Mammary Paget Disease (MPD) & Extramammary Paget disease (EMPD)

MAMMARY PAGET DISEASE (MPD)

MAMMARY PAGET DISEASE (MPD)/ PD OF THE NIPPLE/ PD OF THE BREAST

MPD is an uncommon skin malignancy

characterized by a chronic eczema-like

lesion of the nipple and adjacent areolar

skin.

MAMMARY PAGET DISEASE (MPD)/ PD OF THE NIPPLE/ PD OF THE BREAST

A progressive, well marginated (well

circumscribed), chronic eczematous change

due to invasion of the epidermis by malignant

Paget cells.

Paget cells originate in either invasive intraduct

carcinoma or ductal carcinoma in-situ (DCIS) of

in the deeper breast tissue.

A 55-year-old woman presented with one year history of unilateral

pruritic eczema-like rash confined to the areolar area of one breast.

MPD

A similar condition that involves the skin of the anogenital

regions of female and male where there are an abundance

of apocrine glands is known as extramammary Paget disease

(EMPD).

INCAIDENCE OF MPD

INCIDENCE OF MPD

Uncommon, 1-4% of female breast carcinoma cases are associated with PD of the nipple, the areola, and the surrounding skin.

Almost exclusively in ♀ involvement of the male breast is rarely reported.

Is most frequent in the 5th and 6th decade mean age at diagnosis of 55 years.

Nearly 100% of mammary PD cases are associated with an underlying carcinoma, either invasive intraduct carcinoma(90%) or ductal carcinoma in-situ (10%).

ETIOLOGY OF MPD

ETIOLOGY OF MPD

Intraepidermal extension of malignant ductal

epithelial cells (Paget cells) through the

lactiferous ducts and ductules into the

epidermis (EPIDERMOTROPISM) infiltrate

and proliferate in the epidermis.

ETIOLOGY OF MPD

PAGET

CELLS

Glandularstemcells

Epi-dermalTokercells

ETIOLOGY OF MPD

PAGET CELLS MAY BE DERIVED FROM:

1. GLANDULAR STEM CELLS:

Paget cell 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 or…..

ETIOLOGY OF MPD

PAGET CELLS MAY BE DERIVED FROM:

2. EPIDERMAL TOKER CELLS (clear cells of the nipple epithelium):

Due to the similarity of the immunophenotypes.

Toker cells have been found in about 10% of normal nipples and

rarely in supernumerary nipples and apocrine bearing areas.

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 & sometimes

proliferate, resulting in a condition known as clear cell papulosis.

C/P OF MPD

Paget's disease. Images macroscopic woman than 50 years that had

significant areolar eczema in the left region, which had been increasing in

the last six months, accompanied by itching. See as there accompanying

nipple retraction.

A 15yr old girl presented to the clinic with complaints of itching in the

nipple area of left breast for the past 2 years.

Showing an ulcerated erythematous plaque covering whole of the left

breast, the sub mammary area and adjacent part of abdominal wall,

covered with purulent to hemorrhagic crusts

Erythema, erosions and bloody discharge of 20 years old female

C/P OF MPD

SYMPTOMS 1. Nipple rash

2. Redness

3. Itching – Burning - pain

4. Oozing or Bloody Nipple discharge

5. Nipple retraction

6. Scaling- Crusting of skin

7. Swelling

8. Ulceration

C/P OF MPD

PHYSICAL EXAMINATION AT EARLY STAGE: The lesion usually begins at the nipple and gradually spread to the areola.

The early changes may be minimal, with a unilateralsmall, crusted and intermittently moist area on the nipple giving a brownish stain on clothing, or producing itching, pricking or burning sensations. Less often, there is a serous or blood-staineddischarge from the nipple, or a lump may be noticed in the breast.

The surface changes persist and gradually spread to produce an eczematous appearance.

C/P OF MPD

PHYSICAL EXAMINATION AT A LATER STAGE: Skin of the breast is erythematous and moist or crusted sharplymarginated, indurated & thickened plaques and may spare a segment of the areola.

The edge is slightly raised and irregular in outline.

If the crusts are removed, a red, glazed, moist or vegetating surfaceis revealed.

Itching may be a prominent symptom and excoriations may be found in the established lesion.

The nipple itself may be retracted, and a subjacent palpable massor a lump deeper in the breast may be felt. Nipple invagination is sometimes seen.

C/P OF MPD

The regional LN should be examined;

they are rarely enlarged when a mass

cannot be felt, but are enlarged in more

than half the cases with a detectable

tumor.

C/P OF MPD

The changes may occasionally involve not only the skin of

the breast but also spread on to the chest wall.

Poor prognosis is associated with invasive disease and the

presence of a palpable mass.

C/P OF MPD

Pigmented mammary PD and pigmentedextramammary PD are rare clinical entities in both males and females.

These diseases may mimic malignantmelanoma both clinically and histopathologically. They may also mimic melanoma on dermoscopic examination.

In pigmented lesions of PD, numbers of benign melanocytes are present, which may interfere with the correct diagnosis of PD.

DDx OF MPD

DIFFERENCE BETWEEN MPD & ECZEMA OF THE NIPPLE

DDx OF MPD

1) Eczema of the nipple

2) Bowen’s disease (very uncommon on the nipple)

3) Superficial BCC (very uncommon on the nipple)

4) Psoriasis

5) Amyloidosis

6) Erosive adenomatosis of the nipple.

7) Nipple duct adenoma

8) Drug Eruptions

9) Malignant melanoma

INVESTIGATIONS OF MPD


• Mammography

• MRI

• Ultrasound

I. Imaging: “3”

MPD: an area with microcalcifications in the lower inner left quadrant with

extension towards the nipple which shows retraction and some

calcifications within, there is also minimal extension towards the lower

outer left quadrant.

Paget's disease. Cranio-caudal mammograms of left breast of a patient diagnosed with Paget. Area of 10 cm that affects the external cuadrantswhich identifies multiple pleomorphic microcalcifications, very suspicious of malignancy, which at higher magnification (right) continue the road of

the nipple lactiferous duct (arrow)

MPD in right breast, unifocal, isolated in nipple.

BREAST PAGET DISEASE. 75 years old woman presenting a lesion in the

left nipple since 2 weeks ago. ULTRASOUND left retroareolar area:

where microcalcifications can be identied.


1. MAMMOGRAPHY:

Radiographic changes seen in MPD include the following: “4”

1. Subareolar microcalcifications (helpful in evaluating and locating

clinically occult, nonpalpable underlying breast carcinoma)

2. Architectural distortion

3. Thickening of the nipple and the areola (reflecting edema)

4. Nipple changes (in a minority of patients)

Negative preoperative mammography findings did not

reliably exclude an underlying carcinoma.


2. MRI of the involved breast can detect otherwise occult PD in

the setting of negative mammography findings.


3. ULTRASOUND to establish whether or not there is deeper

pathology in the underlying breast, as this will help determine

the extent of surgery required.


• Tzanck smear

• Biopsy of the tumor

• Sentinel lymph node biopsy

II. Tissue Analysis: “3”


TISSUE ANALYSIS: “3”

1. TZANCK SMEAR: The presence of large cells with a high nuclear-to-

cytoplasmic ratio, occasional acinar formation, and intracytoplasmic

vacuoles is diagnostic for malignant Paget cells.

2. BIOPSY OF THE TUMOR: Punch, wedge, or excisional biopsy.

3. SENTINEL LYMPH NODE BIOPSY: is performed in cases with an

invasive component.

Histopathological section showing large atypical round to oval cells

(arrow) infiltrating the lower part of epidermis having a pale cytoplasm

with prominent hyperchromatic nuclei

(A) The epidermis of the nipple infiltrated by large Paget’s cells with pale

abundant cytoplasm

(B) Single groups of Paget’s cells with vesicular nuclei and prominent

nucleoli

HISTOPATHOLOGY OF MPD

THE EPIDERMIS:

Hyperkeratosis or parakeratosis.

Acanthosis, with papillomatosis.

Enlargement of the rete ridges.

Characteristic Paget’s cells singly or in clusters (nests) are dispersed

between the prickle cells. They vary in number, and when profuse

the Malpighian layer may be disrupted and the surface covered by a

crust.

In the later stages, the epidermis may be atrophic or eroded.


Their ultrastructural features of Paget’s cells are those of

glandular epithelial cells it’s cytoplasm is PAS-positive &

packed with numerous rounded, membrane-bound mucin

granules.

Infiltration occurs by variable numbers of signet-ring forms

tumor cells that are present in all layers of the epidermis.

Mitotic figures are occasionally identified.


PAGET CELLS CLASSICALLY HAVE THE FOLLOWING HISTOLOGICAL FEATURES:

1. Large rounded or ovoid atypical cells

2. Abundant pale-staining cytoplasm

3. Mucin-positive

4. Enlarged, scattered mitochondria

5. Large rounded or ovoid vesicular-to-hyperchromatic nuclei with prominent nucleoli.

6. Scanty nuclear chromatin

7. They are devoid of intercellular bridges


In the ulcerated lesions of MPD, the epidermis is totally

replaced by Paget cells.

A large biopsy or excision may demonstrate the presence of

epidermal Paget cells and an underlying infiltrating or

intraductal carcinoma of the breast.

The Paget’s cells may also be seen in appendage ducts.


THE DERMIS chronic inflammatory reaction in the upper

dermis contains a dense infiltrate of lymphocytes, histiocytes,

plasma cells, and occasionally eosinophils.

AN UNDERLYING BREAST CARCINOMA may be seen on

large biopsy. The cells may accumulate within and distend

the ducts and spread in both directions. A number of ducts

are usually involved. At a later stage, the carcinoma becomes

invasive and behaves like classic breast carcinoma.


Several histologic variants of PD are as follows: “5”

1. Adenocarcinomalike cell type

2. Spindle cell type

3. Anaplastic cell type

4. Acantholytic cell type

5. Pigmented cell type

The clear appearance of cytoplasm in Paget’s disease is due to their

abundant content of neutral and acidic mucopolysaccharides which can

be demonstrated by PAS stain

The malignant cells are usually immunoreactive for Carcinoembryonic

antigen (CEA)

Immunohistochemistry showing positivity with epithelial membrane

antigen (EMA)

SPECIAL STAINS OF PAGET’S CELLS

1. PAS STAIN:

Paget’s cells shows PAS positive diastase-resistant granules,

indicating the presence of neutral mucopolysaccharides and

supports the glandular origin of the cells.

2. Alcian blue:

Positive.

IMMUNOHISTOCHEMISTRY

POSITIVE MARKERS OF PAGET'S CELLS ARE “5”:

1. CEA (Carcinoembryonic Antigen)

2. EMA (Epithelial Membrane Antigen)

3. CK7 Low molecular weight cytokeratins proposed as a specific and

nearly 100% sensitive marker for MPD.

4. CAM-5.2 (Cellular adhesion molecule) Glandular epithelial cell

markers.

5. erbB-2 (>90%)

IMMUNOHISTOCHEMISTRY

NEGATIVE MARKERS OF PAGET'S CELLS, which serve as

differentiating features from malignant melanoma “5”:

1. Anti-s-100 protein

2. Melan A (MART-1)

3. HMB-45

4. Tyrosinase

5. DOPA

STAGING OF MPD

STAGING OF MPD

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

Rx OF MPD

Rx OF MPD

I. Mastectomy (radical or modified) and LN clearance

II. Photodynamic therapy (PDT)

III. Conservative management

Rx OF MPD

I. Mastectomy (radical or modified) and LN

clearance in cases with palpable mass and

underlying invasive breast carcinoma.

Rx OF MPD

II. Photodynamic therapy (PDT) using aminolevulinic acid (5-

ALA) for low-risk malignant cells

Rx OF MPD

III. Conservative management: In patients with no evidence of

an underlying breast carcinoma. Combination of “3 measures”;

1. Local excision of the nipple,

2. Wedge resection of the underlying breast tissue,

3. Radiation therapy: according to the presence or absence

of an invasive component.

EXTRAMAMMARY PAGET DISEASE

EXTRAMAMMARY PAGET DISEASE

EMPD is an uncommon tumor characterized

by a chronic eczema-like lesion of the skin

around the anogenital regions of males and

females.

In women the most common area involved is

the vulva.

The clinical and the histopathological findings

are very similar to the more common type of

MPD.

Grossly inflamed erythema on the vulva extending to the perineum.

There were whitish cheesy lesions on the wall of the vagina. Superficial

erosions were noted on the left posterior area. Her regional nodes were

not enlarged.

This man presented with a pruritic, erythematous, scaly, eroded dermatitis-like rash involved the perianal area of two months duration.

Three months before rash appearance the patient had suffered constipation and many episodes of rectal bleeding. Sigmoidoscopy

disclosed rectal carcinoma whereas perianal skin biopsy was consistent with extramammary Paget's disease.

Extramammary Paget disease, gross. The patient’s lesion on the glans

penis.

Clinical presentation of the well-demarked pink erythematous patch in

the left axilla

EMPD HAS BEEN CLASSIFIED INTO SEVERAL SUBTYPES:

primary cutaneous extramammary Paget disease arises from apocrine glands within the epidermis (in situ) or underlying skin appendages

primary cutaneous extramammary Paget disease (15-25%) is associated with invasive Paget disease or adenocarcinoma in situ.

extramammary Paget disease originates from underlying anal or rectal adenocarcinoma

extramammary Paget disease originates from bladder adenocarcinoma

Type1a

Type 1b

Type 2

Type 3

Rx OF EMPD

Wide local excision, vulvectomy, or Mohs micrographic

surgery is the standard treatment.

Recurrence is common (30-50%), so patients should be re-

examined every 3 months after surgery for the next 2 years,

after which annual follow-ups are recommended.

Recurrence generally leads to further surgery.

Rx OF EMPD

Non-surgical treatments for recurrent disease may include:

1. Radiotherapy

2. Laser ablation

3. Photodynamic therapy

4. 5-fluorouracil cream

5. Imiquimod cream

REFERENCES

Rook 8th edition.

Bolongia 3rd edition.

Google images.

http://www.dermnetnz.org

www.facebook.com/groups/dermatologycourseonline/

Mammary Paget Disease (MPD) & Extramammary Paget disease (EMPD)

Health & Medicine