The Paget's Disease of the breast.

An experience report and recent

TNM Updates
I. Radu, A. Panuța, B. Filip, N. Ioanid, Maria-Gabriela Aniței,
Ana-Maria Mușină, Mihaela-Mădălina Gavrilescu, D.V.
Scripcariu, Alexandra Antonescu, Alexandra Simona Avram, V.
Scripcariu

Clinica I Chirurgie Oncologică

 Definition
Paget disease of the
breast (PD) is histologically
defined as the presence of
neoplastic cells of glandular
differentiation, interspersed
between keratinocytes of
nipple epidermis, and most
often presents as an eczema-
like nipple lesion.
• Paget disease of the breast is named
after the 19th century British surgeon
and pathologist Sir James Paget, who, in
1874, noted a relationship between
changes in the nipple and breast cancer.
• Several other diseases are named after
Sir James Paget, including Paget disease
of bone and extramammary Paget
disease, which includes Paget disease of
the vulva and Paget disease of the penis.
• These other diseases are not related to
Paget disease of the breast.
 Incidence
• PD constitutes approx. 1% of the cases of
BC diagnosed in USA.
• 86% of cases were associated with an
underlying invasive or in situ carcinoma.
• The median patient age was
- 62 years in USA (SEER registry)
- 70 in a Scandinavian study,
- 48.1 in a large Chinese series
pathogenesis
• 1. Epidermotropic theory of PD development – the
neoplastic cells (commonly referred to
as Paget cells) result from the migration of cells
from the underlying adenocarcinoma through the
duct system into the epidermis.
This theory is supported by the existence of an
underlying carcinoma in about 90% of cases of PD,
which usually shares phenotypic similarities
with Paget cells.
Paget’s cells
• Classic histologic picture of
Paget disease, as neoplastic
cells with clear cytoplasm and
pleomorphic nuclei
interspersed singly and in
clusters among normal-
appearing native keratinocytes.
• Notice the chronic
inflammation of underlying
dermis.
• Tumor cells are positive for
HER2 overexpression.
pathogenesis
2. Molecular theory: heregulin-α (produced by
keratinocytes) induces spreading, motility and
chemotaxis of cultured breast cancer cells, a
phenomenon likely mediated through its binding to
HER3 or HER4 receptors, which in turn are
dimerized to highly overexpressed HER2.
• Vimentin associated with increased motility and
invasiveness
• P16 involved in the intraepithelial spread
of Paget cells.
pathogenesis
3. Intraepidermal transformation theory: Paget cells
arise in situ from transformation of multipotential
cells (Toker cells) in the epidermis or from the
terminal portion of the lactiferous duct at its junction
with the epidermis.
• Toker cells are clear cells that are located in the
skin of the nipple-areola complex.
• They are detected in up to 83% of cases when IHC
stains are used, distributed within the epidermis.
Toker cells
• Toker cells (arrows) are
seen in a large proportion
of normal nipples.
• They are believed to be
cells of lactiferous duct
or sebaceous gland origin,
migrating into the
epidermis of the nipple.
• Notice the similarities
with Paget cells, except
for their bland cytologic
features.
CLINICAL PRESENTATION
1. First symptom is nipple pruritus, pain, or burning
sensation(caused by lymphocytic infiltration and
angiogenesis)
2. Dermatological changes; crusty, erythematous
flaking, and irregular, raised, scaly skin lesions may
develop.
3. The spread is from the nipple to the areola and
then to surrounding skin (centrifugal direction)
4. As the disease progresses, bleeding, ulceration and
destruction of the nipple– areola complex occur.
 CLINICAL PRESENTATION
5. In up to 70% of patients with Pagetoid changes of the
nipple, an underlying malignancy is palpable
6. Nipple discharge (36% of patients) usually a result of
advanced local disease, rather than a consequence of Paget's
disease.
7. Rarely, the underlying malignancy causes retractions and
deformity of the nipple–areola complex and modifies the
natural contour of the breast
8. PD also may present hyperkeratosis, hyperpigmentation,
inversion (20% of cases), or distortion.
CLINICAL PRESENTATION (from literature)
 CLINICAL PRESENTATION

• PD may represent tumor persistence or recurrence

in patients with breast cancer treated with nipple-
sparing mastectomy.
• Rare cases may center in the axilla, associated with
underlying accessory mammary tissue.
• A case associated with surrounding ipsilateral
eruptive seborrheic keratoses (Leser-Trelat sign)
has been reported.
INVESTIGATION GOALS: Punch biopsy

• Confirmation that the

cutaneous disease is
Paget's and
• The detection of the
underlying malignancy.
BIOPSY: punch,
excisional. Full-thickness
biopsy is required.
• Histology: Paget cells.
• IHC: these cells stain for CK7,
CAM-5.2, AE1/AE3 and S100.
They do not stain for HMB-45 or
keratins, differentiating them from
melanoma
• Almost 90% of Paget's cells are
HER-2 positive
IMAGING
• bilateral mammography and ultrasound are the initial
steps in the imaging work-up.
• If a lesion is seen, it is investigated in standard
fashion.
• However, the sensitivity of mammography is limited;
in one series, mammography detected only 32% of
underlying carcinomas.
• Breast MRI: for clinically and mammographically
occult malignancies.
 TNM Classification of Breast Tumours, 8th edition (2016)
Tis Carcinoma in situ
Tis (DCIS) Ductal carcinoma in situ
Tis (LCIS) Lobular carcinoma in situa

Tis (Paget) Paget disease of the nipple not associated with

invasive carcinoma and/or carcinoma in situ (DCIS
and/or LCIS) in the underlying breast parenchyma.
Carcinomas in the breast parenchyma associated
with Paget disease are categorized based on the
size and characteristics of the parenchymal
disease, although the presence of Paget disease
should still be noted
Differential diagnosis
• Eczematous or other inflammatory dermatoses:
- atopic dermatitis, irritant or allergic contact
dermatitis, and psoriasis.
• DD of a scaling, eczematous, or ulcerated lesion of
the nipple also includes infections:
- Candidiasis
- Tinea corporis (dermatophyte infection), or
syphilis.
Differential diagnosis
• Various benign or malignant disorders
- erosive nipple adenoma, nevoid hyperkeratosis,
pemphigus vulgaris, sebaceous carcinoma, basal
cell carcinoma, Langerhans cell histiocytosis,
and pagetoid reticulosis–like T-cell lymphoma.
• Skin changes associated with nipple reconstruction
and tattooing may also mimic PD.
Differential diagnosis
Differential diagnosis

Pemphigus of the nipple Fox–Fordyce disease -

apocrine duct occlusion
Differential diagnosis

Hyperkeratosis of the Hyperkeratosis of the

nipple in women. nipple in man.
Differential diagnosis

Papillary adenomatosis of the nipple.

Management
• Historically, PD has been treated with modified
radical mastectomy
• The strong association of PD with underlying DCIS
or invasive cancer, its multicentricity in 20% to
80% of cases and esthetic concerns with central
lumpectomy and nipple-areolar complex
removal, have all been reasons for slow adoption
of breast conservation and sentinel node surgery
for patients presenting with PD
Management
• Breast conservation for PD was first described in
1984 by Lagios and colleagues.
• The European Organization for Research and
Treatment of Cancer 10871 trial is the only
published prospective study of breast conserving
surgery for PD.
• Of 61 patients with PD and DCIS (invasive cancers
were excluded) treated with breast conserving
surgery and radiotherapy, 5.2% showed a local
recurrence at 5 years.
 Our experience in management of Paget’s
Disease of the breast

• From 1264 cases of breast cancer (both sexes)

who have been treated in our surgical unit in a
period of 6 years and 5 months (May 2012 –
October 2018) 19 (1,5%) cases revealed
associated Paget’s disease.
• From 19 cases 18 were women and 1 was a man
(a very rare condition).
 Our experience in management of Paget’s
Disease of the breast
• Descriptive study (observational-transversal series
of cases) - number of cases <30, insufficient for
analytical study

• We included 19 (1.5%) cases of mammary

neoplasms (including DCIS and LCIS) with
associated Paget’s Disease of the breast
 Characteristics of our patients of Paget’s
Disease of the breast
• Average age in female cases was 60 years
• Median age in female cases was 62 with extremes
between 37 and 82 years.
• The only man in the study was 86 y.o. at the moment
of surgical treatment.
• 2/3 of patients were from urban environment
• All cases received clinical examination, breast
imaging, pathological confirmation and IHC
 Characteristics of our patients of Paget’s
Disease of the breast
• From 19 cases with PD 17 (89,47%) were
associated with a clinical detectable associated
tumor in the ipsilateral breast.
• 17 patients received surgical treatment
• 1 patient received an excisional biopsy
• 1 pregnant (6 weeks) patient (37 y.o.) with
metastatic breast cancer refused treatment
 Characteristics of our patients of Paget’s
Disease of the breast
• From 19 cases with PD 17 (89,74%) revealed
invasive breast carcinoma (15 cases of NST and
1 case lobular invasive carcinoma)
• 1 patient had an extensive DCIS associated with
PD
• 1 patient had PD of the breast without
underlying breast tumor
 Surgical treatment
• From 19 cases with PD 15 (83,(3)%) benefit of
Maddens type modified radical mastectomy
(including the male patient)
• 1 case received a BCS (central quadrantectomy)
• 1 case received a simple total mastectomy (extensive
DCIS case)
• 1 case received an excisional biopsy for confirmation
(the pregnant patient)
• 1 patient refused surgical treatment
 Primary breast tumor localization
• In 5 cases multicentricity or
multifocality was revealed
(in 3 cases including the central
quadrant, including the case of
the male with PD)
• Central quadrant – 7 cases
• Other quadrants – 5 cases
• No palpable breast tumor 2
cases
CLINICAL PRESENTATION (from our cases, Dr Radu’s Collection )
Paget’s disease of the breast in a male with invasive breast
carcinoma
 pTNM
From 17 patients that received surgical treatment :
• Stage 0 – 1 case • Stage IIIA – 3 cases
(5,88%) (17,64%)
• Stage IA – 5 cases • Stage IIIB – 2 cases
(29,41%) (11,76%)
• Stage IIA – 2 cases • Stage IIIC – 1 case
(11,76%) (5,88%)
• Stage IIB – 2 case • Stage IV – 1 case
(11,76%) (5,88%)
 Immunohistochemical characteristics

• 8 cases (47,05%) were HER2type (ER-;PR-)

• 5 cases (29,41%) were Luminal B

• 3 cases (17,64%) were Luminal A

Survival 73,6% (14 patients)
 Conclusion
• The data obtained in our study are quite similar to
international statistics on PD
• The relatively high incidence of multicentric and
multifocal breast cancer (26,3%) in our patients
with PD is to mention
• The predominance of HER2type (47%) also is a fact
that confirms the literature data
• The rate of BCS in PD in our statistics is
significantly lower than in other reference centers
Conclusion
• Any lesion of the nipple should be investigated
in order to exclude or confirm an associated
underlying breast cancer.

• Differential diagnosis with other dermatological

condition is especially important when Pagetoid
lessions of the nipple aren’t associated with a
palpable breast mass
Thank you!