Emedicine

Background

Sir James Paget first described Paget disease (PD) of the breast in 1874. He reported a chronic
eczematous disease on the skin of the nipple and the areola in 15 women, with an associated
intraductal carcinoma of the underlying mammary gland. In 1881, Thin illustrated the first
histologic description of PD.
Mammary PD occurs almost exclusively in women; involvement of the male breast is rarely
reported.[1] Patients with Paget disease frequently present with a chronic, eczematous rash on the
nipple and adjacent areolar skin. Proper recognition of this disorder is required to initiate an
appropriate workup (eg, skin biopsy) for differentiating it from other benign inflammatory
dermatoses and for detecting an underlying breast carcinoma.
A similar disease involving the skin of female and male external genitalia (ie, vulva, glans penis)
is known as extramammary Paget disease.[2] The histologic features of mammary PD and
extramammary PD are similar; however, the histogenesis and the pathogenesis are different.

Pathophysiology and Etiology

The pathogenesis of mammary PD and the origin of Paget cells were once controversial. It is
now widely accepted that mammary PD is always associated with an underlying carcinoma of
the breast. By thorough histologic examination, Muir documented intraepidermal extension of
malignant ductal epithelial cells through the lactiferous ducts and ductules into the epidermis
(epidermotropism).[3] The findings are the basis of the epidermotropic theory of mammary PD.
Malignant epithelial (Paget) cells infiltrate and proliferate in the epidermis, causing thickening of
the nipple and the areolar skin. These tumorous epithelial cells are derived from luminal
lactiferous ductal epithelium of the breast tissue (see the image below).

Schematic diagram of female breast depicting widely accepted concept of pathogenesis of

mammary Paget disease. Malignant Paget cells are derived from luminal lactiferous ductal
epithelium (A) of breast tissue with retrograde extension of cancerous Paget cells into epidermis
of overlying nipple (B). Enlarged circle shows details that reveal thickening both of lining
epithelium of breast duct and of nipple skin.
The cells possess microscopic features of glandular cells. Paget cells and underlying ductal
carcinoma cells have been shown to be positive for the oncogene HER2/neu, suggesting common
genetic alterations for both the epidermal and breast tumor cells.
It has been speculated that Paget cells may derive from glandular stem cells or epidermal Toker
cells (clear cells of the nipple epithelium).[4] Toker cells have been found in about 10% of normal
nipples and rarely in supernumerary nipples on the mild line and apocrine bearing areas.[5] Like
Paget cells of both mammary and extramammary sites, Toker cells contain prominent clear
(vacuolated) cytoplasm, and they are considered benign counterparts of Paget cells.
Mammary Paget cells are malignant epithelial cells derived from underlying ductal
adenocarcinoma of the breast that invade into the skin of nipple and areolar areas. Toker cells are
benign and may sometimes proliferate, resulting in a condition known as clear cell papulosis.[5]
Kuan et al[6] reported on the immunohistochemical expression of apomucin MUC1, MUC2, and
MUC5AC in PD and concluded that both epidermal Paget cells and underlying ductal carcinoma
exhibit the same phenotypic apomucins that are also expressed by the Toker cells.
Morandi et al[7] reported that the chromosomal alterations seen in Paget cells (eg, loss of
heterozygosity and mitochondrial DNA displacement loop sequence analysis) are different from
those seen in underlying breast carcinoma cells. They suggested that the epidermal Paget cells
are genetically different from those of breast carcinoma.

A concept of a collision between the neoplastic lesion of mammary PD and the underlying
carcinoma is therefore presented. However, this concept is based on only a few cases. Further
studies are necessary to arrive at a more definitive conclusion concerning collision lesions.
Paget cells often express cell markers that mimic those of the underlying breast carcinoma,
including glandular epithelial cell markers (eg, low-molecular-weight cytokeratins or cellular
adhesion molecule [CAM] 5.2).
They also express tumor markers, including carcinoembryonic antigen (CEA); Ca 15-3 (milk fat
globule protein); oncogenes (TP53,c-erb B-2; about 85% of cases tested for c-erb B-2 are
positive); and other cell markers, such as epithelial membrane antigen (EMA; all cases tested are
EMA positive) and gross cystic disease fluid protein (GCDFP-15) found in tumor cells of ductal
carcinoma of the breast.
Paget cells also share similar immunohistochemical characteristics with eccrine and apocrine
sweat gland epithelium. Paget cells are periodic acid-Schiff (PAS) positive and diastase resistant;
and they are Alcian blue positive at pH 2.5 in 32% and 18%, respectively.
Advances in immunohistochemistry further define the histogenesis of Paget cells. Cytokeratin 7
(CK7) has been proposed as a specific and nearly 100% sensitive marker for mammary PD;
whereas cytokeratin 20 (CK20) is negative in mammary Paget cells, about 33% of cases of
extramammary PD express this marker.
The mechanism by which large neoplastic cells of glandular origin (ie, the Paget cells) infiltrate
and spread to the overlying epidermal layers of the nipple and adjacent areola is induced by a
mobility factor (heregulin-alpha) that acts through the HER2/neu receptor.[8]
Normal epidermal keratinocytes produce and release heregulin-alpha. This factor plays a
significant role in the pathogenesis of PD. Paget cells express heregulin receptors HER2/neu and
coreceptors HER3 and HER4. These receptor complexes on Paget cells bind heregulin-alpha, the
mobility factor, resulting in the chemotaxis of breast ductal carcinoma cells. This process, in
turn, causes migration and infiltration of Paget cells into the overlying epidermis of the nipple
and the areolar skin.
Molecular studies have shown that abnormal plakoglobin (one of the cell-to-cell adhesion
proteins) may be involved in the formation of some cases of PD of the breast and the vulva; and
reduced expression of E-cadherin (another cell-cell adhesion protein) may have a role in the
pathogenesis of extramammary PD.[9]

Epidemiology
In the United States, about 1-4% of female breast carcinoma cases are associated with PD of the
nipple, the areola, and the surrounding skin; nearly 100% of mammary PD cases are associated
with an underlying carcinoma, either in situ (intraductal, 10%) or infiltrating cancer (90%).
Occasional cases of PD have been reported in ectopic breast or supernumerary nipples.[10]
Worldwide, t he exact frequency of mammary PD is unclear.

In female patients with mammary PD, ages range from 24 to 84 years, with a mean age at
diagnosis of 55 years; the average age range is 53-59 years. The average patient age is 5-10 years
older for patients with mammary PD than for individuals with breast carcinoma. The age of onset
in male patients is generally in the fifth and sixth decades, with a range of 48-80 years.
Mammary PD occurs almost exclusively in females; PD of the male breast is extremely rare. The
estimated occurrence of male breast carcinoma is only 1% of the rate in females. A rare case of
PD in the male breast was recorded after treatment of a prostate carcinoma with estrogen. No
racial predisposition is reported for mammary PD.

Prognosis
The prognosis for patients with mammary PD is related to disease stage and appears to be similar
to that of women with other types of breast cancer.
Survival is related to the presence or the absence of a palpable breast tumor. When present, the
prognosis is the poorest.[11] In one study, 31 (62%) of 50 patients with mammary PD presented
with a detectable breast mass.
One half (50%) of patients with PD presenting with a palpable breast mass have associated
axillary lymph node metastasis. Two thirds of patients with axillary node metastasis were
reported to have a palpable breast mass, whereas one third of patients with axillary metastasis did
not have a palpable mass.
Even in patients with mammary PD and no underlying tumor, 30% may develop an invasive
carcinoma at a later date, and 20% of patients already have an associated in situ carcinoma of the
breast. However, other reports indicate that no axillary metastases were detected in patients
without a palpable breast mass.
Patients with an identifiable associated underlying breast tumor have a survival rate of 38-40% at
5 years and a survival rate of 22-33% at 10 years. The death rate for metastatic breast carcinoma
in patients with mammary PD and underlying cancer is 61.3%, with a 10-year cumulative
survival rate of 33%.
The reported survival rate of patients with PD without a palpable breast tumor (prior to surgery)
ranges from 92% to 94% at 5 years and from 82% to 91% at 10 years.
Mastectomy is the standard treatment of mammary Paget disease. Conservative treatment with
preservation of the nipple-areola complex results in a higher rate of recurrence than treatment by
mastectomy.
A small number of patients with mammary PD who did not have a palpable breast mass and who
had a negative mammogram underwent conservative excision of the involved nipple-areola with
a wedge resection of the underlying breast tissue and remained disease free at 10-year follow-up.

Rare cases of recurrent mammary PD have been reported in patients who underwent partial
nipple excision; however, no patient developed breast parenchymal recurrence at a mean followup of 36 months.
In a study of patients with mammary PD (without clinical or mammographic evidence of breast
tumor) who were treated with radiation therapy alone or excision plus radiation, 3 of 20 patients
developed recurrent disease in the nipple-areola at a mean follow-up of 7.5 years. Those patients
eventually underwent a mastectomy.
According to Osteen,[12] 9 (11.4%) of 79 patients treated by local excision (with or without
radiation therapy) developed recurrences.

Patient Education
Patients should be informed that PD of the nipple-areola complex is a rare form of breast cancer
that is clinically characterized by eczematous changes in the nipple. Clinical symptoms include
erythema, itching, a burning sensation, thickening of the skin, inversion of the nipple, and
sometimes a bloody nipple discharge. Usually, symptoms are present for 6 months or more
before the detection of an underlying breast cancer. A biopsy should promptly be performed on
all suspicious lesions of the nipple area for accurate diagnosis and treatment.
Failure to educate patients about the potential for invasive breast carcinoma associated with
mammary PD is a pitfall; without this knowledge, patients may delay further diagnostic
mammography examination and possibly delay detection of an underlying breast cancer.
For patient education resources, see the Womens Health Center and the Cancer and Tumors
Center, as well as Breast Lumps and Pain, Breast Self-Exam, Breast Cancer, and Mastectomy.

History
Patients with mammary Paget disease (PD) present with a relatively long history of an
eczematous skin lesion or persistent dermatitis in the nipple and adjacent areas.[13] Eczematous
skin lesions are associated with several symptoms, including the following:

Erythema
Scaling
Itching
Burning sensation
Ulceration
Oozing with serosanguineous discharge
Bleeding
Some combination of the above symptoms

Early symptoms and signs of mammary PD include the following:

Excoriation from itching

Resolution and recurrence of small vesicles within the skin lesion

Symptoms of pain, itching, and a burning sensation prompt patients to seek medical attention.

Physical Examination
Scaly, erythematous, crusty, and thickened plaques on the nipple, spreading to the surrounding
areolar areas, are typical (see the images below). Axillary PD can arise from underlying axillary
accessory breast tissue.[14]

Biopsy-proven Paget disease

involving nipple of 56-year-old woman. Patient noted erythematous, swollen, enlarged nipple
with focal ulceration and oozing; occasional serosanguineous discharge and bleeding were
present. Patient was later found to have palpable breast mass and mammography results positive
for subareolar microcalcification; no auxiliary lymphadenopathy was found. Patient was treated
by simple mastectomy. At 5-year follow-up, she was alive, without recurrent or metastatic
tumor.

Mammary Paget disease (PD)

affecting 48-year-old woman. Patient had experienced prolonged history of chronic eczematous
dermatitis of nipple and areolar area for several years. Lesion did not respond to topical
treatment, and it progressively distorted nipple with expansion into surrounding skin. Note
markedly scaly, crusted, and deformed nipple with thickened, irregularly outlined adjacent
nipple-areola complex. Excisional biopsy confirmed diagnosis of mammary PD. Patient
developed infiltrating ductal carcinoma of underlying breast tissue with axillary lymph
metastasis. She was treated by mastectomy and radiation. No metastatic tumor was noted in
axillary lymph node. Patient was alive and well 3 years after treatment.
An erythematous patch in mammary PD is usually sharply demarcated and infiltrated (unlike
eczematous dermatitis). Retraction of the nipple or the presence of palpable nodules indicates an
underlying breast cancer. Serosanguineous discharge from the nipple may be present. Lesion size
ranges from 3 mm to 15 cm in diameter; the mean size is 2.8 cm in diameter. Nipple invagination
is sometimes seen (see the image below).

Nipple invagination, deformed

nipple-areola complex, marked erythema, and alternating hyperpigmentation and
hypopigmentation noted in adjacent skin of breast in 65-year-old woman with biopsy-proven
Paget disease. Note focal scaling of previous biopsy site. Nipple changes were associated with
intraductal carcinoma of breast. Patient was treated by conservative excision of lesion and
lumpectomy for in situ carcinoma. No recurrence or metastatic disease was noted at 6-year
follow-up.
Nipple changes are associated with an underlying carcinoma of the breast (ie, in situ, infiltrating
ductal carcinoma) in more than 98% of patients; as many as two thirds of patients have a
palpable breast tumor.
Unilateral involvement is the rule; however, bilateral mammary PD has occasionally been
reported.[15] Rare cases of female patients with PD of supernumerary nipples have been
reported.[16]
Pigmented mammary PD and pigmented extramammary PD are rare clinical entities in both
males and females. These diseases may mimic malignant melanoma both clinically and
histopathologically. They may also mimic melanoma on dermatoscopic examination.[17] In
pigmented lesions of PD, increased numbers of benign melanocytes are present, which may
interfere with the correct diagnosis of PD, resulting in misinterpretation of this condition as
malignant melanoma.[18]

Diagnostic Considerations
Proper recognition of mammary Paget disease (PD) is required to initiate an appropriate workup
(eg, skin biopsy) for differentiating it from other benign inflammatory dermatoses and for
detecting an underlying breast carcinoma. Early dermatologic consultation and a tissue biopsy of
the lesion on the nipple and/or the areolar area are necessary for accurate diagnosis of mammary
PD. Regular mammographic examinations aid in early detection of in situ and invasive breast
cancer. A new development in the diagnosis of mammry Paget disease is the use of reflectance
confocal mircroscopy, which Guitera et al concluded is likely to facilitate earlier diagnosis of

Paget's disease and the instigation of appropriate management with concomitant improvement in
clinical outcomes.[19]
Other problems to be considered include the following:

Nipple duct adenoma

Erosive adenomatosis of the nipple (a benign neoplasm of the major nipple ducts)
Benign Toker cell (clear cell of the nipple epidermis) hyperplasia
Malignant melanoma in situ

Differential Diagnoses

Bowen Disease
Cutaneous Melanoma
Drug Eruptions
Irritant Contact Dermatitis
Nodular Localized Cutaneous Amyloidosis

Mammography
Radiographic changes seen in mammary Paget disease (PD) include the following:

Subareolar microcalcifications (helpful in evaluating and locating clinically occult, nonpalpable

underlying breast carcinoma)
Architectural distortion
Thickening of the nipple and the areola (reflecting edema)
Nipple changes (in a minority of patients)

About 50-70% of patients with biopsy-proven mammary PD show positive findings on

mammography; image-guided biopsy is assisted by positive results on mammography.
Ninety-four percent of patients with biopsy-proven PD as the only physical finding had an
underlying carcinoma, and nearly 60% had unifocal disease. However, negative preoperative
mammography findings did not reliably exclude an underlying carcinoma. Statistical evidence
suggests that in the setting of negative mammography findings, magnetic resonance imaging
(MRI) of the involved breast can detect otherwise occult PD and thus facilitate treatment
planning for patients with PD.[20]

Tissue Analysis
Scrape cytology

Scrape cytology has been suggested as a noninvasive and reliable, rapid diagnostic screening
method for mammary PD. Scrape the affected area of the nipple with a glass slide or a wooden
spatula and stain the smears with Papanicolaou or Giemsa stain. The presence of large cells with

a high nuclear-to-cytoplasmic ratio, occasional acinar formation, and intracytoplasmic vacuoles

is diagnostic for malignant Paget cells.
Using histochemical staining methods for the presence of epithelial mucin and
immunoperoxidase stains (eg, anti-carcinoembryonic antigen [CEA]) enhances cytologic results
and confirms the diagnosis of mammary PD. Drying artifact on the microscopic slides may
produce both false-positive and false-negative results.
Biopsy

Punch, wedge, or excisional biopsy of the lesional skin of the nipple-areola complex to include
the dermal and subcutaneous tissue for detailed microscopic examination provides an adequate
sample for the accurate diagnosis of mammary PD.

Histologic Findings
Common histologic features of Paget disease

Several variants of PD of the breast show identical histopathologic features. The epidermis
exhibits hyperkeratosis, parakeratosis, and acanthosis. Infiltration occurs by variable numbers of
large, rounded or ovoid, signet-ring forms and sometimes mucin-positive, malignant-appearing
tumor cells that are present in all layers of the epidermis. The tumor cells contain abundant palestaining or sometimes eosinophilic cytoplasm and large vesicular-to-hyperchromatic nuclei with
prominent nucleoli (see the images below).

Photomicrograph of mammary Paget

disease lesion. Note nests of malignant Paget cells predominantly involving lower layers of epidermis.
Cytoplasm of tumor cells contains abundant pale-staining, granular, mucinous material. Occasional small
glandular structures can be seen within malignant cell nests (hematoxylin-eosin, 100).

Composite photomicrograph of
mammary Paget disease depicting nests, islands, and individual tumor cells in epidermis (left;
hematoxylin-eosin, 250), along with tumor cells stained positive for carcinoembryonic antigen (CEA)
(right; immunostain with anti-CEA, 250).

The malignant cells infiltrating the epidermis of the nipple are CK7 positive, exhibiting a typical
invasive shotgun pattern. Epidermal keratinocytes are negative for CK7.
Mitotic figures are occasionally identified. The cytoplasm may contain periodic acid-Schiff
(PAS)positive, diastase-resistant granules, indicating the presence of neutral
mucopolysaccharides. Less often, acid mucopolysaccharides (sialomucin) may be identified by
Alcian blue reaction at pH 2.5, but not at lower pH (0.4) or by aldehyde Fuchsin.
Melaninlike pigment that is dihydroxyphenylalanine (DOPA)-negative is occasionally noted.
Paget cells are devoid of intercellular bridges on hematoxylin and eosin (H&E)stained sections.
They often compress the basal keratinocytes that lie between the Paget cells and the papillary
dermis. Paget cells are arranged singly or in a nested pattern, with occasional ductal formations.
Masses of large cells with numerous mitoses are observed in the advancing border of mammary
PD. In the ulcerated lesions of mammary PD, the epidermis is totally replaced by Paget cells.
Paget cells do not invade the dermis directly; however, they frequently extend along the
follicular and sweat gland epithelia.
A large biopsy or excision may demonstrate the presence of epidermal Paget cells and an
underlying infiltrating or intraductal carcinoma of the breast. The epidermal involvement by
Paget cells is not always immediately adjacent to an underlying breast carcinoma.
Types and characteristics of Paget cells

The several histologic variants of PD are as follows:

Adenocarcinomalike cell type - Cells are columnar similar to an adenocarcinoma metastasizing

to the skin.

Spindle cell type - Tumor cells are angular, elongated, arranged in a nested pattern, and grow in
compact masses.
Anaplastic cell type - Cells resemble those seen in Bowen disease. Pleomorphic tumor cells may
be present in a full-thickness, distorted epidermis; a nested pattern is usually not present.
Apoptotic (necrotic) tumor cells, mitotic figures, and multinucleated tumor cells are common.
Acantholysis with cleft formation are helpful features. Positive immunoperoxidase staining for
the presence of markers, such as CEA, epithelial membrane antigen (EMA), and c-erb B-2, favors
a diagnosis of mammary PD and militates against a diagnosis of Bowen disease.
Acantholytic cell type - This subtype may overlap with the anaplastic variant. Prominent
acantholysis may lead to the misinterpretation of mammary PD as an acantholytic disorder
involving the skin of the nipple and the areola.
Pigmented cell type - Rare cases of pigmented mammary PD have been reported. [21] The
pigmented Paget cells are DOPA negative. The melanin pigment is transferred from the
melanocytes into the malignant Paget cells. The number of melanocytes is not increased in
these lesions. A reticulated variant of pigmented PD has recently been described. [22]

Tumorous Paget cells are negative for estrogen and progesterone receptor sites, though one half
of breast carcinomas are positive for these hormone receptors. In cases of positive estrogen and
progesterone receptors in an underlying breast carcinoma, the overlying Paget disease is negative
for these receptors. Paget cells are negative for mammary gland markers, such as lysozyme, kcasein, and alpha-lactalbumin.
The dermis contains a dense infiltrate of lymphocytes, histiocytes, plasma cells, and occasionally
eosinophils.
The ultrastructural features of Paget cells are those of glandular epithelial cells. The pale
cytoplasm of Paget cells lacks the dense CK filaments and keratohyalin granules of
keratinocytes. Numerous free ribosomes, lysosomes, enlarged mitochondria, prominent smooth
and rough endoplasmic reticulum, tonofilaments, Golgi membranes, and microvilli are present
on the cell membrane (see the image below).

Low-power view of transmission

electron micrograph displaying malignant Paget cells in lower layer of epidermis. Note large Paget cell
containing ovoid nucleus (N), scanty nuclear chromatin, large nucleolus, and abundant pale-staining

cytoplasm with smooth and rough endoplasmic reticulum (arrow), scattered enlarged mitochondria,
free ribosomes, and lysosomes. No desmosomal attachments are seen between Paget cells and adjacent
keratinocytes. Tonofilaments are seen in keratinocytes (uranyl acetate and lead citrate, 5,500).

Desmosomal attachments between Paget cells and adjacent keratinocytes are fewer and smaller
than those between keratinocytes. Paget cells do not directly contact the basal lamina, and no gap
junctions or tight junctions are present.
The cytoplasm of Paget cells contains numerous rounded, membrane-bound mucin granules of
varying electron density (see the image below).

Cytoplasm of malignant Paget cell is

packed with numerous rounded, membrane-bound mucin granules with various electron densities
(uranyl acetate and lead citrate, 12,000.)
Histologic features distinguishing Paget disease

The intraductal carcinoma underlying mammary PD typically shows distended lactiferous ductal
lumen by pleomorphic tumor cells with hyperchromatic nuclei, a high nuclear-to-cytoplasmic
ratio, and a frequent gland-in-gland (cribriform) pattern (see the image below).

Photomicrograph of intraductal carcinoma of breast

underneath Paget disease of nipple in 56-year-old woman. Note expansion of ductal lumen, which is
filled with irregularly sized tumor cells of ductal epithelial origin. Nuclear hyperchromatism and gland-ingland (cribriform) pattern are evident. Tumor was detected by positive mammogram result depicting
focus of microcalcification beneath nipple.

Both allergic contact dermatitis and irritant contact dermatitis and fixed drug eruption of the
nipple-areola complex show histologic features of an inflammatory dermatosis. No Paget cells
are seen in these conditions.
Nipple duct adenoma or erosive adenomatosis of the nipple may mimic mammary PD clinically;
however, the histologic features of the former are those of a benign neoplasm of the major nipple
ducts. The adenoma cells are negative for c-erb B-2, which is positive in 85% of cases of PD
tested.
The following 2 histologic features differentiate Paget cells from melanoma cells:

Paget cells are situated suprabasally above flattened basal keratinocytes with occasional ductal
formation, whereas melanoma cells are located in the basal epidermis and all layers of the
epidermis, the so-called intraepidermal pagetoid spread (see the image below)
Paget cells are not present freely in the dermis, whereas melanoma cells are capable of invasion
into the dermis. An intraductal or infiltrating ductal carcinoma of the breast can be seen in
association with mammary Paget disease.

Photomicrograph of malignant
melanoma in situ of skin displays prominent intraepidermal pagetoid spread. Note that
melanoma cells are present in all layers of epidermis, mostly in single units. Cytoplasm of
melanoma cells is vacuolated. Moderate upper dermal chronic inflammatory infiltrate is present
(hematoxylin-eosin, original magnification 250). S-100 protein and homatropine
methylbromide immunostains are positive in melanoma cells, whereas carcinoembryonic
antigen is negative. No epithelial mucin is seen in these tumor cells.
Immunohistochemistry

Immunohistochemistry allows definitive diagnosis of mammary PD. Paget cells can be

demonstrated by immunohistochemical methods using several antibodies to cell surface and
cytoplasmic markers (eg, low-molecular-weight keratins found in simple epithelia, EMA, c-erb
B-2, polyclonal pCEA+).[23]
Paget cells differ from melanoma cells by negative cytoplasmic epithelial phenotype markers
(including pancytokeratin), positive homatropine methylbromide (HMB-45), and positive MelanA (Mart-1) activity in the melanoma cells.[9] Paget cells show negative staining by anti-S-100
protein, which serves as a differentiating feature from malignant melanoma in situ. Most Paget
cases are positive for cytokeratin 7 (CK7) and gross cystic disease fluid protein (GCDFP-15).
Toker (clear) cell hyperplasia of the nipple and the areola is a benign condition without welldefined clinical manifestations. Unlike the Paget cells, the large clear cells do not contain
epithelial mucin, and no association with an underlying breast carcinoma exists. Benign Toker
cells are positive for CK7[24] but negative for CEA and S-100 protein.
The similarity of the immunophenotypes suggests that Toker cells may be the origin of
intraepithelial Paget cells.[5] In cases of florid papillomatosis of the nipple, some CK7-positive
cells may be found in the epidermis, a pitfall to be aware of when diagnosing PD of the nipple.
Furthermore, the intraepidermal portion of the nipple ducts can be a pitfall for intraepidermal
CK7-positive cells.

Pagetoid squamous cell carcinoma in situ (Bowen disease) of the breast is rare, and it can be
distinguished from Paget disease by negative CK7, positive K903, and positive p16 activity in
the former and the reverse result for these antibodies in the latter. CEA is positive in Paget cells
and negative in keratinocytes, thus differentiating Paget disease from Bowen disease.
Pseudo-Paget disease may, on occasion, be seen in the major nipple ducts. Large histiocytes
infiltrate the epithelium and impart a histologic pattern mimicking Paget disease. The large cells
are CK7 negative and strongly positive for CD68.

Staging
Mammary Paget disease has been classified into 4 clinical stages.

Stage 0 - Lesion confined to the epidermis, without underlying in situ ductal carcinoma of the
breast
Stage 1 - Associated with in situ ductal carcinoma just beneath the nipple
Stage 2 - Associated with extensive in situ ductal carcinoma
Stage 3 - Associated with invasive ductal carcinoma

Of all patients with mammary PD, 40-50% have either stage 1 disease or stage 2 disease. These
patients have no palpable breast tumor. A palpable breast tumor is a rule in stage 3; more than
half of patients have coexisting axillary lymph node involvement. Patients with breast carcinoma
previously treated by local excision and radiation therapy may present with PD of the nipple.

Surgical Management
Mastectomy (radical or modified) and lymph node clearance are appropriate therapies for
patients with mammary Paget disease (PD) with a palpable mass and underlying invasive breast
carcinoma.[25] As many as two thirds of patients are reported to have axillary lymph nodes
positive for metastasis. Noninvasive breast carcinoma (in situ carcinoma) is found in about 65%
of patients with mammary PD without a palpable mass.
Conservative management includes a combination of local excision of the nipple, wedge
resection of the underlying breast, and radiation therapy. The number of patients treated by 1 or
more conservative measures (eg, nipple excision and wedge excision of the underlying breast,
cone excision, radiation therapy) is small.
Patients who underwent cone excision and elective tamoxifen therapy had recurrences after an
average follow-up of 4.6 years; some developed metastases. Therefore, cone excision is not
sufficient therapy for patients with disease limited to the nipple.
Wide local excision with axillary node sampling is recommended for patients with or without a
clinical mass.

Radiation therapy alone does not always control occult breast cancer; however, it may be used
for patients who refuse mastectomy or those who are medically unfit for surgery.

Medication Summary
The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Topical Skin Products

Class Summary

These agents provide a photodynamic treatment for low-risk malignant cells and may improve
morbidity.
View full drug information
Aminolevulinic acid (Levulan Kerastick)

A recent Cochrane review of aminolevulinic acid photodynamic therapy for mammary and
extramammary Paget disease identified 21 retrospective and 2 prospective noncomparative
studies with a total of 99 patients. The results suggest that this modality might be considered as
adjunctive therapy for selected patients.[23]
Aminolevulinic acid is a metabolic precursor of the photosensitizer protoporphyrin lX. When
exposed to light of appropriate wavelength and energy, it induces local cytotoxicity through a
photodynamic reaction.