cadherin will decorate of lobules and terminal ducts show cytologic alterations
the cells with clear changes, but not lobular carcinoma in that can mimic atypia, including increased cell size, large
situ. pleomorphic nuclei, and often, prominent but small nucle-
oli (Figure 8). Irradiated nuclei are sometimes hyperchro-
TREATMENT-RELATED CHANGES matic but most often show uniform chromatin.15 In radi-
Estimates had indicated that more than 182 000 new cas- ation changes, the cells with enlarged nuclei are scattered
es of invasive breast cancer and an additional 67 000 cases and admixed with benign epithelium. The lobules are
of carcinoma in situ would require diagnosis and treat- atrophic and mitotic activity is absent. Finding of mitotic
ment in 2008.7 In the modern day and age, treatment of activity is suggestive of recurrent malignant disease. The
breast carcinoma usually consists of breast-conserving myoepithelial cells lining the acini tend to be preserved
therapy (BCT), including tumor excision and radiotherapy to a greater extent than the luminal cells and may be rel-
of the affected breast to eradicate any residual disease. atively prominent (Figure 9).
Studies have demonstrated that the outcome of BCT is Occasionally, fibrosis distorts the terminal-duct lobular
comparable to that of mastectomy.8,9 unit and obscures the myoepithelium. In lobules severely
Both radiation and chemotherapy can induce morpho- affected by radiation treatment, fibrosis may distort the
logic alterations in the breast epithelium; with the in- acini, resulting in a pseudoinfiltrative pattern13 (Figure
creased survival of patients with breast carcinoma, the pa- 10). Close attention to the presence of myoepithelial cells,
thologist must be familiar with the histologic changes in- atrophic epithelial changes, and lack of proliferative activ-
troduced by these therapies. Frequently, patients who un- ity help the pathologist to distinguish this pseudoinfiltra-
dergo prior BCT will require a posttreatment biopsy tive pattern from invasive carcinoma.
because of new clinically or radiologically detected lesions Atypical stromal fibroblasts are commonly encountered
within the breast. This is the most common setting in in irradiated breast (Figure 11). Nonspecific vascular
which the pathologist will encounter nonneoplastic epi- changes, such as intimal and myointimal proliferation of
thelial atypia secondary to treatment effect. small arteries and arterioles, mural hyalinization, and
prominence of capillary endothelial cells have also been
Chemotherapy described.13,15 Fat necrosis and squamous metaplasia are
Cytotoxic chemotherapy primarily affects the carcinoma also frequently encountered in postradiation biopsy spec-
but it also alters the nonneoplastic breast parenchyma, re- imens14 (Figure 12).
sulting in subtle changes. Following chemotherapy, the The aforementioned changes are typically described in
nonneoplastic breast parenchyma undergoes diffuse atro- breast biopsy specimens obtained long after radiotherapy,
phy, with reduced number of lobules and a decrease in but occasionally a breast biopsy specimen is obtained in
size of those remaining3,10 (Figure 6). Lobular atrophy con- the course of radiation or shortly after its completion be-
sists of a spectrum of changes ranging from concentric cause of suspicious radiologic findings (eg, new or resid-
thickening of the basement membrane to almost complete ual calcifications). The epithelial atypia present in early
fibrous obliteration and sclerosis of the acini. The residual posttreatment tends to be severe and diffusely involves the
glands are lined by flattened epithelium, but cytomor- breast epithelium (Figure 13). Severity and extent of the
phologic alterations may sometimes occur and mimic changes make interpretation of these findings even more
atypia. The epithelial cells are often enlarged and appear challenging. A very important point to remember is that
less uniform. The cytoplasm can be vacuolated, granular, the epithelial changes secondary to radiation do not in-
clear, or eosinophilic and, occasionally, the degree of vac- clude mitotic activity. In situ carcinoma persisting after
uolization can mimic that seen in histiocytes.11,12 Morpho- radiation treatment remains largely intact and the mor-
logic alterations in the epithelial cells include nucleome- phology of neoplastic cells in lobules or ducts is not sub-
galy, multinucleation, and prominent nucleoli10 (Figure 7). stantially different from that of the untreated tumor.3,16 Re-
Marked epithelial atypia is not a common finding and one current carcinoma in irradiated breast has a similar nucle-
should be cautious about interpreting any severe epithelial ar grade as that of the untreated tumor in 84% of cases16
alteration as secondary to chemotherapy effect in nonneo- (Figure 14). Therefore, in cases of suspected recurrent or
plastic epithelium. Morphologic comparison with the un- persistent carcinoma after BCT, comparison of the pre-
treated carcinoma is particularly helpful in this situation. treatment and posttreatment tissue sample is extremely
helpful.
Radiation Local recurrence tends to appear later in women treated
The pathologist is often challenged with the difficult with BCT than in those treated with mastectomy. In one
task of evaluating a breast biopsy specimen for a patient report, for example, the actuarial incidence of local recur-
who has previously received radiation therapy. Care is rence was 7%, 14%, and 20% at 5, 10, and 20 years, re-
Arch Pathol Lab Med—Vol 133, May 2009 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).
Figure 13. Early radiation-induced changes. A and B, Breast biopsy taken within 6 months of radiation treatment. Marked epithelial atypia is
present in a lobule and may be mistakenly overinterpreted as residual/recurrent carcinoma with lobular extension. Lack of mitoses and increased
cellularity are clues that the process is not neoplastic (hematoxylin-eosin, original magnifications ⫻400).
Arch Pathol Lab Med—Vol 133, May 2009 Nonneoplastic Epithelial Changes in the Breast—Murray 727
3. Rosen PP. Rosen’s Breast Pathology. 3rd ed. Philadelphia, PA: Lippincott 10. Kennedy S, Merino MJ, Swain SM, Lippman ME. The effects of hormonal
Williams & Wilkins; 2008. and chemotherapy on tumoral and nonneoplastic breast tissue. Hum Pathol.
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