Clinical:
Approximately 1%–3% of women with adenocarcinoma of the
breast have Paget disease. Clinically-Paget disease has common dermatitis-like appearance,
as originally described in 1874, when Sir James Paget recorded that such
lesions may resemble “ordinary chronic eczema” or present as nipple erosion or
ulceration. Paget disease often has a deceptively banal clinical morphology but
should lead the list of differential diagnoses when evaluating unilateral
lesions of the nipple–areola complex in adults.
Paget disease presenting with nipple erosion.
Most women with the histopathologic finding of Paget disease
have a clinical abnormality of the nipple. However, in at least 10% of affected
patients, Paget disease is found incidentally, during microscopic examination
of mastectomy specimens.
Underlying invasive ductal carcinoma or DCIS, detected in
more than 90% of patients with Paget disease, is multifocal in about 50% of
cases and does not necessarily occur near or contiguous with the nipple–areola
complex.
In addition, because of the practice shift from mastectomy
to breast-conserving surgery, a patient whose nipple–areola complex was spared
during surgery may present with Paget disease or epidermotropic metastatic
breast cancer to the nipple after diagnosis and treatment of primary breast
cancer.
Histopathology:
Paget disease is characterized by intraepidermal
infiltration with large cells that have abundant pale cytoplasm and
hyperchromatic nuclei often with prominent nucleoli.
Potential histopathologic pitfalls include pronounced
epidermal hyperplasia or denuded epithelium, sometimes mandating additional
biopsy. The latter is particularly problematic when Paget cells completely
separate from surrounding keratinocytes. Although this phenomenon has been
described as acantholysis, Paget disease cells do not have intercellular
connections with keratinocytes; they instead are tucked individually or in
clusters between normal epithelial cells.
When the appearance of acantholysis is pronounced, pemphigus
may be included in the differential diagnosis. Large acantholytic-like Paget
disease cells may mimic the cytopathic
effect of herpes simplex or varicella-zoster infection, particularly when their
nucleoli are inconspicuous.
Large, rounded,
“acantholytic” cells in Paget disease of the nipple
Intraepidermal
clefting and stromal inflammation in Paget disease of the nipple
Infiltration of
epithelium by pale cells and stromal inflammation in Paget disease involving
the areola
Immunohistochemical
stains often are necessary to confirm the diagnosis of Paget disease
because the differential diagnosis may
include SCC in situ, malignant melanoma in situ, and rarely other entities such
as Langerhans cell histiocytosis.
Pigmented Paget disease and pigmented epidermotropic
metastatic breast cancer have been reported. In contrast with melanoma,
pigmented Paget disease usually is negative for S100, Melan A, and HMB-45.
In contrast with SCC in situ, Paget disease cells typically
express low–molecular-weight keratins 7 and CAM 5.2 but not keratin 20 or
high–molecular-weight keratins.
Paget disease tends to be estrogen- and
progesterone-receptor negative and androgen-receptor positive, especially in
patients with high-grade underlying ductal carcinoma.
HER2 overexpression often is a feature of cases associated
with underlying ductal carcinoma.
Immunohistochemical
stain for keratin 7 highlights epithelial infiltration with Paget disease cells
Immunohistochemical
stain for Cam 5.2 highlights epithelial infiltration with Paget disease cells.
HER2 expression in
Paget disease.
The histopathologic
differential diagnosis also should include benign conditions characterized
by pale-clear intraepidermal cells; these
include pagetoid dyskeratosis,
thought to be due to chronic irritation of the nipples, and clear-cell papulosis, a rare eruption
affecting children that manifests as hypopigmented macules, mainly along milk
lines.
These 2 disorders of large pale cells usually are
distinguishable from Paget disease morphologically. Both are characterized by
pale cells with limited (if any) pleomorphism; these cells tend to be larger
than surrounding keratinocytes and are distributed singly or in small clusters
set neatly in an otherwise normal-appearing epidermis, without discohesion. The clear cells of pagetoid dyskeratosis
are positive for high–molecular-weight keratins, rather than low–molecular-weight
keratins. Clear-cell papulosis
typically has a profile similar to that of Paget disease, including expression
of keratin 7, CAM5.2, and lack of staining for estrogen receptor, but appears
to be negative for HER2.
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