Paget's disease of the breast

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]

Paget’s disease is an eczematous skin change of the ‘ that is usually associated with an underlying breast malignancy. Paget’s disease of the breast was first discovered by James Paget, a British surgeon and physiologist, in 1874.The characteristic erythema and eczematous changes of the nipple seen with Paget’s disease of the breast were first described by Velpeau in 1856. The correlation between intraductal cancer and Paget’s disease of the breast was by Jacobeus in 1904.The background for the epidermotropic theory, that ducts containing carcinoma cells were apparently connected to overlying nipples containing Paget’s cells, was demonstrated by Muir and Inglis in 1939 and 1946 respectively. The first case of Paget’s disease in a male was described by Elbogen in 1908.. Paget’s disease of the breast occurs in 1 – 4% of all female breast carcinoma cases. Paget’s disease of the breast occurs in 0.5–5% of all breast cancer cases and is invariably associated with underlying malignancy either overt or occult. WHO revealed that there are 800,000 up to 1 million new cases of breast cancer each year. An underlying breast carcinoma is found in >90% of patients with Paget’s disease. The majority of these cases are invasive disease although 40 – 45% are associated with ductal carcinoma in situ. Paget’s disease of the breast is more prevalent in postmenopausal women, usually after the sixth decade of life, but it has also been reported in adolescent and elderly patients. Females are more commonly affected with Paget’s disease of the breast than males. Male breast cancer accounts for less than 1% of all breast cancer and Paget’s disease represents 1-3% of all breast malignancies. Mammary Paget’s disease is almost always associated with an underlying breast cancer in 92–100% of cases. Approximately 50% of this patients present with an associated palpable mass in the breast. On microscopic histopathological analysis, epidermal Paget cells which are malignant glandular epithelial cells organized in groups with nest-like patterns or gland-like structures and are preferably located in the epidermal basal layer are characteristic findings of Paget’s disease of the breast. Common risk factors in the development of Paget’s disease of the breast are female more than male, incidence is higher with increase in age and people of African or Ashkenazi Jewish descent. Personal or family history of breast cancer Environmental exposure to radiation, high temperature and electromagnetic fields. Genetic mutations like BRCA1, BRCA2 4-14% of male breast cancer, klinefelter’s syndrome in males. Mutations in RAD51B, PALB2, CYP17, CHEK2, BRIP1, RAD51C and androgen receptors. BRIP1 and RAD51C have not been seen in male patients. Endocrine-related states with hyperestrogenism such as obesity, exogenous estrogen, testicular dystrophic lesions in males. Symptoms of Paget’s disease of the breast include itching, redness, thickened skin, and ulceration of the nipple. Common physical examination findings of Paget’s disease of the breast include eczematous appearance of the nipple associated with yellowish or bloody discharge. Due to close similarity with many skin lesions, the diagnosis of Mammary Paget’s Diseas may be delayed or many cases can be misdiagnosed. Immunohistochemical staining for cytokeratin, epithelial membrane antigen (EMA) and c-erb-B2 oncoprotein is useful for the differential diagnosis. Toker cells found in the epidermis of the nipple, close to the opening of lactiferous ducts, along the basal layer of the epidermis, are morphologicaland immunohistochemical similar to mammary Paget’s cells. In contrast to Paget’s cells which are strongly associated with both Ki-67 and Her-2/c-erbB-2 and these markers are mostly used to distinguish Paget’s cells from Toker cells. In case of atypical Toker cells a combination of CD138 and p53 is very helpful in distinguishing these atypical cells from Paget’s cells. Paget’s disease of the breast must be differentiated from atopic dermatitis, eczema, psoriasis, malignant melanoma, Bowen’s disease, basal cell carcinoma, benign intraductal papilloma, nevoid hyperkeratosis of the nipple and areola (NHNA), squamous metaplasia of lactiferous ducts (SMOLD)/ Zuska’s disease and pagetoid dyskeratosis. The prognosis for people with Paget’s disease of the breast is primarily determined by the underlying tumor. Unfavorable prognosis is seen in cases with palpable breast tumor, enlarged lymph nodesand in patients younger than 60 years of age. Prognosis is worse in males than in females. Mean survival was found to be 80.0 months for males and 108.2 months for females. Five-year survival rate has been reported to be 20-30% in males, compared to 30-40% in females. This has been hypothesized to be due to the small size of mammary gland in males. A full-thickness biopsy of the nipple and areola is important for establishing the diagnosis of Paget’s disease of the breast. Findings on biopsy diagnostic of Paget’s disease of the breast include presence of Paget cells, which are arranged in solid groups.Ultrasonography of the breast may be performed to detect the breast cancer associated with Paget’s disease of the breast. It must be considered as a part of the initial evaluation in patients with negative mammography. MRI may be performed to detect the breast cancer associated with Paget’s disease of the breast. In the setting of clinically and mammographically occult Paget’s disease MRI can be very useful, mainly since mammography and ultrasonography have limitations in the evaluation of patients with Paget’s disease. MRI also has a role in the preoperative evaluation of patients and might be healpful in facilitating treatment decisions. Mammogram may be performed to detect the breast cancer associated with Paget’s disease of the breast, but is not always a reliable procedure for detecting it as it has limited reliability in the detection of underlying DCIS in people with this disease. The use of touch/scrape smears for cytological diagnosis is recommended to prevent delay in diagnosis. Mainly in patients who are reluctant to undergo other diagnostic procedures such as wedge biopsy, shave biopsy, surgical excision. A negative result does not exclude the diagnosis of Paget’s disease of the breast. In vivo reflectance confocal microscopy allows visualization of the upper layers of the skin at a cellular resolution, may also assist in the early diagnosis of Paget’s disease in reluctant patients.Chemotherapy and radiotherapy are indicated for Paget’s disease of the breast as adjuvant therapy or palliative treatment in patients with underlying ductal carcinoma or invasive breast cancer. Mastectomy is the mainstay of treatment for Paget’s disease of the breast. Patients who do not have a palpable lump are treated with removal of the nipple and areola, followed by whole-breast radiation therapy, whereas patients with associated ductal carcinoma in situ or invasive breast cancer are treated with complete resection of the underlying disease with excision of the nipple–areola complex and radiation therapy of the remaining breast tissue. When lymph nodes are involved, more extensive axillary lymph node surgery may be needed. Adjunctive radiation may be required.

Paget’s disease of the breast was first discovered by James Paget, a British surgeon and physiologist, in 1874.The characteristic erythema and eczematous changes of the nipple seen with Paget’s disease of the breast were first described by Velpeau in 1856. The correlation between intraductal cancer and Paget’s disease of the breast was by Jacobeus in 1904.The background for the epidermotropic theory, that ducts containing carcinoma cells were apparently connected to overlying nipples containing Paget’s cells, was demonstrated by Muir and Inglis in 1939 and 1946 respectively. The first case of Paget’s disease in a male was described by Elbogen in 1908.

There is no classification system established for Paget’s disease of the breast.

On gross pathology, eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, infiltration of the nipple, and inversion of the nipple are characteristic findings of Paget’s disease of the breast. Eczema changes of the nipple-areolar complex are said to occur due to invasion of the overlying epidermis by malignant (Paget) cells.The commonly accepted hypothesis is that most cases of Paget’s disease of the breast originate from in situ or invasive ductal carcinoma of the underlying breast tissue. On microscopic histopathological analysis, epidermal Paget cells which are malignant glandular epithelial cells organized in groups with nest-like patterns or gland-like structures and are preferably located in the epidermal basal layer characteristic of Paget’s disease of the breast.On gross pathology nipple and areola show eczematoid, erythematous, moist or crusted lesions, with or without fine scaling, infiltration of the nipple, and inversion of the nipple are characteristic findings of Paget’s disease of the breast.Immunohistochemistry is very useful in Paget’s disease of the breast for differential diagnoses and histogenesis. The overexpression of the low molecular weight cytokeratins, notably CK7, and lack of expression of high molecular weight cytokeratins, such as CK10, CK14 and CK20 are observed in 98-100% of Paget’s disease of the Breast.

Mutations predisposing patients to Paget’s disease of the breast have not yet been described in the literature.It is currently hypothesized that intraepidermal cells of Paget’s disease may be intrinsically genetically different than those of the underlying breast carcinoma.This has been seen by specific chromosomal alterations identified by loss of heterozygosity and mitochondrial DNA displacement loop sequence analysis.The most widely accepted theory is that the disease results from an underlying intra-ductal breast carcinoma. The cancer cells are hypothesized to travel through lactiferous ducts to the nipple and its surrounding skin. Another theory is that the disease can develop independently in the nipple as an in-situ carcinoma.

Due to close similarity with many skin lesions, the diagnosis of Mammary Paget’s Diseas may be delayed or many cases can be misdiagnosed. Immunohistochemical staining for cytokeratin, epithelial membrane antigen(EMA) and c-erb-B2 oncoprotein is useful for the differential diagnosis. Toker cells found in the epidermis of the nipple, close to the opening of lactiferous ducts, along the basal layer of the epidermis, are morphologicaland immunohistochemical similar to mammary Paget’s cells. In contrast to Paget’s cells which are strongly associated with both Ki-67 and Her-2/c-erbB-2 and these markers are mostly used to distinguish Paget’s cells from Toker cells. In case of atypical Toker cells a combination of CD138 and p53 is very helpful in distinguishing these atypical cells from Paget’s cells. Paget’s disease of the breast must be differentiated from atopic dermatitis, eczema, psoriasis, malignant melanoma, Bowen’s disease, basal cell carcinoma, benign intraductal papilloma, nevoid hyperkeratosis of the nipple and areola (NHNA), squamous metaplasia of lactiferous ducts (SMOLD)/ Zuska’s disease and pagetoid dyskeratosis.

Paget’s disease of the breast occurs in 0.5–5% of all breast cancer cases and is invariably associated with underlying malignancy either overt or occult. WHO revealed that there are 800,000 up to 1 million new cases of breast cancer each year. An underlying breast carcinoma is found in >90% of patients with Paget’s disease. The majority of these cases are invasive disease although 40 – 45% are associated with ductal carcinoma in situ. Paget’s disease of the breast is more prevalent in postmenopausal women, usually after the sixth decade of life, but it has also been reported in adolescent and elderly patients. Females are more commonly affected with Paget’s disease of the breast than males. Male breast cancer accounts for less than 1% of all breast cancer and Paget’s disease represents 1-3% of all breast malignancies.

Common risk factors in the development of Paget’s disease of the breast are female more than male, incidence is higher with increase in age and people of African or Ashkenazi Jewish descent. Personal or family history of breast cancer Environmental exposure to radiation, high temperature and electromagnetic fields. Genetic mutations like BRCA1, BRCA2 4-14% of male breast cancer, klinefelter’s syndrome in males. Mutations in RAD51B, PALB2, CYP17, CHEK2, BRIP1, RAD51C and androgen receptors. BRIP1 and RAD51C have not been seen in male patients. Endocrine-related states with hyperestrogenism such as obesity, exogenous estrogen, testicular dystrophic lesions in males.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Paget’s disease of the breast.^[1]

The prognosis for people with Paget’s disease of the breast is primarily determined by the underlying tumor. Unfavorable prognosis is seen in cases with palpable breast tumor, enlarged lymph nodesand in patients younger than 60 years of age. Prognosis is worse in males than in females. Mean survival was found to be 80.0 months for males and 108.2 months for females. Five-year survival rate has been reported to be 20-30% in males, compared to 30-40% in females. This has been hypothesized to be due to the small size of mammary gland in males.

There is no established system for the staging of Paget’s disease of the breast. REDIRECT Breast cancer staging

Symptoms of Paget’s disease of the breast include itching, redness, thickened skin, and ulceration that begins at the nipple and spreads to the areola but can spread to surrounding skin. Lesion is sharply demarcated from the adjacent normal skin. Advanced lesions present as a round, ovoid or polycylic eczema-like plaque with a pink or red discoloration.

Common physical examination findings of Paget’s disease of the breast include eczematous appearance of the nipple associated with yellowish or bloody discharge.

A full-thickness biopsy of the nipple and areola is important for establishing the diagnosis of Paget’s disease of the breast. Findings on biopsy diagnostic of Paget’s disease of the breast include presence of Paget cells, which are arranged in solid groups.

Ultrasonography of the breast may be performed to detect the breast cancer associated with Paget’s disease of the breast. It must be considered as a part of the initial evaluation in patients with negative mammography.

MRI may be performed to detect the breast cancer associated with Paget’s disease of the breast. In the setting of clinically and mammographically occult Paget’s disease MRI can be very useful, mainly since mammography and ultrasonography have limitations in the evaluation of patients with Paget’s disease.MRI also has a role in the preoperative evaluation of patients and might be healpful in facilitating treatment decisions.

Mammogram may be performed to detect the breast cancer associated with Paget’s disease of the breast, but is not always a reliable procedure for detecting it as it has limited reliability in the detection of underlying DCIS in people with this disease.

The use of touch/scrape smears for cytological diagnosis is recommended to prevent delay in diagnosis. Mainly in patients who are reluctant to undergo other diagnostic procedures such as wedge biopsy, shave biopsy, surgical excision. A negative result does not exclude the diagnosis of Paget’s disease of the breast. In vivo reflectance confocal microscopy allows visualization of the upper layers of the skin at a cellular resolution, may also assist in the early diagnosis of Paget’s disease in reluctant patients.

Chemotherapy and radiotherapy are indicated for Paget’s disease of the breast as adjuvant therapy or palliative treatment in patients with underlying ductal carcinoma or invasive breast cancer. Surgery is the mainstay of treatment for Paget’s disease of the breast.

Mastectomy is the mainstay of treatment for Paget’s disease of the breast. Patients who do not have a palpable lump are treated with removal of the nipple and areola, followed by whole-breast radiation therapy, whereas patients with associated ductal carcinoma in situ or invasive breast cancer are treated with complete resection of the underlying disease with excision of the nipple–areola complex and radiation therapy of the remaining breast tissue. When lymph nodes are involved, more extensive axillary lymph node surgery may be needed.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

Paget’s disease of the breast was first discovered by James Paget, a British surgeon and physiologist, in 1874.The characteristic erythema and eczematous changes of the nipple seen with Paget’s disease of the breast were first described by Velpeau in 1856. The correlation between intraductal cancer and Paget’s disease of the breast was by Jacobeus in 1904.The background for the epidermotropic theory, that ducts containing carcinoma cells were apparently connected to overlying nipples containing Paget’s cells, was demonstrated by Muir and Inglis in 1939 and 1946 respectively. The first case of Paget’s disease in a male was described by Elbogen in 1908.

• The characteristic erythema and eczematous changes of the nipple seen with Paget’s disease of the breast were first described by Velpeau in 1856.
• Paget’s disease of the breast was first discovered by James Paget, a British surgeon and physiologist, in 1874^[1].
• Extramammary Paget’s disease (EMPD) is a histologically identical entity first described by Crocker in 1889^[2].
• The correlation between intraductal cancer and Paget’s disease of the breast was by Jacobeus in 1904.
• These findings of breast cancer being the underling cause of Paget’s disease was later supported by Muir and Inglis in 1935^[3].
• The background for the epidermotropic theory, that ducts containing carcinoma cells were apparently connected to overlying nipples containing Paget’s cells, was demonstrated by Muir and Inglis in 1939 and 1946 respectively^[4].
• The first case of Paget’s disease in a male was described by Elbogen in 1908^[5].

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

There is no classification system established for Paget’s disease of the breast.

There is no classification system established for Paget’s disease of the breast.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[5]

On gross pathology, eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, infiltration of the nipple, and inversion of the nipple are characteristic findings of Paget’s disease of the breast. Eczema changes of the nipple–areolar complex are said to occur due to invasion of the overlying epidermis by malignant (Paget) cells. The commonly accepted hypothesis is that most cases of Paget’s disease of the breast originate from in situ or invasive ductal carcinoma of the underlying breast tissue. On microscopic histopathological analysis, epidermal Paget cells which are malignant glandular epithelial cells organized in groups with nest-like patterns or gland-like structures and are preferably located in the epidermal basal layer characteristic of Paget’s disease of the breast.On gross pathology nipple and areola show eczematoid, erythematous, moist or crusted lesions, with or without fine scaling, infiltration of the nipple, and inversion of the nipple are characteristic findings of Paget’s disease of the breast.Immunohistochemistry is very useful in Paget’s disease of the breast for differential diagnoses and histogenesis. The overexpression of the low molecular weight cytokeratins, notably CK7, and lack of expression of high molecular weight cytokeratins, such as CK10, CK14 and CK20 are observed in 98-100% of Paget’s disease of the breast.

• The pathogenesis of Paget’s disease of the breast still remains controversial.
• The commonly accepted hypothesis is that most cases of Paget’s disease of the breast originate from in situ or invasive ductal carcinoma of the underlying breast tissue.This is supported by two different theories:^[1][2]

• Epidermotropic theory
• Intraepidermal transformation theory

Epidermotropic Theory

• According to this hypothesis malignant epithelial cells from intraductal carcinoma, extend into the overlying epidermis through mammary duct epithelium and proliferate in the epidermis causing thickening of the nipple and areolar skin.^[1]
• Normal epidermal keratinocytes produce and release the mobility factor heregulin-alpha which is chemotactic for heregulin receptors (Her-2) and coreceptors Her 3 and Her 4 which are produced by Pagets cells. This is thought to result in migration of these cells to the nipple epidermis.
• HER-2/neu has been shown to enhance the motility of tumor cells by interacting with a motility factor called heregulin-alpha secreted by epidermal keratinocytes.
• This chemotactic hypothesis is supported by the relatively high over-expression of HER-2/neu in Paget cells (90%) in comparison to it’s expression in breast cancer without Paget’s disease.
• This is supported by the observation that Paget cells often share cell surface markers with the underlying breast carcinoma (e.g CAM 5.2, CEA, c-erb 2 and EMA).^[3]

Intraepidermal transformation theory

• According to this hypothesis Paget cells are keratinocytes that have undergone malignant transformation.
• Thus it is speculated that Paget’s disease is an in situ carcinoma and is independent from any underlying parenchymal carcinoma.
• It is assumed that the underlying intraductal carcinoma coexisting with this disease is unrelated to the overlying eczematous change.
• Toker cells also known as pre-Paget cells are normal cells in the nipple epithelium which histologically demonstrate characteristics of both keratinocytes and Paget cells.
• This theory is further supported by:

• Cases in which there is no underlying malignancy nor there is any dermal invasion.
• Cases of collision tumors in which breast cancer is located peripheral to the nipple lesion, suggesting two concurrent but separate processes.
• Cases suggesting the Paget cells may have originated intraepidermally, by the presence of microvilli and desmosomal attachments between Paget cells and keratinocytes.
• Cases in which there is genetic variation between Paget cells and cells of the underlying carcinoma.^[4][5][3]

• On gross pathology nipple and areola show eczematoid, erythematous, moist or crusted lesions, with or without fine scaling, infiltration of the nipple, and inversion of the nipple are characteristic findings of Paget’s disease of the breast.^[2]

• Paget’s disease of the breast is histopathologically characterized by the presence of epidermal Paget cells.
• Paget cells are malignant glandular epithelial cells with abundant and clear cytoplasm, usually containing mucin and pleomorphic and hyperchromatic, centrally situated, variably atypical nucleus.^[2]
• Mitotic figures are frequently observed in cells which may be arranged singly or in form of clusters, solid nests, or gland-like structures with a central lumen.
• Paget cells are abundant mostly in the basal epidermal layer, mainly along the pilosebaceous apparatus.
• These cells stain positive for aldehyde fuchsin, mucin and periodic acid-Schiff. And are resistant to diastase digestion.^[7].
• The number of cells vary from a few to large quantities; even completely replacing the epidermal cells.
• This radial distribution of neoplastic cells along the basal layers of the epithelium is known as Pagetoid spread. It is also observed in malignant melanoma, Bowen’sdisease, mycosis fungoides, Langerhans cell histiocytosis, and spitz nevus.^{[8][7][9][10]}
• Invasion of adnexal structures can occur.
• Orthokeratosis and parakeratosis may be present.
• The dermis displays reactive characteristics, with telangiectasia, chronic inflammation, and ulceration in more advanced cases.
• There are several histologic variants of Paget’s disease include:^[6]
  • Adenocarcinoma-like cell type
  • Spindle cell type
  • Anaplastic cell type
  • Acantholytic cell type
  • Pigmented cell type

• Immunohistochemistry is very useful in Paget’s disease of the breast for differential diagnoses and histogenesis.^{[12][2][13][8][14][15][16][17]}

• The current understanding of immunohistochemistry of mammary Paget’s disease of breast is largely based on female cases.
• Previous studies have shown significantly difference in the immunohistochemical profiles and the prognostic roles of these markers, between male and female patients.^[18][19]
• The single most useful stain for differentiation Paget’s disease of the Breast from other intraepidermal neoplasms is cytokeratin 7.
• The overexpression of the low molecular weight cytokeratins, notably CK7, and lack of expression of high molecular weight cytokeratins, such as CK10, CK14 and CK20 are observed in 98-100% of Paget’s disease of the Breast.
• Furthermore, they also express carcinoembryonic antigen, epithelial membrane antigen, and some mucins.
• Since breast cancers associated to Paget’s disease are poorly differentiated, estrogen and progesterone antigens are frequently negative.
• Mori et al found overexpression of oncogenic ras and p21 in mammary and extramammary diseases.^[20]
• Paget cells express p53, p21, Ki-67, cyclin D1, androgen receptors and Her-2 oncoprotein.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]

Mutations predisposing patients to Paget’s disease of the breast have not yet been described in the literature.It is currently hypothesized that intraepidermal cells of Paget’s disease may be intrinsically genetically different than those of the underlying breast carcinoma.This has been seen by specific chromosomal alterations identified by loss of heterozygosity and mitochondrial DNA displacement loop sequence analysis.The most widely accepted theory is that the disease results from an underlying intra-ductal breast carcinoma. The cancer cells are hypothesized to travel through lactiferous ducts to the nipple and its surrounding skin. Another theory is that the disease can develop independently in the nipple as an in-situ carcinoma.

• The cause of Paget’s disease of the breast has not been identified.
• There are two widely excepted hypothesis:^[1][2][3]

• The most widely accepted theory is that the disease results from an underlying intra-ductal breast carcinoma. The cancer cells are hypothesized to travel through lactiferous ducts to the nipple and its surrounding skin.
• Another theory is that the disease can develop independently in the nipple as an in-situ carcinoma.

• Mutations predisposing patients to Paget’s disease of the breast have not yet been described in the literature.
• It is currently hypothesized that intraepidermal cells of Paget’s disease may be intrinsically genetically different than those of the underlying breast carcinoma.
• This has been seen by specific chromosomal alterations identified by loss of heterozygosity and mitochondrial DNA displacement loop sequence analysis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]

Due to close similarity with many skin lesions, the diagnosis of Mammary Paget’s diseas may be delayed or many cases can be misdiagnosed. Immunohistochemical staining for cytokeratin, epithelial membrane antigen (EMA) and c-erb-B2 oncoprotein is useful for the differential diagnosis. Toker cells found in the epidermis of the nipple, close to the opening of lactiferous ducts, along the basal layer of the epidermis, are morphological and immunohistochemical similar to mammary Paget’s cells. In contrast to Paget’s cells which are strongly associated with both Ki-67 and Her-2/c-erbB-2 and these markers are mostly used to distinguish Paget’s cells from Toker cells. In case of atypical Toker cells a combination of CD138 and p53 is very helpful in distinguishing these atypical cells from Paget’s cells. Paget’s disease of the breast must be differentiated from atopic dermatitis, eczema, psoriasis, malignant melanoma, Bowen’s disease, basal cell carcinoma, benign intraductal papilloma, nevoid hyperkeratosis of the nipple and areola (NHNA), squamous metaplasia of lactiferous ducts (SMOLD)/ Zuska’s disease and pagetoid dyskeratosis.

• The Paget’s disease of the breast is associated with changes in the nipple-areola complex.
• Any patient presenting with changes in the nipple or areola requires surgical biopsy of the nipple-areola complex for definitive diagnosis.
• Immunohistochemical staining for cytokeratin, epithelial membrane antigen (EMA) and c-erb-B2 oncoprotein is useful for the differential diagnosis.
• Due to close similarity with many skin lesions, the diagnosis of mammary Paget’s Diseas may be delayed or many cases can be misdiagnosed.
• Toker cells found in the epidermis of the nipple, close to the opening of lactiferous ducts, along the basal layer of the epidermis, are morphological and immunohistochemical similar to mammary Paget’s cells
• They are observed in about 10% of standard histological preparations of normal nipples and can be confused with Paget’s disease not associated with invasive carcinoma or DICS.
• Mainly in cases of Toker cell hyperplasia with cytologic atypia, it may be difficult to distinguish them from Paget’s cells.
• They are mainly distinguished from Paget’s cells due to the latter having large, pleomorphic and cytologically atypical nuclei.
• CK7 and Her-2/c-erbB-2 have been proposed to be specific and sensitive markers for Paget cells.
• Toker cells are said to be consistently positive for CK7 and estrogen receptors. Ki-67 and Her-2/c-erbB-2 are rarely expressed in these cells.
• In contrast to Paget’s cells which are strongly associated with both Ki-67 and Her-2/c-erbB-2 and these markers are mostly used to distinguish Paget’s cells from Toker cells.
• In case of atypical Toker cells a combination of CD138 and p53 is very helpful in distinguishing these atypical cells from Paget’s cells.^{[1][2][3][4][5][6]}

Paget’s disease of the breast is often confused with

• Eczema
• Dermatitis of the nipple
• Lactiferous duct ectasia
• Chronic eczema
• Psoriasis
• Nipple duct adenoma
• Malignant melanoma(particularly the pigmented lesions)
• Bowen’s disease
• Superficial basal cell carcinoma
• Squamous metaplasia of lactiferous ducts (SMOLD)/ Zuska’s disease
• Benign intraductal papilloma
• Nevoid hyperkeratosis of the nipple and areola (NHNA)
• Pagetoid dyskeratosis
• Mastitis
• Breast abcess

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]

Paget’s disease of the breast occurs in 0.5–5% of all breast cancer cases and is invariably associated with underlying malignancy either overt or occult. WHO revealed that there are 800,000 up to 1 million new cases of breast cancer each year. An underlying breast carcinoma is found in >90% of patients with Paget’s disease. The majority of these cases are invasive disease although 40 – 45% are associated with ductal carcinoma in situ. Paget’s disease of the breast is more prevalent in postmenopausal women, usually after the sixth decade of life, but it has also been reported in adolescent and elderly patients. Females are more commonly affected with Paget’s disease of the breast than males. Male breast cancer accounts for less than 1% of all breast cancer and Paget’s disease represents 1-3% of all breast malignancies.

• Paget’s disease of the breast occurs in 0.5–5% of all breast cancer cases and is invariably associated with underlying malignancy either overt or occult.
• WHO revealed that there are 800,000 up to 1 million new cases of breast cancer each year.^[1]
• An underlying breast carcinoma is found in >90% of patients with Paget’s disease.
• The majority of these cases are invasive disease although 40 – 45% are associated with ductal carcinoma in situ.^[2]

• Paget’s disease of the breast is more prevalent in postmenopausal women, usually after the sixth decade of life, but it has also been reported in adolescent and elderly patients.

• Females are more commonly affected with Paget’s disease of the breast than males.^[3]
• Male breast cancer accounts for less than 1% of all breast cancer and Paget’s disease represents 1-3% of all breast malignancies.^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]

Common risk factors in the development of Paget’s disease of the breast are female more than male, incidence is higher with increase in age and people of African or Ashkenazi Jewish descent. Personal or family history of breast cancer, environmental exposure to radiation, high temperature and electromagnetic fields. Genetic mutations like BRCA1, BRCA2 4-14% of male breast cancer, klinefelter’s syndrome in males. Mutations in RAD51B, PALB2, CYP17, CHEK2, BRIP1, RAD51C and androgen receptors. BRIP1 and RAD51C have not been seen in male patients. Endocrine-related states with hyperestrogenism such as obesity, exogenous estrogen, testicular dystrophic lesions in males.

Common risk factors in the development of Paget’s disease of the breast are.^[1][2][3][4]

• Gender female > male
• Age incidence is higher with increase in age
• Personal history of breast cancer
• Family history of breast cancer
• Irradiation
• Genetic mutations
  • BRCA1
  • BRCA2 4-14% of male breast cancer
  • Klinefelter’s syndrome in males
  • Mutations in RAD51B, PALB2, CYP17, CHEK2, BRIP1, RAD51C and androgen receptors.
  • BRIP1 and RAD51C have not been seen in male patients.
• Endocrine-related states with hyperestrogenism such as:

• obesity
• Exogenous estrogen
• Testicular dystrophic lesions in males

• Environmental exposure to radiation, high temperature and electromagnetic fields.
• Orchitis/epididymitis in males.
• Volatile organic compounds (like: tetrachloroethylene, perchloroethylene, trichloroethylene, dichloroethylene, and benzene)
• Socio-demographic factors such as:

• People of African or Ashkenazi Jewish descent
• Excessive use of alcohol

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Paget’s disease of the breast.^[1]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Paget’s disease of the breast.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2]

The prognosis for people with Paget’s disease of the breast is primarily determined by the underlying tumor. Unfavorable prognosis is seen in cases with palpable breast tumor, enlarged lymph nodesand in patients younger than 60 years of age. Prognosis is worse in males than in females. Mean survival was found to be 80.0 months for males and 108.2 months for females. Five-year survival rate has been reported to be 20-30% in males, compared to 30-40% in females. This has been hypothesized to be due to the small size of mammary gland in males.

• The prognosis for people with Paget’s disease of the breast depends on a variety of factors, and is primarily determined by the underlying tumor.
• Some factors indicate an unfavorable prognosis, such as:^[1][2]

• Presence of palpable breast tumor
• Enlarged lymph nodes
• Histological type of breast cancer
• Patients younger than 60 years

• Prognosis of Paget’s disease is worse in males than in females.

• In patients with Paget’s disease of the breast mean survival was found to be 80.0 months for males and 108.2 months for females.
• Five-year survival rate has been reported to be 20-30% in males, compared to 30-40% in females. This has been hypothesized to be due to the small size of mammary gland in males.^[3][4]
• The presence of invasive cancer in the affected breast and the spread of cancer to nearby lymph nodes are associated with reduced survival.
• Lymph node involvement is correlated with median survival rates, reaching 75-95% when negative and 20 to 25% when positive.
• In another study, the mean 10-year survival rate was estimated at 47% in cases with positive lymph nodes and 93% in those with negative lymph nodes.
• When the disease occurs in males, the prognosis is poor, with an average 5-year survival rate of 20-30%.
• Patients with Paget disease concomitant infiltrating duct carcinoma (PD‐IDC)had the worst prognosis with 5‐year survival rate = 84.1%.
• The Paget disease concomitant intraductal carcinoma (PD‐DCIS) had the best prognosis with 5‐year survival rate = 97.5%.
• Among patients with Paget disease those who are married have a better prognosis than who were not.
• Marital status is said to be associated with the hormone receptor status in patients with PD‐IDC.^[5][6]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

Paget’s disease of the breast was first discovered by James Paget, a British surgeon and physiologist, in 1874.The characteristic erythema and eczematous changes of the nipple seen with Paget’s disease of the breast were first described by Velpeau in 1856. The correlation between intraductal cancer and Paget’s disease of the breast was by Jacobeus in 1904.The background for the epidermotropic theory, that ducts containing carcinoma cells were apparently connected to overlying nipples containing Paget’s cells, was demonstrated by Muir and Inglis in 1939 and 1946 respectively. The first case of Paget’s disease in a male was described by Elbogen in 1908.

• The characteristic erythema and eczematous changes of the nipple seen with Paget’s disease of the breast were first described by Velpeau in 1856.
• Paget’s disease of the breast was first discovered by James Paget, a British surgeon and physiologist, in 1874^[1].
• Extramammary Paget’s disease (EMPD) is a histologically identical entity first described by Crocker in 1889^[2].
• The correlation between intraductal cancer and Paget’s disease of the breast was by Jacobeus in 1904.
• These findings of breast cancer being the underling cause of Paget’s disease was later supported by Muir and Inglis in 1935^[3].
• The background for the epidermotropic theory, that ducts containing carcinoma cells were apparently connected to overlying nipples containing Paget’s cells, was demonstrated by Muir and Inglis in 1939 and 1946 respectively^[4].
• The first case of Paget’s disease in a male was described by Elbogen in 1908^[5].

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