Paget's disease of the breast overview

# Overview
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 Pagets disease of the breast were first described by Velpeau in 1856. The correlation between intraductal cancer and Pagets 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 Pagets 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 0.55% 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 92100% 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 Pagets 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.

# Historical Perspective
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 Pagets disease of the breast were first described by Velpeau in 1856. The correlation between intraductal cancer and Pagets 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 Pagets 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.

# Classification
There is no classification system established for Paget's disease of the breast.

# Pathophysiology
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.

# Causes
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.

# Differential Diagnosis
Due to close similarity with many skin lesions, the diagnosis of Mammary Pagets 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.

# Epidemiology and Demographics
Paget's disease of the breast occurs in 0.55% 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.

# Risk Factors
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.

# Screening
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.

# Natural History, Complications and Prognosis
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.

# Diagnosis

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

## History and Symptoms
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.

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

## Biopsy
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
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
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.

## Other Imaging Findings
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.

## Other Diagnostic Studies
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.

# Treatment

## Medical Therapy
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.

## Surgery
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.