Paget disease is an uncommon manifestation of mammary carcinoma that affects 1% to 3% of patients with breast carcinoma.²³ The majority of these women have a clinically evident nipple lesion. Ten percent to 28% of cases of Paget disease are detected only in histologic sections of the nipple removed at mastectomy, having caused no clinical abnormality. After reviewing incidence data recorded by nine registries in the Surveillance Epidemiology and End Results (SEER) program, Chen et al.²³ reported a 45% decline in the incidence of reported Paget disease between 1988 (age-adjusted incidence/100,000, 1.31) and 2002 (age-adjusted incidence/100,000, 0.64). The decline in incidence was limited to patients who had documented DCIS or invasive duct carcinoma (IDC). The incidence of Paget disease without associated clinical ductal carcinoma remained stable during this period. As a consequence, the relative portion of Paget disease without associated clinical ductal carcinoma increased from 12% to 15%. The authors did not discriminate between clinically apparent Paget disease and occult Paget disease discovered in routine sections of the nipple from mastectomy specimens. It is likely that the shift to breastconserving surgery during this period contributed to the apparent decline in the incidence of Paget disease because fewer nipple samples were available for histologic examination. The fact that the incidence of Paget disease without underlying carcinoma, which is only detectable clinically, remained stable during this interval appears to support this interpretation.

The age range of patients with Paget disease in several large series consisting cumulatively of 508 patients was 26 to 88 years,^18,24,25,26 and the average age at diagnosis in one series of 1,738 women was 62.5 years.²³ In this group, the mean age for women with Paget disease and IDC was 63.8 years, for women with Paget disease and ductal carcinoma in situ (DCIS) 66.2 years, and for women with Paget disease without underlying carcinoma 66.2 years.²³ Paget disease arose in the ectopic nipple of a 13-year-old girl²⁷ and in the nipple of a 90-year-old woman.²⁸

One might expect Paget disease to occur more frequently in men than in women because almost all carcinomas of the male breast involve the subareolar region,²⁹ but fewer than 1% of reported cases of Paget disease have been found in men.³⁰ It occurred in 2.8% of 229 patients in one series of men with breast carcinoma.³¹ About one-half of the early reports of Paget disease of the male breast lack histologic confirmation, so the literature contains fewer than 50 bona fide cases of Paget disease in men. Desai et al.³² tabulated details of 33 convincing cases described before 1996, and several well-documented case descriptions have been published since.^{33,34,35,36,37,38,39,40,41,42,43,44,45,46} In the series by Goss et al.,³¹ men with Paget disease spanned 23 to 97 years in age, essentially the range seen in women with the disease.

Paget disease typically involves only one breast, but both synchronous involvement in women^{47,48,49,50,51,52} and men⁴³ and metachronous development^53,54,55 have occurred rarely.

Researchers have not identified factors that specifically predispose to the development of Paget disease, but a few reports mention factors that generally predispose patients to the development of breast carcinomas. Loizou et al.⁵⁶ described a 36-year-old woman who underwent “extensive cardiac fluoroscopy” at birth and again at the age of 7 years who developed Paget disease at the age of 36 years. Paget disease has been found associated with breast carcinoma developing in men with Klinefelter syndrome.^53,57

Several cases of Paget disease have presented in unusual clinical settings. Kawawa et al.⁵⁸ detailed the case of a 66-year-old woman with Paget disease and neurofibromatosis, and Holloway et al.³⁸ described a similar case in a man. Fouad⁵⁹ reported a case of a man with Paget disease and lymphomatoid papulosis. A 35-year-old woman who had systemic scleroderma involving the skin of the breast with coexistent Paget disease has been described.⁶⁰ Kao et al.⁶¹ observed DCIS and Paget disease in ectopic breast tissue on the chest of a 58-year-old woman, and two reports document Paget disease in accessory nipples.^27,62 Two women developed Paget disease confined to the areola.^63,64 Mendez-Fernandez et al.⁶⁵ detected Paget disease in the nipple of a woman 8 years after subcutaneous mastectomy for fibrocystic disease. Two cases of axillary Paget disease associated with mammary carcinoma have been described.^66,67

Recurrences of conventional breast carcinomas sometimes take the form of Paget disease. It developed in the nipple of a woman treated with excision alone⁶⁸ and those of 15 women treated with breast-conserving excision and irradiation,^{69,70,71,72,73,74,75,76} 3 women treated with subcutaneous mastectomy,⁷⁷1 woman treated with an areola-sparing mastectomy,⁷⁸ and 7 women treated with a nipple-sparing mastectomy.⁷⁹ Basu et al.⁸⁰ reported an especially unusual case of a 64-year-old woman who underwent a left mastectomy and subsequent transverse rectus abdominus muscle (TRAM) flap reconstruction for carcinoma. During that procedure, the left nipple was reconstructed by means of the nipple-sharing technique using tissue from the right nipple. Six years later, Paget disease developed in the right nipple, and 7 years after that it arose in the reconstructed left nipple.

Pain and itching are frequent complaints. Physical examination typically reveals a thickened, erythematous, scaling papule or plaque with irregular borders involving the nipple. The changes may be limited to the nipple or extend to the areola, and in advanced cases the lesion also involves the skin surrounding the areola (Fig. 30.2). Haagensen⁸¹ wrote that “erosions that involve the areola or the skin of the adjacent breast leaving the nipple uninvolved are not Paget disease”; however, examples confined to the areola have been described.^63,64 Advanced cases often demonstrate ulceration, crusting, serous or bloody discharge from the nipple, and nipple retraction or inversion.⁸² In one exceptional case, the alterations extended to the skin of the abdomen,⁸³ and in another, they involved the skin of the back and the proximal one-third of the arm.⁸⁴

Because of the nonspecific nature of the clinical signs of Paget disease, a delay of 6 to 12 months prior to biopsy during which the symptoms are treated topically is not uncommon. In the series of Ascensão et al.,⁸⁵ the symptomatic intervals from 1 week to 20 years were recorded, and the average period of delay was 2.25 years.

The findings in Paget disease can be mistaken for eczema⁸⁶ or other inflammatory conditions such as seborrheic dermatitis, contact dermatitis, postirradiation dermatitis, psoriasis, and pagetoid dyskeratosis.⁸⁷ Pennell et al.⁸⁸ reported a case of cutaneous para-areolar schistosomiasis that mimicked Paget disease. Minute vesicles sometimes erupt and seem to heal, and this phenomenon may bring to mind the presence of a bullous disease such as pemphigus. Guyton et al.⁸⁹ described a case of pemphigus vulgaris initially thought to represent Paget disease and cited other examples of confusion of these two entities.^90,91 Rae et al.⁹² described a 63-year-old woman in whom both pemphigus vulgaris and Paget disease involved the right nipple. Neoplastic lesions clinically confused with Paget disease include adult Langerhans cell histiocytosis,⁹³ intraepidermal squamous carcinoma (Bowen disease), and unusual examples of basal cell carcinoma⁹⁴ and melanoma.⁹⁵

In an uncommon variant of Paget disease known as pigmented Paget disease, accumulation of melanin imparts
a brown color to the affected region. The publication by Soler et al.⁹⁶ lists details of 17 published cases, and other reports describe 7 additional examples.^{39,42,45,97,98,99,100} One notes that a disproportionately high number of cases occurred in men.^{37,39,42,44,45,46,101} For additional information regarding pigmented Paget disease, see Chapter 42.

Fifty percent to 60% of patients have a palpable tumor in the breast that exhibits Paget disease. In one study, the mean age of women with a tumor (49 years) was significantly less than that of women without a tumor (58 years).²⁵ An invasive carcinoma was detected in more than 75% to 90% of women who had Paget disease accompanied by a tumor,^18,24,102 and 45% to 66% of them reportedly had axillary lymph node (ALN) metastases.^18,24,25,102 In the absence of a clinically apparent tumor, invasive carcinoma occurs in no more than 40% of cases, and axillary metastases have been reported in 5% to 13% of cases.^18,24,25,102

A number of mammographic abnormalities may be found in the breast underlying Paget disease.^103,104 Lesions anywhere in the breast may be indicative of a separate distant coexistent carcinoma. In the nipple-subareolar region, the significant findings include thickening of the nipple, an underlying mass, possibly with nipple retraction, and calcifications. Patients with clinically apparent Paget disease tend to have radiologic findings in the nipple-subareolar region. When Paget disease is not evident clinically, mammography more often discloses lesions away from the nipple region. Such abnormalities include a suspicious mass, asymmetry, architectural distortion, and suspicious calcifications. These observations notwithstanding, mammography is not a reliable procedure for either detecting Paget disease or determining its extent. In 22%¹⁰⁵ to 50%¹⁰³ of patients with Paget disease, the mammograms appeared normal and they underestimated the extent of disease in nearly one-half of the patients.^{103,105,106,107,108} In a study of 25 breasts that proved to have Paget disease on pathologic examination, only three cases (12%) had nipple abnormalities on mammography.¹⁰⁹ Fourteen patients with clinical evidence of Paget disease in this series had underlying carcinomas. Among these 14 patients, mammography identified the underlying tumor in 6 (43%). Ultrasonography can sometimes reveal calcifications, dilatation of ducts, or flattening, asymmetry, or thickening of the nipple-areolar complex. The frequency of detection of abnormalities is similar to that of mammography.^106,110 Magnetic resonance imaging (MRI) of patients with Paget disease can disclose abnormal nipple enhancement, thickening and enhancement of the nipple-areolar complex, and coexisting enhancing DCIS or suspicious masses.^111,112 In both individual case reports^113,114,115 and small series,^112,116 this modality improved the detection of associated carcinomas in patients with clinical signs of Paget disease and negative mammography and ultrasonography.

The characteristic histopathologic feature of this condition is the presence of adenocarcinoma cells (Paget cells) in the keratinizing epithelium of the nipple epidermis (Fig. 30.3). These cells occur singly in superficial epidermal layers. In rare instances, they extend into eccrine ducts³⁶ and hair follicles.¹¹⁹ Paget cells are more likely to form clusters in the basal portions of the epidermis and to have a distribution similar to that of junctional melanocytes. The resemblance
to melanoma is enhanced if the carcinoma cells take up melanin pigment released by epidermal cells.^120,121 Isolated Paget cells appear to lie in vacuoles within the epidermis. The cytoplasm is usually pale or clear, and it may contain mucin secretion vacuoles. Nuclei of Paget cells tend to have prominent nucleoli. Rarely, Paget disease forms glands within the epidermis of the nipple^122,123 (Fig. 30.3F).

Other microscopic aspects of Paget disease sometimes obscure the lesion, and they may interfere with the diagnosis. Hyperplasia and hyperkeratosis of the epidermis occur to some degree, and they are occasionally severe enough to suggest pseudoepitheliomatous hyperplasia (Fig. 30.4). The superficial, dermal stroma of the nipple is usually infiltrated by a moderate-to-marked lymphocytic reaction. When ulceration denudes the affected epithelium, a biopsy of the exposed stroma will reveal only the underlying inflammatory reaction. Unless this misleading appearance is recognized, the biopsy findings may reinforce
an erroneous clinical diagnosis of an inflammatory condition. It is, therefore, important to state in the pathologic report whether epidermal tissue is present. Absence of epidermis is an indication for rebiopsy when Paget disease is suspected clinically.