NORD gratefully acknowledges V. K. Gadi, MD, PhD, Associate Professor, University of Washington Medical Center; Associate Member, Fred Hutchinson Cancer Research Center, for assistance in the preparation of this report.
Paget's disease of the breast is a rare form of breast cancer that almost exclusively occurs in women. However, rare cases have been reported in men. Paget's disease of the breast is characterized by inflammatory, "eczema-like" changes of the nipple that may extend to involve the areola, which is the circular, darkened (pigmented) region of skin surrounding the nipple. Initial findings often include itching (pruritus), scaling, and crusting of and/or discharge from the nipple. In individuals with Paget's disease of the breast, distinctive tumor cells (known as Paget cells) are present within the outermost layer of skin (epidermis) of the nipple, when viewed under a microscope. Most women with this disorder have an underlying cancer (malignancy) affecting the milk ducts (ductal carcinoma). The milk ducts are the channels that carry milk secreted by lobes of the breast to the nipple. The exact cause of Paget's disease of the breast is not fully understood.
Paget's disease of the breast was originally reported in 1874 by Sir James Paget, an English surgeon, who also described an unrelated skeletal condition known as Paget's disease of the bone. It is essential to note that these disorders are distinct entities that are medically unrelated.
Paget’s disease of the breast is a malignant (cancerous) condition that initially appears as chronic, inflammatory, “eczema-like” changes of the nipple and adjacent areas.
In individuals with Paget’s disease of the breast, initial characteristic skin changes may include the appearance of reddish (erythematous), scaling, crusting, and/or abnormally thickened skin patches (plaques) or lesions on the nipple that may extend to adjacent areas of the areola. Some affected individuals may also have abnormal discharge from the nipple. Additional symptoms may include itching (pruritus) or burning sensations and/or oozing or bleeding of the affected area. Eventually, pain and sensitivity of the affected area may be present. Early on, the skin symptoms of Paget’s disease of the breast may fluctuate, improving only to worsen again. Paget’s disease of the breast usually affects one breast (unilateral), but there are rare cases in which both breasts are involved (bilateral).
The initial skin changes of Paget’s disease of the breast may appear relatively benign and many individuals may overlook such symptoms, mistakenly attributing them to an inflammatory skin condition or infection. As a result, diagnosis may be delayed, often up to six months or more. Most individuals with the condition eventually seek medical attention due to associated itching or burning sensations, soreness, or pain of the affected area.
Most women with Paget’s disease of the breast have an underlying malignancy, which may be completely contained within the milk ducts (ductal carcinoma in situ) or may have invaded the surrounding tissue, potentially spreading to the lymph nodes under the arms (axillary lymph nodes) and other regions of the body (metastatic disease).
Approximately 50 percent or more of affected individuals may have a lump or mass that may be felt (palpated) below the nipple. Some individuals with Paget’s disease of the breast may have additional symptoms or physical findings. For example, in some instances, the nipple may turn inward (retracted nipple).
The overall disease course may vary greatly from one person to another, depending upon the nature and size of an underlying malignancy, whether a palpable breast tumor is present upon diagnosis, whether metastatic disease is present, specific treatment measures followed, and other possible factors.
Two main theories have been proposed to explain the development of Paget’s disease of the breast. One theory suggests that distinctive cancer cells called Paget’s cells break off from an underlying tumor or malignancy within the breast and travel through the milk ducts to the nipples. Supportive evidence includes laboratory studies demonstrating that Paget cells and the underlying breast cancer share certain characteristics, thus appearing to originate from the same cell population. In addition, malignant cells have been shown to extend along breast ductal tissue from the underlying breast tumor to the nipple. Accordingly, many researchers have concluded that Paget cells appear to be derived from the lining (epithelium) of the milk ducts, invading and multiplying (proliferating) within the surface tissue (epidermis) of the nipple and adjacent areas of the areola. This theory explains why most individuals with Paget’s disease of the breast have an underlying form of cancer.
The second theory suggests that the presence and spread of Paget cells represents a distinct disease process originating in the outer skin layer of the nipple. The malignant changes occur without warning and for no known reason (spontaneously). This theory would explain the rare cases where no underlying malignancy is present or where the underlying malignancy is a different tumor type.
As with other cancers, the exact underlying cause or causes of malignancy associated with Paget’s disease of the breast remain unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals and ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators at the National Cancer Institute and elsewhere are conducting ongoing basic research to learn more about the many factors that may result in cancer.
In individuals with cancer, including breast malignancies, tumor development results from abnormal changes in the structure of certain cells. The specific cause of such changes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. In many patients, these abnormal changes may appear to occur spontaneously for unknown reasons (sporadically).
Cells that undergo malignant transformation typically revert to a less specialized, more primitive form (anaplasia or loss of differentiation), meaning that they are no longer capable of performing their intended, specialized functions within the tissue in question. Malignant cells pass their abnormal changes on to their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate. This uncontrolled cellular growth may eventually result in invasion of surrounding tissues, infiltration of regional lymph nodes, and spread of the malignancy (metastasis) via the bloodstream, the lymphatic circulation, or other means.
Paget’s disease of the breast is a rare form of breast cancer that almost exclusively affects women. However, there have been rare cases in which the disorder has occurred in men. Paget’s disease of the breast most commonly affects middle-aged individuals, primarily occurring between 50 to 60 years of age, although it has been reported in individuals in their 20s. It is thought to represent less than 5 percent of all breast cancer clinical presentations. The exact prevalence and incidence of Paget’s disease of the breast in the general population is unknown.
Paget’s disease of the breast is diagnosed based upon thorough clinical examination, identification of characteristic physical findings, a complete patient history, and a variety of specialized tests. The disorder can be confused with other skin conditions such as eczema potentially causing a delay in the diagnosis.
Clinical Testing and Work-Up
Tests that may be used to help diagnose Paget’s disease of the breast include blood tests, surgical removal (biopsy) and microscopic examination of affected breast tissue, mammography or other specialized imaging of the breasts, and/or microscopic evaluation of any nipple discharge for cancerous cells (cytologic smear).
During a biopsy a small sample of breast tissue is taken and examined under a microscope to determine whether Paget cells are present. If a lump is found in the breast, a sample of that tissue will also be taken.
A mammogram is an x-ray of the breast tissue and may be used to determine whether Paget cells are present. Mammography is also used to detect or rule out whether an underlying cancer is present. Additional specialized imaging techniques such as an ultrasound or magnetic resonance imaging (MRI) may be used to create additional images of the breast and to determine whether an underlying cancer is present.
If nipple discharge is present, a sample may be taken and studied to detect the presence of Paget cells.
If affected individuals have an underlying invasive cancer, then a sentinel lymph node biopsy may be performed. During this biopsy, a sample of tissue is taken from the lymph nodes under the armpits (axillary lymph nodes) to check and see whether cancer has spread to this area. A physician will locate and remove the sentinel lymph node, which refers to the first (or first few) lymph node(s) to which cancer cells are most likely to spread.
The therapeutic management of individuals with Paget’s disease of the breast may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses and other healthcare professionals.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as extent of the primary tumor (stage) and degree of malignancy (grade); the nature, size, and invasiveness of an underlying breast malignancy and the presence or absence of metastatic disease; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.
Treatment has traditionally included surgical removal of breast tissue, adjacent lymph nodes, and, in some cases, underlying muscles of the upper chest wall and other tissues (modified radical or radical mastectomy). Some individuals may only require a simple mastectomy, in which the breast and the lining over the chest muscles are removed.
In selected cases where there is no palpable breast mass and negative mammograms, or in those with disease confined to the nipple and areola, conservative tissue-sparing surgery (lumpectomy) may be recommended. During this surgery, the nipple and areola are removed along with a small section of breast tissue. A physician will attempt to remove as little breast tissue as necessary. Individuals who received a lumpectomy will receive follow up radiation therapy.
Individuals with Paget’s disease of the breast will receive additional, supportive therapy called adjuvant therapy that is designed to complement surgery and prevent the cancer from recurring. Adjuvant therapy may include radiation therapy, anti-cancer drugs (chemotherapy) and hormone therapy.
Paget’s disease of the breast has a prognosis that is intimately tied with the underlying ductal cancer. The underlying ductal cancers often have poor prognostic features than typical, often screen detected breast cancers including higher grade, larger size, and negative hormone receptor expression (loss of estrogen and progesterone) receptors. However, a Paget’s presentation does not make the prognosis any worse than the underlying malignancy’s prognosis.
Photodynamic therapy (PDT), a procedure in which a drug known as a photosensitizer is used along with a special type light, has been used to treat some individuals with extramammary Paget’s disease and in rare cases of Paget’s disease of the breast. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A specific wavelength of light is used to active the drug which binds with oxygen creating a chemical that destroys the affected cells. Initial results have shown that PDT is safe, well tolerated and may be a less invasive alternative therapy for individuals with Paget’s disease of the breast. However, studies so far have been limited and more research is necessary to determine the long-term safety and effectiveness off PDT for the treatment of individuals with Paget’s disease of the breast.
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