eMedicine Specialties > Dermatology > Malignant Neoplasms
Paget Disease, Mammary
Updated: Dec 17, 2009
Introduction
Background
Sir James Paget first described Paget disease of the breast in 1874. He reported a chronic eczematous disease on the skin of the nipple and the areola in 15 women, with an associated intraductal carcinoma of the underlying mammary gland. In 1881, Thin illustrated the first histologic description of Paget disease. Crocker described the first case of extramammary Paget disease (skin disorder presenting with clinical findings similar to those in mammary Paget disease) on the glans penis in 1889. In 1901, Dubreuilh reported a case on the vulva.
Mammary Paget disease occurs almost exclusively in women. Involvement of the male breast is rarely reported. Patients with Paget disease frequently present with a chronic, eczematous rash on the nipple and adjacent areolar skin. Proper recognition of this disorder is required to initiate an appropriate workup (eg, skin biopsy) for differentiating it from other benign inflammatory dermatosis and for detecting an underlying breast carcinoma. A similar disease involving the skin of female and male external genitalia (ie, vulva, glans penis) is known as extramammary Paget disease. Histologic features of mammary Paget disease and extramammary Paget disease are similar; however, the histogenesis and the pathogenesis are different.
Pathophysiology
The pathogenesis of mammary Paget disease and the origin of Paget cells were once controversial. It is now widely accepted as an underlying intraductal carcinoma of the breast with retrograde extension into the overlying epidermis through mammary duct epithelium. Malignant epithelial (Paget) cells infiltrate and proliferate in the epidermis, causing thickening of the nipple and the areolar skin. These tumorous epithelial cells are derived from luminal lactiferous ductal epithelium of the breast tissue, as shown in the image.
Schematic diagram of a female breast depicting the widely accepted concept of pathogenesis of mammary Paget disease. The malignant Paget cells are derived from luminal lactiferous ductal epithelium (A) of the breast tissue with retrograde extension of cancerous Paget cells into the epidermis of the overlying nipple (B). Details are shown in the enlarged circle that reveal thickening of both the lining epithelium of the breast duct and the nipple skin.
They possess microscopic features of glandular cells. Paget cells and underlying ductal carcinoma cells have been shown to be positive for the oncogene Her-2 Neu, suggesting common genetic alterations for both the epidermal and breast tumor cells.
Speculation is that Paget cells may derive from glandular stem cells and/or epidermal Toker cells (clear cells of the nipple epithelium).Toker cells have been found in about 10% of normal nipples and rarely in supernumerary nipples on the mild line and apocrine bearing areas.1 Similar to Paget cells of both mammary and extramammary sites, Toker cells contain prominent clear (vacuolated) cytoplasm and are considered benign counterparts of Paget cells. Mammary Paget cells are malignant epithelial cells derived from underlying ductal adenocarcinoma of the breast that invade into the skin of nipple and areolar areas. Toker cells are benign and may sometimes proliferate.1
In 2001, Kuan et al2 reported on the immunohistochemical expression of apomucin MUC1, MUC2, and MUC5AC in Paget disease and concluded that both epidermal Paget cells and underlying ductal carcinoma exhibit the same phenotypic apomucins that are also expressed by the Toker cells. In 2003, Morandi et al3 reported chromosomal alterations, such as loss of heterozygosity and mitochondrial DNA displacement loop sequence analysis, seen in Paget cells are different from those in underlying breast carcinoma cells. They suggested that the epidermal Paget cells are genetically different from those of breast carcinoma.
A concept of a "collision" (coexisting) of neoplastic lesion of mammary Paget disease and underlying carcinoma is therefore presented. However, this study is based on only a few cases. Further studies are necessary to arrive at a more definitive conclusion concerning collision lesions.
Paget cells often express cell markers that mimic those of the underlying breast carcinoma, including glandular epithelial cell markers (ie, low-molecular-weight cytokeratins [CKs], or CAM 5.2). They also express tumor markers, including carcinoembryonic antigen (CEA); Ca 15-3 (milk fat globule protein); some oncogenes (TP53, c-erb B-2) (approximately 85% of cases tested for c-erb B-2 are positive); and other cell markers, such as epithelial membrane antigen (EMA) (all cases tested are EMA positive) and gross cystic disease fluid protein (GCDFP-15) that are found in tumor cells of ductal carcinoma of the breast. Paget cells also 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 at pH 2.5 in 32% and 18%, respectively.
Advances in immunohistochemistry further define the histogenesis of Paget cells. CK7 has been proposed as a specific and nearly 100% sensitive marker for mammary Paget disease; while CK20 is negative in mammary Paget cells, about 33% of cases of extramammary Paget disease express this marker.
The mechanism by which large neoplastic cells of glandular origin, ie, the Paget cells infiltrate and spread to the overlying epidermal layers of the nipple and adjacent areola is induced by a mobility factor (heregulin-alpha) that acts through the HER2/NEU receptor.4 Normal epidermal keratinocytes produce and release the mobility factor heregulin-alpha. This factor plays a significant role in the pathogenesis of Paget disease. Paget cells express heregulin receptors HER2/NEU and coreceptors HER3 and HER4. These receptor complexes on Paget cells bind heregulin-alpha, the mobility factor, resulting in the chemotaxis of breast ductal carcinoma cells. This process, in turn, causes migration and infiltration of Paget cells into the overlying epidermis of the nipple and the areolar skin.
Molecular studies have shown that abnormal plakoglobin (one of the cell-to-cell adhesion proteins) may be involved in the formation of some cases of Paget disease of the breast and the vulva; and reduced expression of E-cadherin (another cell-cell adhesion protein) may have a role in the pathogenesis of extramammary Paget disease.5
Frequency
United States
About 1-4% of female breast carcinoma cases are associated with Paget disease of the nipple, the areola, and the surrounding skin; nearly 100% of mammary Paget disease cases are associated with an underlying carcinoma, either in situ (intraductal, 10%) or infiltrating cancer (90%). Occasional cases of Paget disease have been reported in ectopic breast (1) or supernumerary nipples (2).6
International
The exact frequency of mammary Paget disease is unclear.
Mortality/Morbidity
One half (50%) of patients with Paget disease presenting with a palpable breast mass have associated axillary lymph node metastasis. Two thirds of patients with axillary node metastasis were reported to have a palpable breast mass, whereas one third of patients with axillary metastasis did not have a palpable mass. Even in patients with mammary Paget disease and no underlying tumor, 30% may develop an invasive carcinoma at a later date, and 20% of patients already have an associated in situ carcinoma of the breast. However, other reports indicate that no axillary metastases were detected in patients without a palpable breast mass.
- Survival is related to the presence or the absence of a palpable breast tumor. When present, the prognosis is the poorest. About 31 (62%) of 50 patients with mammary Paget disease present with a detectable breast mass.
- Patients with an identifiable associated underlying breast tumor have a survival rate of 38-40% at 5 years and a survival rate of 22-33% at 10 years. The death rate of metastatic breast carcinoma in patients with mammary Paget disease and underlying cancer is 61.3%, with a 10-year cumulative survival rate of 33%.
- The reported survival rate of patients with Paget disease without a palpable breast tumor (prior to surgery) ranges from 92-94% at 5 years and from 82-91% at 10 years.
Race
No racial predisposition is reported for mammary Paget disease.
Sex
Mammary Paget disease occurs almost exclusively in females. Paget disease of the male breast is extremely rare. The estimated occurrence of male breast carcinoma is only 1% of the rate in females. A rare case of Paget disease in the male breast was recorded after treatment of a prostate carcinoma with estrogen.
Age
In female patients with mammary Paget disease, ages range from 24-84 years, with a mean age at diagnosis of 55 years; the average age range is 53-59 years. The average age of patients with mammary Paget disease is 5-10 years older than individuals with breast carcinoma. The age of onset in male patients is generally in the fifth and sixth decades, with a range from 48-80 years.
Clinical
History
Patients with mammary Paget disease present with a relatively long history of an eczematous skin lesion or persistent dermatitis in the nipple and adjacent areas.
- Eczematous skin lesions are associated with several symptoms.
- Erythema
- Scaling
- Itching
- Burning sensation
- Ulceration
- Oozing with serosanguineous discharge
- Bleeding
- Some combination of the above symptoms
- Early symptoms and signs of mammary Paget disease
- Excoriation from itching
- Resolution and recurrence of small vesicles within the skin lesion
- Symptoms of pain, itching, and a burning sensation prompt patients to seek medical attention.
Physical
- Scaly, erythematous, crusty, and thickened plaques on the nipple, spreading to the surrounding areolar areas, are typical (see images).
A biopsy-proven Paget disease involving the nipple of a 56-year-old woman. She noted the erythematous, swollen, enlarged nipple with focal ulceration and oozing. Occasional serosanguineous discharge and bleeding were present. The patient was later found to have a palpable breast mass and mammography results positive for subareolar microcalcification. No auxiliary lymphadenopathy was found. She was treated by simple mastectomy. At 5-year follow-up, the patient was alive without recurrent or metastatic tumor.
Clinical photograph of mammary Paget disease affecting a 48-year-old woman. She had experienced a prolonged history of chronic eczematous dermatitis of the nipple and areolar area for several years. The lesion did not respond to topical treatment, and it progressively distorted the nipple with expansion into the surrounding skin. Note a markedly scaly, crusted, and deformed nipple with a thickened, irregularly outlined adjacent nipple-areola complex. An excisional biopsy confirmed the diagnosis of mammary Paget disease. The patient developed an infiltrating ductal carcinoma of the underlying breast tissue with axillary lymph metastasis. She was treated by mastectomy and radiation. No metastatic tumor was noted in the axillary lymph node. She was alive and well 3 years after treatment.
- An erythematous patch in mammary Paget disease is usually sharply demarcated and infiltrated (unlike eczematous dermatitis).
- Retraction of the nipple (see image) or the presence of palpable nodules indicates an underlying breast cancer.
Nipple invagination, deformed nipple-areola complex, marked erythema, and alternating hyperpigmentation and hypopigmentation noted in the adjacent skin of the breast in a 65-year-old woman with biopsy-proven Paget disease. Note focal scaling of the previous biopsy site. The nipple changes were associated with an intraductal carcinoma of the breast. The patient was treated by conservative excision of the lesion and lumpectomy for the in situ carcinoma. No recurrence or metastatic disease was noted at 6-year follow-up.
- Serosanguineous discharge from the nipple may be present.
- Lesion size ranges from 3 mm to 15 cm in diameter; the mean size is 2.8 cm in diameter.
- Nipple invagination is sometimes seen (see image).
Nipple invagination, deformed nipple-areola complex, marked erythema, and alternating hyperpigmentation and hypopigmentation noted in the adjacent skin of the breast in a 65-year-old woman with biopsy-proven Paget disease. Note focal scaling of the previous biopsy site. The nipple changes were associated with an intraductal carcinoma of the breast. The patient was treated by conservative excision of the lesion and lumpectomy for the in situ carcinoma. No recurrence or metastatic disease was noted at 6-year follow-up.
- Nipple changes are associated with an underlying carcinoma of the breast (ie, in situ, infiltrating ductal carcinoma) in more than 98% of patients; as many as two thirds of patients have a palpable breast tumor.
- Unilateral involvement is the rule; however, bilateral mammary Paget disease has occasionally been reported.7
- Rare cases of female patients with Paget disease of supernumerary nipples have been reported.8
- Pigmented mammary Paget disease and pigmented extramammary Paget disease are rare clinical entities in both males and females. These diseases may mimic malignant melanoma both clinically and histopathologically. In pigmented lesions of Paget disease, increased numbers of benign melanocytes are present, which may interfere with the correct diagnosis of Paget disease, resulting in misinterpretation of Paget disease as malignant melanoma.9
Causes
Mammary Paget disease is always associated with an underlying carcinoma of the breast. The dermatosis reflects epidermotropism with spread of ductal carcinoma cells through the lactiferous ducts and ductules to the surface epidermis. By thorough histologic examination, Muir documented intraepidermal extension of malignant ductal epithelial cells from underlying breast tissue into the epidermis. The findings are the basis of the epidermotropic theory of mammary Paget disease.
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References
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Further Reading
Keywords
Paget disease, mammary Paget disease, PD, mammary PD, mammary Paget's disease, Paget's disease of the nipple and areola, Paget's disease of the skin, apocrine type, eczematoid epitheliomatous dermatosis, malignant papillary dermatosis
