By Amelia Scholtz
|A photomicrograph of a biopsy specimen reveals Paget cells (arrows), which are larger than the surrounding keratinocytes and have prominent nuclei and moderate amounts of pale cytoplasm (hematoxylin and eosin stain, original magnification x100).
A small, scaling rash around the nipple may not be just another case of eczema or dermatitis. Paget disease of the breast, a rare malignancy, is often mistaken for a benign dermatological condition. But Paget disease typically indicates underlying ductal carcinoma in situ or invasive breast cancer.
Paget disease of the breast is frequently misdiagnosed on initial presentation as eczema, which also may present as a rash affecting the nipple-areola complex. But Paget disease is seen in 1%–3% of new breast cancer cases. Paget disease of the breast is typically found in postmenopausal women 50–60 years old, although the disease also occurs in women of other ages and in men.
Unlike eczema and other benign skin conditions, Paget disease produces a firmness of the underlying tissue rather than a mere skin abnormality. In its initial stages, Paget disease typically appears as an erythematous, scaling lesion on the nipple. Patients may experience burning, pain, or itching at the lesion site. Flattening or retraction of the nipple, the spreading of the lesion to the areola, and a bloody discharge are associated with more advanced disease. Bilateral presentations of the disease are extremely rare.
Paget disease of the breast should also be distinguished from other types of malignant disease. Malignant melanoma may, like Paget lesions, have a scaly appearance. But unlike Paget disease of the breast, melanoma lesions do not bleed, itch, or cause pain. Also, melanoma typically involves changes in skin pigmentation while Paget disease does not. Inflammatory breast cancer, like Paget lesions, may present as an erythematous abnormality on the skin. However, Michael Stauder, M.D., an assistant professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, said, “Inflammatory breast cancer is characterized by rapid onset of disease often accompanied by a palpable underlying mass.”
In 85%–88% of Paget disease cases, the nipple ulceration is accompanied by underlying ductal carcinoma in situ or invasive cancer, which may be multifocal. In the remaining cases, however, Paget disease is restricted to the skin, with no evidence of malignancy in the underlying breast—so-called pure Paget disease.
Perhaps owing to its rarity, Paget disease’s pathogenesis is still not well understood. “There are two theories to explain how the disease originates, and I don’t think they’re mutually exclusive,” said Henry Kuerer, M.D., a professor in the Department of Surgical Oncology.
On the one hand, the epidermotropic theory holds that Paget cells develop as part of an underlying breast malignancy. Some Paget cells then migrate via the lactiferous ducts into the breast epidermis. Similarities revealed by immunohistochemical staining between Paget cells and ductal epithelial cells support this theory. Moreover, Paget cells, which are large and contain pale cytoplasm and prominent nuclei, may differ significantly from other nipple tissue. One limitation of the epidermotropic theory is that it does not account for the development of Paget disease in the absence of an underlying tumor.
On the other hand, the transformation theory holds that epidermal keratinocytes become malignant and transform into Paget cells. The existence of cases in which underlying disease is absent or relatively distant from the skin lesion lends weight to this theory. The identification in 1967 of what appear to be precursors to Paget cells—Toker cells—also supports the transformation theory. Defined by their clear cytoplasm, Toker cells have been observed across a spectrum from benign, to neoplastic, to atypical, to malignant.
It is possible that the two theories describe alternative pathways through which Paget’s disease may develop; however, this is a continued source of controversy, and many researchers favor the epidermotropic theory. According to Savitri Krishnamurthy, M.D., a professor in the Department of Pathology, the epidermotropic theory accounts for more Paget disease cases than does the transformation theory. “We don’t know precisely how Paget disease of the breast develops,” she said, “but I think it’s more common to see ductal movement of malignant cells than it is to see this transformation of Toker cells.”
Because of the initial clinical similarities between Paget disease and various benign conditions, patients commonly experience symptoms for several months before the histological diagnosis is made. The diagnostic workup for patients with symptoms resembling Paget disease typically begins with documentation of symptoms and a physical examination of both breasts. No risk factors specific to Paget disease have been identified to date, but clinicians consider risk factors for invasive breast cancer and ductal carcinoma in situ.
Patients with symptoms of Paget disease may be prescribed topical steroids at initial presentation to treat what appears to be a benign condition. “If the patient has developed scaling in the past week or so, it’s probably not appropriate to initially treat the problem as malignant,” Dr. Stauder said. “But if the abnormality has developed over months or years, there’s a need for more detailed investigation.”
If the lesion is not permanently resolved with steroid treatment, the patient should undergo bilateral mammography or ultrasonography. Inconclusive imaging results may necessitate a magnetic resonance imaging (MRI) study. Failure to find an underlying malignancy is one of the most serious problems that can occur in the diagnostic and treatment process. For this reason, Dr. Kuerer explained, “It’s critical that we have definitive, good imaging.”
When Paget disease is suspected, imaging is followed by biopsies of both the nipple lesion and any abnormalities or underlying malignancies located on imaging. In cases of suspected pure Paget disease, only the abnormal area of the nipple will be biopsied. Because MRI studies are sensitive but insufficiently specific, Dr. Kuerer said that MRI results should always be confirmed with a biopsy.
|In its early stage (left), Paget disease appears as an erythematous, scaling lesion on the nipple. In more advanced Paget disease (right), the lesion has spread to the areola and the nipple appears flattened. Photos used with permission from Kuerer’s Breast Surgical Oncology, ©2010 McGraw-Hill.
Although the sequence of initial clinical presentation, then imaging, and finally pathological confirmation is the ideal for diagnosing Paget disease of the breast, the diagnosis is more often made by analysis of tissue obtained intraoperatively. Dr. Krishnamurthy said that most cases of Paget disease are identified after routine evaluation of the skin of the nipple-areola complex in patients who have undergone mastectomy for an underlying malignancy. In such cases, the patient may have undergone surgery for a tumor within the breast without Paget disease’s being suspected prior to pathological analysis.
Whether conducted on tissue obtained preoperatively or removed surgically, pathological analysis of Paget disease specimens typically reveals Paget cells scattered or in small groups in the nipple epidermis. Pathologists perform a detailed histopathological examination as well as ancillary histochemical and immunochemical staining to distinguish Paget cells from normal and malignant keratinocytes, melanoma cells, and Toker cells. For example, Paget cells and some Toker cells can stain positive for mucins, but keratinocytes and melanoma cells do not. The immunophenotype of Paget cells differs from Toker cells; Paget cells are very often HER2 positive and hormone receptor negative, whereas Toker cells are usually HER2 negative and hormone receptor positive. Dr. Krishnamurthy said, “Clinical presentation, imaging characteristics, morphological features, and ancillary staining all should fit together to reach a diagnosis of Paget disease of the breast.”
Until the 1990s, mastectomy was the standard treatment for all cases of Paget disease of the breast. Today, treatment choices are largely determined by the underlying disease.
If underlying and multicentric disease is absent or the underlying disease is relatively close to the nipple-areola complex, the patient may be a candidate for breast-conserving surgery. Neoadjuvant chemotherapy may allow some patients with underlying disease who would otherwise require mastectomy to undergo breast-conserving surgery instead. “Depending on the size of the patient’s breast, we can remove parts of the nipple-areola complex and then reconstruct that area,” Dr. Kuerer said. “We leave as much tissue as possible as long as there are negative surgical margins.” A range of reconstructive techniques provide favorable cosmesis after breast-conserving surgery.
For patients with underlying malignancy or multicentric disease, mastectomy remains the standard treatment; these patients also undergo intraoperative sentinel lymph node biopsy. This biopsy is typically not performed during breast-conserving surgery unless there is also evidence of invasive cancer.
For many patients, the nipple-areola complex is important for sexual intimacy, and the effects of the complex’s resection on intimacy should be discussed with patients early in the treatment process. Peer-to-peer and individual counseling programs are an important source of support in this regard.
After surgery, most patients with underlying disease will undergo adjuvant radiation therapy, which is administered to the whole breast. An intraoperative finding of node-positive disease may necessitate adjuvant chemotherapy in addition to radiation. In a minority of patients with underlying disease, various factors may make adjuvant radiation therapy inadvisable. For example, Dr. Stauder suggested that a patient more than 70 years old with invasive carcinoma who has a small tumor and poor functional status would not be a good candidate for radiation therapy. Instead, if their underlying disease is hormone receptor positive, such patients may receive oral systemic therapy with hormone receptor antagonists such as tamoxifen and/or aromatase inhibitors such as anastrozole. Patients with pure Paget disease will rarely undergo radiation therapy but may receive oral systemic therapy if their disease is hormone receptor positive.
Prognosis and trends
For patients with underlying disease, the prognosis, like treatment, depends on the stage and type of the underlying disease. The largest study of Paget disease of the breast to date—a 2006 review of Surveillance, Epidemiology, and End Results data—found that women with Paget disease and underlying invasive breast cancer had a 15-year disease-specific survival rate of 61%, whereas the rate was 94% for women with Paget disease with in situ carcinoma and 88% for those with pure Paget disease. Tumor size and lymph node status were found to be key determinants of disease-specific survival.
Because of the rarity of Paget disease of the breast and the fact that treatment is determined by the underlying disease, new developments in Paget disease–specific research and treatment are few. Research into the pathogenesis of Paget disease would help to deepen the understanding of the disease’s progression and allow for more precise selection of treatment regimens for individual patients. However, Dr. Stauder said that in the absence of Paget disease–specific data, “The existence of relevant equivalent data on ductal carcinoma in situ and invasive breast cancer still allows for prudent treatment planning.”
Indeed, there is reason for optimism: The 2006 study showed that from 1988 to 2002 the incidence of Paget disease with underlying invasive or in situ disease decreased and the incidence of pure Paget disease remained stable. Dr. Kuerer speculated that the increased use of screening mammography might account for the reduced incidence of Paget disease with underlying disease. He said, “I think there’s going to be a higher proportion of Paget disease cases involving only the nipple-areola complex—so-called pure Paget disease—because women are so knowledgeable about signs of potential breast disease that we’re catching breast cancer earlier.”