Paget’s Disease of the Breast, underlying breast cancer mimicking as Benign Dermatological Conditions: Clinical Challenges and Diagnostic Considerations

Muhammad Nouman Tariq; Insha Aleena; Akeel Ahamed Salahudeen; Sundas Asif; Maryam Kiani; Arshi Wasim; Khushbu Komalbhai Patel; Zurnish Rauf; Umar Jamshed Qureshi; Rizwan Uppal; Muhammad Rehan Uppal; Umar Saeed; Zahra Zahid Piracha; Muhammad Ahmad; Muhammad Zeeshan Tariq

doi:10.37547/tajmspr/Volume07Issue06-04

Authors

Muhammad Nouman Tariq
International Center of Medical Sciences Research (ICMSR), Islamabad PAKISTAN Akhtar Saeed Medical and Dental College
Insha Aleena
Mahatma Gandhi Medical College and Research Institute (Sri Balaji Vidyapeeth University)
Akeel Ahamed Salahudeen
Nishtar Medical University, Multan
Sundas Asif
Yusra Medical and Dental College/Bahria University Islamabad
Maryam Kiani
Bannu Medical College
Arshi Wasim
Calcutta National Medical College
Khushbu Komalbhai Patel
Our Lady of Fatima University, Philippines
Zurnish Rauf
Jinnah Hospital, Lahore, Pakistan Letterkenny University Hospital, Donegal, Ireland
Umar Jamshed Qureshi
Akhtar Saeed Medical and Dental College
Rizwan Uppal
Islamabad Diagnostic Center (IDC), F8 Markaz, Islamabad PAKISTAN
Muhammad Rehan Uppal
Islamabad Diagnostic Center (IDC), F8 Markaz, Islamabad PAKISTAN
Umar Saeed
Foundation University Islamabad (FUI), Islamabad PAKISTAN
Zahra Zahid Piracha
International Center of Medical Sciences Research (ICMSR), Islamabad PAKISTAN International Center of Medical Sciences Research (ICMSR), Austin, TX, United States of America International Center of Medical Sciences Research (ICMSR), Chadwell Heath, United Kingdom
Muhammad Ahmad
from NISHTAR MEDICAL COLLEGE MULTAN
Muhammad Zeeshan Tariq
University of Huddersfield.

DOI:

https://doi.org/10.37547/tajmspr/Volume07Issue06-04

Abstract

Mammary Paget's disease (MPD), also known as Paget's disease of the breast, is an uncommon dermatological cancer of the nipple-areolar complex that can cause anything from redness and itching to more serious symptoms like breast lumps, destruction of the nipple-areolar complex, or nipple discharge. It is typically linked to either invasive ductal carcinoma or an underlying ductal carcinoma in situ. MPD can cause delayed diagnosis and improper therapy because it frequently presents as various benign and malignant dermatological disorders, such as eczema, atopic dermatitis, psoriasis, and squamous and basal cell carcinomas. Since only one-third of patients have a palpable lump when they first arrive, MPD should be suspected in patients who are older and have unilateral, persistent lesions. In order to distinguish MPD from other skin illnesses, our review paper highlights the major findings of clinical features and diagnostic workup. It also includes case studies of MPD mimicking other skin conditions. According to a study of the literature, research advises against using mammograms and ultrasounds alone to diagnose MPD, especially when there isn't a palpable lump. This demonstrates that the MRI is a better and more precise imaging method. However, because MRI results can occasionally be negative when there is a biopsy-proven MPD present, any suspicious lesion needs to be biopsied in order to undergo histological and immunohistochemical analysis. This highlights the need for clinicians to explore any suspicious lesion of the nipple or breast using the complete triple evaluation technique to exclude an underlying cancer. It is vital to establish therapeutic criteria to treat any nipple lesion to limit the risk of misdiagnosing any underlying cancer, which can be potentially lethal if left alone.

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TYPE

Original Research

PAGE NO.

25-47

DOI

10.37547/tajmspr/Volume07Issue06-04

OPEN ACCESS

SUBMITED

22 April 2025

ACCEPTED

24 May 2025

PUBLISHED

24 June 2025

VOLUME

Vol.07 Issue 06 2025

CITATION

Muhammad Nouman Tariq, Insha Aleena, Akeel Ahamed Salahudeen,
Sundas Asif, Maryam Kiani, Arshi Wasim, Khushbu Komalbhai Patel,
Zurnish Rauf, Umar Jamshed Qureshi, Rizwan Uppal, Muhammad
Rehan Uppal, Umar Saeed, Zahra Zahid Piracha, Muhammad Ahmad, &

Muhammad Zeeshan Tariq. (2025). Paget’s Disease of the Breast,

underlying breast cancer mimicking as Benign Dermatological
Conditions: Clinical Challenges and Diagnostic Considerations. The
American Journal of Medical Sciences and Pharmaceutical Research,
7(06), 25

–

47. https://doi.org/10.37547/tajmspr/Volume07Issue06-04

COPYRIGHT

© 2025 Original content from this work may be used under the terms
of the creative commons attributes 4.0 License.

Paget’s Disease of the

Breast, underlying breast
cancer mimicking as
Benign Dermatological
Conditions: Clinical
Challenges and Diagnostic
Considerations

Muhammad Nouman Tariq

International Center of Medical Sciences Research (ICMSR),
Islamabad PAKISTAN
Akhtar Saeed Medical and Dental College

Insha Aleena

Mahatma Gandhi Medical College and Research Institute (Sri
Balaji Vidyapeeth University)

Akeel Ahamed Salahudeen

Nishtar Medical University, Multan

Sundas Asif

Yusra Medical and Dental College/Bahria University Islamabad

Maryam Kiani

Bannu Medical College

Arshi Wasim

Calcutta National Medical College

Khushbu Komalbhai Patel

Our Lady of Fatima University, Philippines

Zurnish Rauf

Jinnah Hospital, Lahore, Pakistan
Letterkenny University Hospital, Donegal, Ireland

Umar Jamshed Qureshi

Akhtar Saeed Medical and Dental College

Rizwan Uppal

Islamabad Diagnostic Center (IDC), F8 Markaz, Islamabad
PAKISTAN

Muhammad Rehan Uppal

Islamabad Diagnostic Center (IDC), F8 Markaz, Islamabad
PAKISTAN

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The American Journal of Medical Sciences and Pharmaceutical Research

Umar Saeed

Foundation University Islamabad (FUI), Islamabad PAKISTAN

Zahra Zahid Piracha

International Center of Medical Sciences Research (ICMSR),
Islamabad PAKISTAN
International Center of Medical Sciences Research (ICMSR),
Austin, TX, United States of America
International Center of Medical Sciences Research (ICMSR),
Chadwell Heath, United Kingdom

Corresponding Authors: Dr Zahra Zahid Piracha and
Dr Umar Saeed

Acknowledgments:

We would like to express our sincere gratitude to
the following individuals for their invaluable support
and contributions to this research:

Muhammad Ahmad

from NISHTAR MEDICAL COLLEGE MULTAN

Muhammad Zeeshan Tariq

University of Huddersfield.

Abstract:

Mammary Paget's disease (MPD), also known

as Paget's disease of the breast, is an uncommon
dermatological cancer of the nipple-areolar complex
that can cause anything from redness and itching to
more serious symptoms like breast lumps, destruction
of the nipple-areolar complex, or nipple discharge. It is
typically linked to either invasive ductal carcinoma or an
underlying ductal carcinoma in situ. MPD can cause
delayed diagnosis and improper therapy because it
frequently presents as various benign and malignant
dermatological disorders, such as eczema, atopic
dermatitis, psoriasis, and squamous and basal cell
carcinomas. Since only one-third of patients have a
palpable lump when they first arrive, MPD should be
suspected in patients who are older and have unilateral,
persistent lesions. In order to distinguish MPD from
other skin illnesses, our review paper highlights the
major findings of clinical features and diagnostic
workup. It also includes case studies of MPD mimicking
other skin conditions. According to a study of the
literature, research advises against using mammograms
and ultrasounds alone to diagnose MPD, especially
when there isn't a palpable lump. This demonstrates
that the MRI is a better and more precise imaging
method. However, because MRI results can occasionally

be negative when there is a biopsy-proven MPD present,
any suspicious lesion needs to be biopsied in order to
undergo histological and immunohistochemical analysis.
This highlights the need for clinicians to explore any
suspicious lesion of the nipple or breast using the
complete triple evaluation technique to exclude an
underlying cancer. It is vital to establish therapeutic
criteria to treat any nipple lesion to limit the risk of
misdiagnosing any underlying cancer, which can be
potentially lethal if left alone.

Introduction:

Mammary Paget's disease (MPD), first identified by Sir
James Paget in 1874, is an uncommon condition
affecting the nipple, often linked to underlying breast
cancer. Paget described it as a persistent, ulcerating skin
lesion with a yellowish discharge, and over time, it
became clear that it was associated with more severe
conditions, such as breast carcinoma [1,2]. In his study,
Paget observed 15 female patients with similar
symptoms, all of whom later developed breast cancer.
Initially mistaken for a benign skin condition, it was later
understood to be malignant in nature. A parallel
condition, extramammary Paget's disease, can also
occur in the genital area of both men and women. While
the two conditions share similar histological features,
they have distinct causes and mechanisms [2,3]. MPD is
a form of intraepithelial malignancy, typically
characterized by the presence of large malignant cells,
known as Paget cells, within the squamous epithelium of
the nipple. These cells can spread to the areola and
adjacent skin. Occasionally, Paget's disease may even
appear in accessory nipples or other abnormal breast
tissues [5]. The disease is most commonly diagnosed in
postmenopausal women, particularly those in their 50s
or 60s. It accounts for about 1% to 3% of all breast
cancer diagnoses. In the majority of cases, MPD is
associated with either ductal carcinoma in situ (DCIS) or
invasive ductal carcinoma (IDC), typically in the central
or multifocal regions of the breast. The presence of
invasive cancer plays a major role in determining the
prognosis. Additionally, bilateral cases

—

where tumors

develop simultaneously in both breasts

—

occur in

approximately 1% of all breast cancer cases, which
makes it harder to assess the overall disease
progression.

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Research shows MP

D (Mammary Paget’s Disease)

appears rarely in men since 1% of cases emerge and the
affected patients usually reach age 68. Epidemiological
research reveals that Paget's disease occurrence has
decreased by 45% throughout the previous two
decades. The discovery of DCIS (ductal carcinoma in situ)
during regular mammography screenings has been the
main reason for this downward trend [6,7]. According to
the literature Paget's disease presents in three distinct

forms based on its relationship to the underlying DCIS
(ductal carcinoma in situ) and its distance from the
nipple: (1) Paget's disease arising from DCIS located
within 2 cm of the nipple in lactiferous ducts, (2) Paget's
disease accompanied by invasive carcinoma spreading
beyond 2 cm from the nipple-areolar complex, and (3)
Paget's disease occurring without an underlying
carcinoma (Figure 1) [8].

FIGURE 1: MPD with underlying carcinoma

Medical professionals must understand that Paget’s

disease shows multiple occurrences throughout the
breast tissue and resembles standard breast cancer
forms. The appearance of MPD matches regular skin
rashes which leads to incorrect diagnoses or medical

professionals overlooking this condition. The diagnosis
of this condition depends mainly on physical
examination and medical history review to assess
symptom duration. The diagnosis of persistent unilateral
nipple changes requires diagnostic methods that include

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nipple cytological scraping and MRI or biopsy to perform
histopathological analysis and immunohistochemical
staining. The advances in radiological methods do not
eliminate the need for tissue biopsy when breast lesions
appear suspicious because this prevents missed cancer
diagnoses [9,10]. According to Ashikari et al. MPD
required six to 11 months for diagnosis whereas ductal
carcinoma typically needs one to two months for proper
identification [11]. The following article examines MPD
diagnostic criteria while discussing conditions that
resemble Paget's disease to help pathologists and
clinicians achieve early diagnosis.

Pathogenesis

Scientists have yet to determine MPD's origins because
different hypotheses exist about how this condition
develops. Two main theories about MPD development
have become widely accepted in the field. According to
the epidermotropic theory Paget cells develop from
mammary adenocarcinoma when neoplastic ductal
epithelial cells move from ducts to reach the nipple
epidermis. Research indicates that Paget cells and ductal
epithelial

cells

display

comparable

immunohistochemical results yet Paget cells exhibit
staining patterns that differ from the nipple epidermal
keratinocytes. Histological investigations have shown
that ductal carcinoma cells directly connect to Paget
cells found in the nipple. The HER2/neu (human
epidermal growth factor receptor) demonstrates

frequent overexpression in Paget’s disease because

Pelorca et al. [14-17] report that 83.5% of MPD cases
belong to the HER2 or luminal HER2 molecular subtypes.
The motility factor known as heregulin-

α produced by

epidermal keratinocytes works through HER2 binding to
direct malignant cells to the nipple surface. The high rate
of breast cancer diagnoses in MPD cases supports this
theory since it occurs in more than 90% of MPD patients.
The intraepidermal transformation theory receives less
acceptance than its alternative. The independent
development of epidermal keratinocyte malignancies
appears possible when they arise without connection to
breast cancer and through degeneration or in situ
transformation processes. The theory suggests that
Paget cells develop from either pluripotent keratinocyte
stem cells or apocrine gland duct cells which
subsequently become malignant.

Several studies have documented cases of Paget lesions
without dermal invasion, as well as the presence of
desmosomal connections between Paget cells and
adjacent cells, which may prevent their migration. In
1881, George Thinn introduced the transformation
theory, which proposed the development of
carcinogenesis in the absence of an underlying
carcinoma. He suggested that continuous secretions
from the breast ducts cause damage to the epithelium,
leading to the transformation of keratinocytes into
malignant cells. Some researchers have observed
specific pre-Paget cells, which appear to be intermediate
between keratinocytes and Paget cells. This observation
supports Thinn's theory, indicating that epidermal cells
could potentially acquire ductal cell characteristics as
they undergo malignant transformation. Despite various
studies, no definitive evidence has conclusively proven
either theory, though the epidermotropic theory has
gained broader acceptance (Figure 2) [2,3,15,18-20].

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FIGURE 2: Pathogenesis of MPD

(A) Epidermotropic theory: Paget cells originate in the
underlying adenocarcinoma, with neoplastic epithelial
cells migrating through the ductal system to the nipple
epidermis. (B) Intraepidermal transformation theory:
Paget cells arise from degeneration or in situ
transformation of epidermal keratinocytes in the nipple-
areola complex.

Risk factors

The risk factors for Mammary Paget’s disease overlap

with those of regular breast cancer and include aging
population and obesity alongside alcohol intake and
BRCA1 and BRCA2 genetic mutations together with prior
chest radiation exposure and hormone replacement
therapy usage and prolonged oral contraceptive use and
breast cancer heredity. The research conducted by
Zheng et al. analyzed Chinese women with primary

breast cancer through a multi-center retrospective
study to examine demographic and risk factors in MPD
patients relative to other breast cancer types. Research
results showed that age together with menstrual status
and education level and parity and breastfeeding
practice and age at menopause and family history of
breast cancer and metabolic rate showed no differences
between groups [21]. The research by Jamali et al.
showed that MPD reaches its peak occurrence between
5 to 10 years after the peak time for invasive breast
carcinoma [22]. The majority of MPD patients remain
childless whereas breast cancer patients with different
types have given birth [23].

Diagnosis

The symptoms of MPD usually appear as skin changes
inside the nipple-areola complex through itching and

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eczema alongside redness. A defined lesion patch
appears first before developing into an eczematoid or

erythematous plaque. The manifestation of Paget’s

disease differs from non-cancerous eczema because it
appears only on one side of the div [8,11]. The disease
evolution results in skin damage that causes erosion of
the tissue and ulceration of the skin surface alongside
serous or bloody discharge together with nipple
deformities including flattening or inversion. Advanced
Paget disease stages present with crusted lesions,
scaling skin and skin dimpling as well as fissures
according to medical reports. The rash produces a
diameter which extends to 15 cm according to research
[1,24]. The majority of patients feel burning sensations
and pain during the pre-visual skin change period of
their condition while 15% to 20% of patients report
these symptoms [25,26]. Rare occurrences show Paget's
lesions spreading from the nipple into adjacent
perimammary skin and the opposite breast according to
medical reports [27,28]. Medical reports have
documented the appearance of brownish skin lesions
which look like superficial melanoma [29]. The
significant indicators for dermoscopy of MPD lesions
include unorganized pink patches and white lines. The
appearance of pigmented skin lesions includes gray
granules and dots whereas ulcers and white scales are
found in non-pigmented skin lesions [30].

Because MPD can look like the skin condition eczema
doctors sometimes wrongly diagnose it therefore
patients receive topical creams without identifying the
true cause of their condition [8,31]. A persistent nipple
condition that includes pain or erythema along with
persistent itching warrants MPD investigation [32]. A
clinical examination of 52 Paget disease patients
confirmed that most women presented with observed
nipple masses along with redness, itching, ulceration,
yet bleeding and discharge appeared less frequently
[33]. Tumors at an advanced stage sometimes display
spread to lymph nodes in the armpit area. The research
on 20 MPD patients determined that axillary lymph node
metastasis occurred in fifty percent of cases and several
patients displayed this condition when no breast lump
could be detected [23,34]. The research showed that
13% of patients who did not have detectable breast
lumps had axillary lymph node metastasis [11]. The
research by Fu et al. determined that almost every

patient with undetectable breast masses had carcinoma
combined with Paget's disease [35].

Imaging

If the skin changes do not improve after two weeks of
corticosteroid treatment, further diagnostic steps,
including imaging and biopsy, are recommended [2]. A
thorough evaluation should involve high-quality imaging
to rule out cancer, given the strong link between
Mammary Paget's disease (MPD) and breast carcinoma
[8]. Studies suggest that patients with palpable masses
typically exhibit multifocal disease, whereas those
without a mass may still have multifocal or multicentric
lesions [36]. Mammography is the first choice for
detecting potential malignancies in MPD cases, with
breast ultrasound considered if mammogram results are
unclear [2]. For patients who show no abnormalities on
mammograms or ultrasounds and do not have palpable
masses, breast MRI is recommended [37]. Although
mammography plays a vital role in diagnosing and
managing Paget's disease, it is not foolproof, with up to
50% of patients presenting normal mammograms [8].
Typical mammographic findings include thickening of
the skin around the nipple-areolar complex, changes in
breast tissue density, nipple retraction, identifiable
lumps, or microcalcifications [2,37].

In a study conducted by Pelorca et al., 85.9% of patients
underwent mammography, and abnormalities were
detected in 87.7% of cases, with microcalcifications
being the most frequent finding (58.9%), followed by
nodules (37%) [38]. Challa and Deshmane examined 20
women with MPD, performing mammography on 11 of
them. Two patients showed no abnormalities, while
among the nine with identified issues, five had fine
microcalcifications, two had underlying masses, and two
exhibited increased skin thickness around the nipple.
Two patients had multicentric calcifications involving
more than two quadrants, and multicentricity was
observed in 25% of cases [34]. Mammography often
misses some malignancies, with detection rates varying
from 15% to 65% in different studies [29,32,39]. Besides
detecting underlying masses or DCIS, mammography is
also crucial in monitoring patients who have undergone
conservative breast surgery, helping to rule out
recurrence [37].

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Mammography has a high sensitivity of 97% for
detecting cancer in patients with a palpable breast lump,
but in the absence of a lump, it only identifies underlying
malignancies in about half of the cases [2,4,40].
Therefore, a negative mammogram does not entirely
exclude the possibility of cancer [1]. Ultrasound is used
to confirm mammographic findings and is also helpful
when mammograms are normal. Ultrasound can detect
parenchymal heterogeneity, hypoechoic areas, dilated
ducts, distinct masses, and skin thickening [37,40]. It can
also evaluate axillary lymph nodes [2]. However,
microcalcifications often do not appear on ultrasound.
In some cases, areas of DCIS with pleomorphic
calcifications seen on mammograms are better
visualized through ultrasound, though ultrasound may
not always clarify mammogram findings and can
sometimes only show skin thickening [37].

When combined with mammography, ultrasound does
not significantly increase the detection sensitivity of
underlying lesions. However, it is valuable for
characterizing abnormalities or guiding biopsies of any
palpable masses detected by mammography [3]. In a
study by Günhan-Bilgen and Oktay, ultrasound
identified masses in 35 out of 52 MPD cases, most of
which were irregular or lobulated (95%), without
posterior shadowing [32]. MRI is particularly sensitive
for detecting breast tumors, especially when both
mammography and ultrasound fail to identify
abnormalities. It can highlight papillary-areolar complex
thickening, nipple enlargement, in situ ductal lesions,
and invasive tumors, even when clinically suspected
[40,41]. MRI can also demonstrate different patterns of
enhancement, such as asymmetric, irregular, or discoid,
and is especially useful for evaluating the extent of
disease in patients who might require breast-conserving
surgery (BCS). For those with suspected or confirmed
MPD, MRI helps identify multifocal or multicentric
lesions that may not be visible through clinical
examination or other imaging tests [2].

In Pelorca's study with 85 MPD patients, ultrasound was
performed in 79 individuals (92.9%), detecting solid
lumps in over 70% of cases. MRI was conducted on a
subset of patients, identifying tumors in nearly 70% of
cases and nipple-areolar complex thickening in around
43%. The study found no significant differences in

imaging results between clinical or hidden Paget's
disease forms, whether assessed with mammography,
ultrasound, or MRI [38]. Another study by Siponem et al.
showed that MRI had the highest sensitivity for
detecting invasive carcinoma (100%) and DCIS (44%),
followed by mammography (74% and 39%) and
ultrasound (74% and 19%) [2,42]. However, Morrogh et
al. reported that MRI failed to detect cancer in three out
of 34 women with biopsy-confirmed MPD [39].

MRI is highly sensitive but may have a lower specificity,
leading to the identification of abnormalities that could
result in unnecessary mastectomy rather than breast-
conserving surgery. If MRI is used, it is crucial that it be
performed at a facility capable of MRI-guided biopsies,
and patients should be informed about the high false-
positive rates associated with MRI, which may require
additional biopsies [3]. For example, a 52-year-old
woman with changes in nipple color had a negative
mammogram and no palpable lump, but an MRI
revealed underlying carcinoma, including diffuse
segmental enhancements indicative of DCIS [43]. While

Paget’s disease is mainly diagnosed based on clinical

signs, imaging findings may not rule out hidden breast
cancer, especially in the absence of detectable lumps or
palpable abnormalities [37].

Histopathological and Immunohistochemical Features

of MPD

Fast MPD diagnosis becomes possible through tissue
scraping because the affected area shows specific
cellular traits including high nuclear-to-cytoplasmic ratio
and vacuolated cytoplasm of enlarged cells. The
diagnostic process includes three biopsy methods which
include superficial shave biopsy of the epidermis as well
as wedge biopsy and punch biopsy. A wedge biopsy
serves as the preferred choice because it collects
sufficient epidermal tissue. When Paget cells are located
in ulcerated areas medical personnel will find
insufficient cells through shave biopsy while punch
biopsy yields limited epidermal and stromal samples for
diagnostic examination [44]. Standard medical practice
recommends surgical removal of Paget disease as the
primary treatment approach that should be considered
even when biopsy results are unclear. Medical
professionals perform full-thickness biopsies primarily

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to evaluate nipple-areolar skin changes [45].

Paget cells exist as the diagnostic sign for MPD. The cells
of intraepithelial adenocarcinoma present as various-
sized structures which exist in the basal layer while
missing the cellular connections that join cells together.
Small clusters and large sheets of cells adopt a nest-like
or glandular arrangement while replacing the normal
epidermal cells. The cellular cytoplasm of Paget cells
contains high amounts of neutral mucopolysaccharides
along with mucin positivity. Under microscopy viewing
Paget cells display pale vacuolated cytoplasm which
contains clear material and show hyperchromatic
pleomorphic nuclei together with one or two prominent
nucleoli [46]. There is commonly a dense lymphocytic
inflammatory infiltrate in the dermis layer near the
surface. The benign Toker cells originating from
sebaceous glands possess abundant cytoplasm that can
potentially resemble Paget cells. Scientists have
confirmed that these cells exist in 10% of regular nipple
samples and occasionally arise in both supernumerary
nipples and apocrine glands [47]. Immunohistochemical
staining serves as a vital tool to identify different

molecular subtypes of MPD for proper therapeutic
decisions and survival predictions and disease staging.
The evaluation technique supports doctors to
differentiate MPD from other medical conditions that
may affect the nipple. Research indicates that HER2
overexpression occurs commonly in patients with MPD.
The analysis of breast tissue cells revealed ER expression
in 40% of cases and PR expression in 30% of cases.
Among breast cancer subtypes Luminal A and B occur
more frequently in other cancer types but MPD
exclusively presents with HER2 positive characteristics.
Research has confirmed that cytokeratin exists in 95% of
examined Paget cells. GATA-3 staining serves as an
important diagnostic tool for MPD since Paget cells use
heregulin-

α to create a chemotactic movement that

enables their nipple epidermis spread [48-54].

MPD mimicking dermatological conditions

MPD can sometimes be mistaken for a variety of benign
or chronic skin conditions, such as chronic eczema,
atopic dermatitis, contact dermatitis, psoriasis, erosive
adenomatosis, squamous cell carcinoma, basal cell
carcinoma, and malignant melanoma (Figure 3, Table 1).

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FIGURE 3: Diagnostic flowchart of the differential diagnosis of nippleareola complex diseases

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Disease

Clinical Features

Diagnostics (HPE)

Diagnostics (IHC)

MPD

(Mammary

Paget’s Disease)

(44-54)

Scaling, eczema, erythema,
ulceration,

erosion,

hyperpigmentation of nipple
and discharge from the nipple.

Incisional biopsy shows PAS-
positive mucin-containing
vacuolated pagetoid cells.

Positive for CK 7/8,
epithelial
membrane antigen,
CEA,

HER2/neu,

mammary Paget’s

disease marker.

Chronic Eczema

(55-61)

Scaling,

erythema,

hyperpigmentation,
lichenification.

Medical

history

and

symptom

description

analysis,

triggers,

and

physical examination.

Patch testing, skin
biopsy, blood tests
for IgE.

Atopic Dermatitis

(62-65)

Erythema,

papules-vesicles,

erosions, pruritus.

Clinical examination, history
of eczema, and elevated IgE
levels.

-

Contact Dermatitis

(63-68)

Erythema,

papules-vesicles,

erosions, pruritus.

Clinical examination and
identification of the contact
allergen.

-

Psoriasis

(69-73)

Defined patches with scales,
erythema,

infiltration,

and

pruritus.

Clinical examination, biopsy
for

acanthosis,

hyperkeratosis,

Munro

microabscesses, and Kogoj's
pustules.

-

Bowen’s Disease

(88, 89)

Patchy lesions, slow growth,
irregular

borders,

scaling,

itching, burning.

Dermoscopy, biopsies, and
histopathological
examination of biopsies.

-

Erosive Adenomatosis

(87)

Ulcers on the nipple or areola,
discharge pain, and itching.

Clinical examination, biopsy
for

histopathological

examination.

-

Nipple Adenoma

(77-84)

Firm nodules, crusting, or
erosion of the nipple, possible
sub-areolar calcifications.

Determined

by

biopsy.

Adenomatosis proliferates
ducts with surrounding
myoepithelial cells, without
cellular atypia.

Positive for CK 8/18
and p53.

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Toker Cell Hyperplasia

(74-76)

Changes in nipple appearance:
growth,

color,

burning,

discharge.

Biopsy to differentiate from
MPD, with PAS-positive
mucin-stained cells.

Positive for CK 7/8
and epithelial cell
markers.

Malignant Melanoma

(97-100)

Black

ulcerative/crusting

erosion of the nipple-areolar
complex.

Biopsy

needed

to

differentiate from MPD;
HPE

for

melanocytic

patterns and absence of
skin invasion.

Positive for HMB-
45, Melan-A, S-100.

Invasive Squamous Cell
Carcinoma

(90, 91)

Scaly ulcerative lesions of
nipple-areola complex.

Biopsy for histopathology.

Positive

for

cytokeratin
markers.

Basal Cell Carcinoma

(92-95)

Ulcerative lesions of nipple-
areolar complex.

Clinical examination and
biopsy.

Positive for Ber-EP4.

TABLE 1: Differential diagnosis of skin lesions of the nipple-areola complex

PAS: periodic acid-Schiff; CK: cytokeratin; CEA: carcinoembryonic antigen; HER2/neu: human epidermal growth
factor receptor 2; HMB: hydroxymethylbutyrate; HPE: histopathological examination; IHC: immunohistochemistry;

MPD: mammary Paget’s disease; IgE: immunoglobulin E

Benign Conditions

Eczema: Mammary Paget's disease (MPD) gets mistaken
for the skin condition eczema which affects numerous
patients through skin irritation. Numerous MPD cases
were mistakenly diagnosed as eczematoid dermatitis
thus leading to delayed appropriate medical care.
Doctors diagnose eczema by taking patient histories
while examining the skin and testing skin areas with
allergens. The medical diagnosis of chronic eczema
needs a skin biopsy because it presents bilaterally while
IgE antidiv levels remain elevated in most cases. A 46-
year-old female patient experienced her left breast
develop a red ulcerated plaque that progressively grew
worse until the actual MPD condition became evident
according to Bansal et al. It took three years of receiving
steroid treatments and antibiotics before MPD received
its proper diagnosis through biopsy testing. A 24-year-
old woman underwent incorrect diagnoses for thirteen
years until MPD was finally acknowledged as her true
condition according to Kanwar et al.

Atopic dermatitis: It stands as a skin problem which

affects the nipple and approximately 23% of patients.
The skin condition shows erythema as well as papules
and vesicles with frequent itching being a symptom.
When patients continue scratching their skin tissue can
become thickened which is known medically as

lichenification. For accurate diagnosis of Paget’s disease

doctors must perform biopsies on the nipple and areola
area but punch biopsy results might be false. Medical
testing of atopic dermatitis reveals acanthosis alongside
spongiosis and lymphocytic exocytosis when examining
the skin while the dermis contains lymphocyte and
eosinophil cell infiltration. The chronic stage of this
condition shows higher levels of mast cells together with
Langerhans cells and eosinophils and develops
hyperkeratosis. The immunohistochemistry analysis will
show TH-2 cytokines (IL2 and IL13) specific to atopic
dermatitis in both the epidermis and perivascular dermis
tissue.

Dermatitis: Doctors should investigate allergic contact
dermatitis as an ongoing nipple eczema treatment-
resistant case. Doctors start diagnostic procedures by

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performing patch tests to determine the allergens that
might be causing reactions since nickel and items found
in fabric cleaners and nipple creams have been
established as possible allergens. New symptoms of
contact dermatitis usually manifest as vesicles and
erythema and persistent itchiness begins to appear 24-
48 hours after allergen exposure. The friction from
nursing and lactation pump usage along with
occupations and habits increase the likelihood of
developing irritative dermatitis. The histological
features of irritative eczema include eosinophilic
spongiosis together with acanthosis and lymphocytic
exocytosis while perivascular infiltration of lymphocytes
and neutrophils is commonly observed.

Psoriasis:

Psoriasis

functions

as

a

persistent

autoimmune disease which occasionally impacts the
nipple and areola. The most typical psoriasis
manifestation includes plaque-type lesions with redness
and scaling and skin tissue swelling which frequently
emerges after physical trauma (Koebner phenomenon).
Psoriasis appears extremely rarely on the nipple and
areola yet reports exist of patients with breast cancer
background experiencing these symptoms. The
histological examination of psoriasis shows regular
acanthosis together with stratum granulosum thinning
and parakeratosis and neutrophilic infiltration which
includes Munro's microabscesses in the stratum
corneum. A patient's presentation of MPD and psoriasis
suggested potential simultaneous development of these
conditions according to medical reports.

Toker cell hyperplasia exists as a benign condition that
should be distinguished from MPD. Toker cells exist as
isolated firm non-pigmented lesions which can appear
either in one nipple or both nipples. The cells most often
occur in female bodies and exist either normally or as
hyperplastic forms. Atypical and hyperplastic Toker cells
display some histological similarities with Paget cells
through their positive reactions to estrogen receptor
(ER) and progesterone receptor (PR). The markers
CD138 and p53 show negative results in these cells while
ER and PR remain positive thus distinguishing them from
Paget's cells. The results of immunohistochemical
examinations on atypical Toker cells show weak
HER2/neu protein expression. The research conducted
by Di Tommaso et al. revealed that among 390

mastectomy patients Toker cells appeared in 40 cases
yet atypical findings were observed in 12.5% of these
cases. The correct diagnosis of eczema-like symptoms
requires extensive clinical evaluation that includes both
tissue sampling and laboratory testing of tissue
specimens. The diagnostic process becomes more
complex when atypical cells including Toker cells appear
because it requires precise determination of whether
the condition is benign or malignant.

The histological features of psoriasis typically show
consistent acanthosis, a reduction in the stratum
granulosum, parakeratosis, neutrophil infiltration

beneath the corneal layer (Kogoj’s spongiform pustules),

and the presence of neutrophils within the stratum

corneum (Munro’s microabscesses) [72]. Interestingl

y, a

rare case involving both psoriasis and Mammary Paget's
disease (MPD) was reported in an elderly woman [73].

Di Tommaso et al. investigated the frequency of Toker
cell hyperplasia along with distinctive features to
differentiate abnormal cells from Paget's disease-
related malignant cells. The appearance of Toker cell
hyperplasia includes a small solitary firm lesion that
lacks pigment and does not cause discomfort. The
condition affects one or both nipples primarily among
female patients. The analysis of over 390 breast
mastectomy patients revealed Toker cells in the nipples
of 40 patients. The examined cells consisted of normal
Toker cells in 60% of cases and hyperplastic Toker cells
in 27.5% of cases while 12.5% of cases contained both
hyperplastic and atypical Toker cells. The analysis
through immunohistochemical methods revealed that
Toker cells displayed positive reactions to estrogen
receptors (ER) and progesterone receptors (PR) while
remaining negative for both CD138 and p53. The
immunoreactivity of HER2/neu was weak in specific
atypical Toker cells but remained absent in Paget cells.
Immunohistochemical tests demonstrated that both
Toker and Paget cells expressed cytokeratin 7 (CK 7) and
epithelial membrane antigen (EMA) while remaining
negative for p63. The research team employed CD138
and p53 staining together to distinguish atypical Toker
cells from Paget cells. The research emphasizes the
necessity of correct identification between Toker cells
and malignant Paget cells which occur in Paget's disease
[74].

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An 83-year-old woman visited gynecological services
with a non-pruritic, erythematous and non-tender
eczematous nipple lesion that had existed for 17 years
according to Ramos et al. The possible diagnoses
included both chronic eczematous nipple conditions and

Paget’s disease of the nipple. The punch biopsy showed

isolated epithelioid cells existing in the epidermis while
the PAS staining test produced negative results. The final

diagnosis of Toker cell hyperplasia excluded Paget’s

disease of the nipple because immunohistochemical
results showed CK 5/7 positivity but p53 negativity [75].
A 47-year-old woman showed an eczematous lesion on
her right areola for ten years according to van der Putte
et al. The biopsy analysis showed a single-cell type
collection that stayed within the epidermis yet left all
other tissue layers and their environment unaffected.
The initial assessment identified the lesion as MPD but
subsequent analysis confirmed it as mammary gland
hyperplasia within the epithelium which met all criteria
for Toker cell hyperplasia diagnosis [76]. Nipple
adenoma exists as a rare condition that doctors must
distinguish from MPD through specialized laboratory
testing

including

histopathological

and

immunohistochemical analysis [77]. The proliferation of
lactiferous ducts leads to the development of nipple
adenoma which represents a rare form of benign
condition. A firm nodule alongside crusting and erosion
and ulceration and nipple discharge are among the
clinical manifestations of this condition [78]. Nipple
adenoma exists as a condition that may present with or
without visible mass tissue beneath the nipple [79].

The significant proliferation of myoepithelial cells in
nipple adenoma causes the nipple to enlarge and swell
without spreading to other parts of the div. The
condition leads to nipple destruction that produces
symptoms which doctors might m

istake for Paget’s

disease [80]. The clinical characteristics shared by nipple
adenoma and MPD make their differentiation a difficult
task for healthcare providers. The progression rate of
Paget's disease surpasses nipple adenoma since it
causes intense itching and skin damage yet nipple
adenoma shows a distinct feature as a single nipple
lesion with less noticeable exudate. The two conditions
require histopathological evaluation because their
clinical symptoms lack specificity for proper
differentiation. The definitive diagnosis of nipple

adenoma requires both biopsy examination and surgical
removal of the tissue [82]. Nipple adenomas remain
undetectable by mammography but calcifications might
occasionally show up [83]. Biopsy results show that the
lesion exists in the retroalveolar area with a gray
appearance as a non-encapsulated mass that contains
ductal and adenomatous proliferation surrounded by
epithelial

and

myoepithelial

cells.

Immunohistochemically,

nipple

adenomas

show

positive staining for CK 8/18, CK 5/6, and p63 [84].

Paget's disease stands apart from other conditions due
to its exclusive feature of Paget cells that include
malignant epithelial adenocarcinoma cells of varying
sizes. The oval-shaped vacuolated cells with mucin
content show positive results for periodic acid-Schiff
(PAS) stain. The immunohistochemistry results for this
condition display positive staining patterns for CK 7/20
together

with

the

possibility

of

detecting

carcinoembryonic antigen (CEA) and cytokeratin [53,54].
A 63-year-old woman developed a giant nipple adenoma
according to Ono et al. who initially exhibited nipple
erosions and excoriations that doctors mistakenly
thought were MPD. The final pathological examination
revealed nipple adenoma containing myoepithelial cell
proliferation and positive CK 5 and 14 staining results
[85].

Erosive adenomatosis of the nipple exists as a very
uncommon medical condition. The research by
Gnangnon et al. presented a case study that detailed the
benign breast neoplasm characteristics through its
ductal nipple nodule manifestation. Nodules from this
condition destroy nipple tissue which results in extreme
pain and milky discharge and altered nipple appearance.
A 45-year-old female patient showed a progressively
enlarging mass located on her left nipple. The patient
received treatment for erosive adenomatosis through
nipple resection followed by breast reconstruction
surgery. The benign nature of this condition leads to
clinical symptoms that resemble those of malignant
nipple conditions including MPD so proper treatment
planning becomes necessary. The most successful
treatment option is surgery which leads to positive
prognostic outcomes for patients [87].

The clinical presentation of nipple adenoma and erosive

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adenomatosis and MPD matches yet their diagnostic
approaches and therapeutic options remain distinct
from one another. The correct diagnosis of these
conditions

depends

on

early

histopathological

examination which leads to proper treatment
approaches for improved patient results.

Malignant Conditions

Only a small proportion of Mammary Paget's Disease
(MPD) cases

—

roughly 1%

—

are diagnosed in men, with

the average age of these male patients being 68.
Notably, some studies have observed a 45% reduction in
the occurrence of Paget's disease over the past 20 years.
This decline is largely attributed to the advancements in
mammography screening, which have led to the early
detection of ductal carcinoma in situ (DCIS) [6,7]. The

scientific community has categorized Paget’s disease

into three distinct types, based on the underlying
pathology:Bowen's disease shares similar characteristics
with other skin conditions, such as psoriasis and eczema.
In addition, Bowen's disease's clinical manifestations
may often lead to a differential diagnosis of seborrheic
keratosis, actinic keratosis, and a host of other benign
skin conditions. Due to its similar phenotypic features
and clinical presentation, Paget's disease is frequently
referenced as a differential diagnosis of Bowen's
disease. The physical ma

nifestation of Bowen’s disease

often possesses a scaley, rough, or crusted surface. The
borders surrounding these asymmetrical lesions are
often characterized as ill-defined, a distinguishing
feature of the condition. In addition, the color of the
lesion may vary from light pink to rugged brown or even
a scarlet crimson on highly melanated individuals, such
as those of African descent. However, it is essential to
note that Bowen's disease may manifest differently
from person to person, and the previously listed
characteristics are not exclusive to making a diagnosis
[88]. Unexpectedly, a diagnosis of basal cell carcinoma
was made and proceeded accordingly, reflecting the
masquerading capacity of basal cell carcinoma [94].
Moennich et al. reported a case of a 47-year-old woman
who had complained of spontaneous bloody discharge
from her right nipple. On a shave biopsy, atypical
basaloid cells were found and stained positive for
antihuman epithelial antigen (Ber-EP4). Surgery
proceeded with the histological diagnosis of basal cell

carcinoma of the nipple-areolar complex. During the
surgery, when the mass was subjected to a frozen
section, the larger specimen showed features of atypical

and pleomorphic ductal cells similar to Paget’s disease,

and the larger specimen when subjected to IHC stained
positive for CK 7 and HER2/neu. The initial plan was
abandoned, and surgery for lumpectomy with nipple
removal and adjuvant radiation was proceeded with
[95].

Malignant Melanoma and Pigmented Paget’s Disease: A

rare varian

t of Paget’s disease, known as pigmented

MPD, can mimic malignant melanoma both clinically and
histologically. Paget's disease produces melanocyte-
stimulating factors from pagetoid cells that cause
melanin deposition throughout the tissue area thus
creating a pattern that resembles melanoma in situ. The
pigment that appears as melanoma originates from
epithelial cells in the nearby area. Malignant melanoma
starts as a dark mole on the nipple that evolves into
tissue spread leading to nipple ulceration [96]. The
histopathology examination of MPD reveals cells
containing melanin that might be mistaken for
melanoma cells. Special stains called mucicarmine
reveal mucin-

containing vacuoles within Paget’s cells

but these structures do not exist in malignant melanoma
cells [51,54]. The distinction between these two entities
requires immunohistochemical staining methods. The
immunohistochemical tests show that S100 and HMB
proteins are present in melanoma cells but absent in
Paget's cells which express CK 7 [96]. Malignant
melanoma demonstrates a negative reaction to both
estrogen and progesterone receptor tests (ER and PR)
which distinguishes it from MPD [51,53,54] The

distinction between Paget’s disease and melanoma

proves difficult because both conditions share
comparable tissue examination results and the way
samples are obtained. The diagnosis of MPD typically
requires core needle biopsies yet fine needle biopsies
used for melanoma diagnosis may potentially spread
tumor cells. Medical experts suggest performing an
excision biopsy on all suspicious lesions [97].

The research by Dehner et al. documented ten cases of
nipple primary melanoma while one case showed MPD
as a concurrent finding. The diagnosis of primary
malignant nipple melanoma requires exclusion of

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pigmented MPD since this condition remains quite rare

[98]. Pigmented Paget’s disease led to a misdiagnosis of

malignant melanoma according to Saito et al.'s report
[99]. The medical report by Lee et al. detailed how
pigmented MPD manifested as a dark-colored mass on
the nipple. The histological examination first pointed
toward malignant melanoma because it revealed
neoplastic cells that contained pigmentation. The
immunohistochemical test revealed CK 7 positivity
which confirmed the diagnosis of MPD instead of
melanoma because melanoma would have shown HMB
and S100 positivity [100].

Management

Various

patient-specific

factors

affecting

MPD

treatment decisions include clinical symptoms together
with diagnostic results. Multidisciplinary teams provide
most treatment plan development for patients who
include oncoplastic surgeons along with radiologists and
breast care nurses and other specialists like medical
geneticists and clinical psychologists and palliative care
specialists. Surgical treatment represents the primary
approach for MPD while BCS or mastectomy selection
depends on nipple-areola complex DCIS or IDC status
and patient presentation and quality of life [101,102].
Healthcare professionals use National Comprehensive
Cancer Network (NCCN) guidelines as their primary
source for making treatment choices regarding MPD.
The guidelines recommend individualized surgical
decisions that consider breast cancer coexistence
because it determines which surgical procedure would
be most appropriate. A patient's treatment plan
following NCCN guidelines depends on diagnostic tests
such as breast and nipple-areola complex (NAC) biopsies
to select the optimal treatment approach. The
treatment options for DCIS include BCS without lymph
node removal or total mastectomy with sentinel lymph
node biopsy (SLNB) instead of axillary dissection and
breast/nipple reconstruction can be performed.
Patients diagnosed with isolated NAC Paget's disease
without breast cancer have four treatment options that
include central lumpectomy followed by NAC removal
and whole-breast radiation therapy or total mastectomy
with or without SLNB or central lumpectomy with NAC
removal and no radiation therapy [101,102].

Mastectomy used to be the standard treatment for MPD

until recent developments allowed BCS to become a
suitable option for patients who do not have underlying
carcinoma through wide local excision of the NAC
combined with adjuvant therapy. The approach proves
appealing because it generates better patient
satisfaction results. The possibility of positive surgical
margins continues to be a concern because it may lead
patients to require additional surgeries or complete
mastectomy procedures [103,104]. The research by
Kollmorgen et al. revealed that 29% of MPD cases
without carcinoma needed mastectomy due to their
peripheral location which made wide local excision
impossible [19]. For patients without palpable masses or
abnormal mammograms, BCS with wire-guided local
excision, followed by radiotherapy, can be an effective
surgical option [25]. One study comparing the 10-year
survival rates of patients who underwent BCS versus
mastectomy found a comparable survival rate

—

67% for

BCS and 79% for mastectomy. However, the sample size
for the BCS group (n=12) was significantly smaller than
that for the mastectomy group (n=102) [105]. The
European Organization for Research and Treatment of
Cancer Trial recommended that BCS with whole-breast
radiotherapy, if clear surgical margins are achieved, is a
reasonable treatment approach for MPD and localized
DCIS, with a 5% recurrence rate at five years post-
operation [103]. This treatment strategy demonstrates
the importance of personalized care and the flexibility in
surgical options depending on the extent of the disease
and the patient's overall health and preferences.

The study by Chen et al. demonstrated that patients who
underwent mastectomy or BCS experienced cancer-
specific survival rates of 92% and 94% respectively over
a 15-year period for patients with or without DCIS [106].
The research conducted by Dalberg et al. demonstrated
that BCS produced better disease-free survival results of
94% compared to 85% for mastectomy after ten years
[107]. The meta-analysis conducted by Li et al. with 685
patients demonstrated that local recurrence occurred in
5.6% of patients who underwent mastectomy while BCS
resulted in 13.2% recurrence. The authors pointed out
that diagnostic inconsistencies along with different
treatment approaches prevented researchers from
concluding which procedure offered superior outcomes
between mastectomy and breast-conserving surgery.
The patients who experienced relapse after breast-

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conserving surgery developed invasive breast cancer
resulting in unfavorable outcomes [108]. The procedure
of sentinel lymph node biopsy (SLNB) should be
performed during mastectomy when invasive cancer
exists after histopathological examination to prevent
complete lymph node dissection [109].

Patients receiving BCS combined with radiotherapy
treatment for MPD and DCIS experienced a 90% overall
survival rate during 15 years and a 97% breast cancer-
specific survival rate [110]. A review of 38 research
studies demonstrated that BCS treatment with
radiotherapy produced better local recurrence results
than BCS without radiotherapy [101]. The lack of
radiotherapy during BCS resulted in local recurrence
rates reaching 40% and 33% in separate studies. The
authors determined that cone excision stands as an
inappropriate treatment method for MPD [111-113].
Post-resection breast or nipple reconstruction following
resection becomes vital for patients to reach their
aesthetic goals in the secondary management phase.
The restoration of breast symmetry after total or skin-
sparing

mastectomy

procedures

uses

Grisotti

mastopexy and Wise-pattern mammaplasty and
oncoplastic surgeries as standard techniques. The
Grisotti flap technique delivers outstanding aesthetic
results when treating Paget's disease patients with
central cancer locations. The reconstructive process
requires psychological attention because patients might
choose

immediate

or

delayed

nipple-areolar

reconstruction through skin flaps or medical tattooing to
match reconstructed nipples and areolas with opposite
sides. A patient underwent left mastectomy followed by
SLNB and immediate TRAM flap reconstruction from the
ipsilateral abdomen through pedicled transverse rectus
abdominal muscle (TRAM) technique. Medical
professionals consider the deep inferior epigastric
perforator (DIEP) flap as the best option but its use
remains restricted because it requires microvascular
surgery and specialized surgical expertise [2].
Neoadjuvant chemotherapy is gaining popularity for
breast cancer treatment and has shown improvements
in clinical outcomes [114]. According to NCCN
guidelines, chemotherapy is recommended for MPD
associated with invasive ductal carcinoma (IDC), but not
for MPD linked with DCIS. Therefore, the presence of
invasive carcinoma is an important consideration when

deciding on chemotherapy [115]. MPD cases are
predominantly classified as HER2-positive, and
hormone-sensitive chemotherapy can help reduce
disease recurrence and extend survival by targeting
tumor cells. For cases of MPD without invasive
components or with DCIS and estrogen receptor (ER)-
positive cells, low-dose tamoxifen (5 mg daily for three
years) is recommended as an adjuvant treatment [46].

Recent studies have shown promising results with
Glypican-3 (GPC3), a cell surface proteoglycan often
overexpressed in certain cancer types, serving as a
potential biomarker to differentiate MPD and IDC from
other breast cancer subtypes. GPC3 expression is
specifically found in HER2-positive tumors, suggesting
its potential as a therapeutic target for breast cancer
subtypes expressing GPC3 [116].

Prognosis and complications

Mammary Paget's Disease (MPD) can lead to a variety of
complications that significantly affect patient outcomes,
with local recurrence being the most common. Even
after successful treatment, there remains a risk of the
disease returning. However, recent research suggests
that the likelihood of recurrence following breast-
conserving surgery (BCS) is similar to that observed in
patients who undergo mastectomies [107]. Additionally,
individuals with invasive carcinoma are more prone to
experiencing local recurrence than those with non-
invasive carcinoma [101]. This finding aligns with
numerous studies indicating that MPD has a negative
impact on breast cancer survival. A study by Ordz-Pagan
et al. illustrated this by comparing the survival rates of
patients with breast cancer alone versus those with
MPD, showing a five-year survival rate of 93.8% for
breast cancer patients alone compared to 81.2% for
those with MPD [117]. Beyond local recurrence, MPD
also presents the risk of distant metastases, which are
often seen in the bones, lungs, liver, and brain. Lymph
node involvement is particularly common in MPD cases
[118]. When MPD occurs alongside invasive ductal
carcinoma (IDC), the likelihood of axillary lymph node
metastasis increases [33]. Both recurrence and
metastasis often necessitate aggressive treatment
strategies, including systemic chemotherapy, additional
surgical procedures, and adjuvant therapies [42].

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Several demographic factors have been found to
correlate with poorer five-year survival rates, including
race, age, and gender. Black patients tend to have a
shorter survival time compared to other ethnic groups.
Additionally, older patients generally have lower
survival rates [119]. Though MPD is less common in men,
their prognosis is generally worse, with a five-year
survival rate for women ranging between 30-50%, while
in men, it drops to 20-30% [120]. Pathological factors
such as lymph node status, tumor grade, cancer stage,
and the presence of metastases also play a significant
role in survival outcomes. Lymph node involvement is a
strong predictor of survival, with patients who have
negative lymph nodes showing a five-year survival rate
of 75-95%, compared to only 20-25% for those with
positive lymph nodes [5]. The involvement of axillary
lymph nodes further indicates a worse prognosis [33].
DCIS (ductal carcinoma in situ) patients have a better
survival outlook compared to those with invasive
carcinoma. The five-year survival rate for DCIS ranges
between 94-98%, while for invasive carcinoma, it ranges
from 73% to 93% [121]. These pathological factors
highlight the importance of early detection and timely
intervention to improve patient prognosis.

CONCLUSIONS

MPD is a rare, localized lesion found on the nipple-
areolar complex, frequently associated with underlying
breast cancer. The disease often begins with vague
symptoms such as itching, eczema, or redness of the
nipple, which can easily be mistaken for benign skin
conditions, including dermatitis or eczema. As the
disease progresses, the nipple-areolar complex may
erode,

resembling

more

aggressive

malignant

conditions like squamous cell carcinoma or basal cell
carcinoma. The persistent redness and itching
commonly raise concerns for both patients and doctors,
signaling the need for further investigation.

MPD presents unique diagnostic and treatment
challenges that healthcare providers must navigate. To
improve early detection and treatment outcomes, it is
crucial to establish standardized diagnostic criteria to
minimize the risk of misdiagnosis. Each patient should
receive personalized care, considering the specific
manifestation of their disease and associated risks.
Future research should aim to integrate advanced

molecular diagnostics with traditional imaging and
histopathological techniques, while also exploring novel
therapeutic approaches to enhance patient care.

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