Paget disease of the breast (PDB)

INTRODUCTION — 

In 1874, Sir James Paget described 15 women with chronic nipple ulceration who all went on to develop cancer of the involved breast within two years [1]. The ulceration was described as an eczema-like eruption on the nipple and areola with a copious clear yellowish exudate. Ultimately, this would become known as Paget disease of the breast (PDB) or mammary Paget disease. While Paget believed that the nipple changes were themselves benign, it was subsequently discovered that the characteristic cells within the epidermis of the nipple (Paget cells) were in fact malignant [2].

This topic will discuss the clinical presentation, pathogenesis, pathology, diagnosis, and management of mammary Paget disease.

Patients with mammary Paget disease most often undergo the same diagnostic evaluation, staging, and treatment as other patients with non-Paget breast cancer. These principles are discussed elsewhere. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer" and "Diagnostic evaluation of suspected breast cancer" and "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)

Extramammary Paget disease is a rare, slow-growing, malignant skin disease that affects areas of the body with many apocrine sweat glands, such as the vulva, perineum, scrotum, perianal area, and inner thighs. It is a cutaneous adenocarcinoma that primarily affects the epidermis but can sometimes extend into the dermis. It can be related to an underlying cancer, but usually not breast cancer. Extramammary Paget disease is discussed in other topics. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Paget disease of the vulva' and "Cutaneous adnexal tumors", section on 'Extramammary Paget disease' and "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'Extramammary Paget disease'.)

EPIDEMIOLOGY — 

PDB is much less common than other presentations of breast cancer, accounting for only 1 to 3 percent of new cases of female breast cancer that are diagnosed annually in the United States [3]. PDB can occur in men [4]; however, this is an extremely rare finding. Although cases have been described in patients ranging in age from 26 to 88, the peak incidence is between 50 and 60 [3,5,6].

Histologic (subclinical) evidence of PDB may be more frequent. In a series of 3000 consecutive mastectomy specimens, the incidence of clinical Paget disease was 0.7 percent, but histologic evidence of the disease was present in 4.9 percent of the mastectomies [7].

At least some epidemiologic data suggest that the incidence of PDB is decreasing over time. In two reports of PDB reported to the Surveillance, Epidemiology, and End Results (SEER) database, the incidence of PDB decreased by 45 percent between 1988 and 2002 [8] and continued to decrease by 4.3 percent per year from 2000 to 2011 [9]. The decreasing incidence of PDB has been attributed to detection of invasive breast cancer or ductal carcinoma in situ through the wider use of screening mammography at a point earlier than the development of pagetoid changes [8].

Although PDB is a less common presentation of breast cancer than a palpable mass or mammographic abnormality, it is an important consideration in the differential diagnosis of a chronic persistent abnormality of the nipple.

PATHOGENESIS — 

Two theories have been proposed to explain the pathogenesis of PDB: the epidermotropic theory, which is by far the more widely accepted, and the transformation theory.

Epidermotropic theory — According to the prevailing epidermotropic theory, the Paget cell arises from an underlying mammary adenocarcinoma, with the neoplastic ductal epithelial cells migrating through the ductal system of the breast into the epidermis of the nipple.

In many series, immunohistochemical staining is concordant in Paget cells and the ductal epithelial cells but discordant in Paget cells and the epidermal keratinocytes of the surrounding nipple tissue (table 1) [10-16].

Similarly, the expression of several molecular markers is concordant in PDB and underlying parenchymal breast tumors [11,17]. Over 80 percent of PDBs have overexpression or amplification of the gene for HER2 [17-20]. In one report, all 23 cases of PDB stained with an anti-HER2 monoclonal antibody; staining was also positive in all the underlying ductal carcinomas but never in normal nipple epidermis [21]. It is hypothesized that the spread of Paget cells to the nipple epidermis from the duct system may be mediated through a motility factor that exerts its effect via the HER2 receptor (figure 1) [22]. (See 'Hormone receptors' below.)

Taken together, these data lend support to a common genetic alteration and/or possibly a common progenitor cell for both the Paget cells and the underlying ductal carcinoma.

Transformation theory — In contrast, the transformation theory proposes that epidermal keratinocytes within the nipple transform into malignant Paget cells and that PDB in fact represents an epidermal carcinoma in situ that is independent of any underlying ductal carcinoma [23]. George Thin proposed this theory in 1881, believing that secretions from the breast ducts damaged the epithelium, transforming normal keratinocytes into cancer cells [2].

The transformation theory was bolstered by the following observations:

●In a small percentage of cases, no parenchymal cancer can be identified in association with PDB.

●When an underlying parenchymal carcinoma is present, it is often located peripheral to the nipple, suggesting two independent neoplastic processes. As an example, in one series of 80 women with breast cancer and PDB, 29 of the underlying breast tumors were located more than 2 cm from the areolar margin [5].

●Desmosomal attachments have been identified between Paget cells and adjacent epidermal keratinocytes [24]. These authors describe a "pre-Paget cell" with an appearance intermediate between that of a keratinocyte and a Paget cell, suggesting that epidermal cells can acquire the characteristics of ductal cells as they undergo malignant transformation. Others suggest the presence of a unique precursor, the Toker cell, to explain cases of PDB with no contiguous ductal carcinoma [25,26].

The transformation theory has fallen out of favor, in part because if enough tissue sections are studied, involvement of the large (lactiferous) ducts immediately beneath the nipple can usually be demonstrated.

CLINICAL PRESENTATION

Pagetoid lesion — The hallmark of PDB is a scaly, raw, vesicular, or ulcerated lesion that begins on the nipple and then spreads to the areola (picture 1). Occasionally, a bloody discharge is present. PDB is usually unilateral, although bilateral cases have been described [27]. Nipple retraction is also a rare finding but may occur with more advanced disease.

Pain, burning, and/or pruritus are commonly associated with PDB and may be present before the development of clinically apparent disease. Thus, any patient complaining of these symptoms but without an obvious lesion should be followed closely if the symptoms persist.

Despite the superficial nature of the findings, the median duration of signs and symptoms prior to histologic diagnosis is between six and eight months [10,21]. A detailed history should document the length of time the lesion has been present and any associated symptoms, including pain, nipple discharge, bleeding, burning, and pruritus.

Associated findings — An underlying breast malignancy is present in 85 to 88 percent of cases of PDB, and a palpable mass is present in approximately one-half. Thus, the patient history should also cover the patient's individual risk profile for breast cancer, including any risk factors for hereditary breast cancer. Bilateral breast examination and imaging should be performed, focusing on any associated breast abnormalities. (See "Factors that modify breast cancer risk in females" and "Overview of hereditary breast and ovarian cancer syndromes" and "Clinical manifestations, differential diagnosis, and clinical evaluation of a palpable breast mass", section on 'Physical examination'.)

DIAGNOSIS — 

PDB should be suspected in patients with unilateral erythematous nipple lesions and in those who fail to respond to topical steroid therapy. PDB is diagnosed pathologically by the presence of malignant, intraepithelial adenocarcinoma cells (Paget cells) within the epidermis of the skin biopsy taken from the affected nipple. (See 'Paget cells' below.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis includes both benign etiologies (eczema, contact dermatitis, radiation dermatitis, nipple adenoma/adenomatosis) and malignant conditions (Bowen disease [squamous carcinoma of the epidermis], basal cell carcinoma, superficial spreading malignant melanoma) [18,19,23,28,29].

Eczematous skin changes are usually bilateral and respond quickly to topical steroid therapy; Paget disease should still be suspected in someone presenting with bilateral eczematous nipple changes, especially if the changes persist for more than three weeks following topical steroid treatment [30]. In order to avoid undue delay in definitive diagnosis, any persistent nipple abnormality beyond four to six weeks should be considered an indication for biopsy and/or breast imaging.

Certain malignant skin conditions (eg, Bowen disease or malignant melanoma) can be distinguished from PDB by the use of immunohistochemistry stains on biopsy specimens. (See 'Immunohistochemistry' below.)

DIAGNOSTIC EVALUATION — 

The diagnostic workup of suspected PDB focuses on both establishing the diagnosis and identifying an underlying breast cancer. An underlying breast cancer (in situ or invasive) is present in 85 to 88 percent of cases, although often without an associated breast mass or mammographic abnormality [5,8].

●A palpable breast mass is present in 50 percent of cases of PDB; the mass is often located more than 2 cm from the nipple-areolar complex [31,32].

●In 20 percent of cases, a mammographic abnormality is present without a palpable mass [33].

●Approximately 12 to 15 percent of cases are not associated with a palpable mass, mammographic abnormality, or parenchymal breast cancer [8].

●In 25 percent of cases, there is neither an underlying mass nor a mammographic abnormality, but an occult ductal carcinoma in situ (DCIS) is present.

Patients with either a palpable mass or a mammographic abnormality are more likely to have an underlying invasive cancer, while DCIS is found more often in the absence of a palpable mass or mammographic abnormality [34].

Imaging — The main purpose of imaging studies in patients diagnosed with PDB is to identify any concomitant breast mass or other abnormalities that can be biopsied to diagnose either invasive or in situ breast cancer. The selection of imaging modalities (mammography, ultrasound, or magnetic resonance imaging [MRI]) is not unique to PDB but similar to the diagnostic evaluation of any patient with suspected breast cancer. The age-based diagnostic algorithms can be found elsewhere. (See "Diagnostic evaluation of suspected breast cancer".)

Mammography and ultrasonography — Bilateral mammography is mandatory to identify an associated mass as well as exclude synchronous cancers or widespread calcifications that might preclude breast conservation therapy. Approximately one-half of cases of PDB have an associated mammographic abnormality [33,35]. The mammographic findings in 17 women in one study included suspicious microcalcifications, a mass, architectural distortion, nipple retraction, and asymmetric thickening of the nipple-areolar complex [33]. In seven cases, the mammographic abnormalities were located distant from the nipple-areolar complex.

As noted above, while women with a negative mammogram in the setting of PDB appear to have a low likelihood of underlying invasive breast cancer (particularly in the absence of a palpable mass [34,36]), an occult-associated intraductal carcinoma may be present and quite extensive. In the above-noted series, all of the 17 women with negative mammograms had DCIS, five with extensive multicentric disease [33]. In another series, mammography failed to identify 64 percent of cases of multifocal underlying breast cancer (both in situ and invasive cancer) in women with PDB and no palpable mass [37]. (See "Breast imaging for cancer screening: Mammography and ultrasonography".)

Ultrasound should be used to further evaluate and guide core biopsy of any palpable mass or mass-like mammographic abnormality. Whole-breast ultrasound in addition to mammography has been examined in the context of Paget disease but does not appear to increase sensitivity over mammography alone [38-40].

Magnetic resonance imaging — MRI is a sensitive imaging tool for invasive breast cancer, particularly for mammographically occult disease, and its sensitivity for detecting DCIS, particularly high-grade DCIS, is also high. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer" and "Breast ductal carcinoma in situ: Epidemiology, clinical manifestations, and diagnosis", section on 'Magnetic resonance imaging'.)

There are few data addressing the utility of breast MRI in women with PDB and a negative mammogram [41-47]. The largest series included 34 women with PDB, 32 of whom had histologically confirmed breast cancer (7 invasive, 25 DCIS) [41]. All patients underwent preoperative mammography, while 13 had an ipsilateral breast MRI. Among the 23 women with biopsy-proven PDB and negative mammography, eight underwent MRIs that detected otherwise occult disease in four women (three DCIS, one invasive cancer), three of whom required mastectomy because of extensive disease. However, MRI did not detect three cancers (two unifocal DCIS, one invasive cancer) in the other four patients. In another retrospective series of 51 patients who underwent resection for PDB, 52 percent underwent preoperative MRI [48]. A meta-analysis of six studies reported that MRI was more sensitive in detecting underlying cancer in patients with PDB than mammography (68 versus 39 percent), while both had a specificity of 100 percent [49].

Thus, MRI may disclose occult cancer in some women with PDB and no findings on mammography or physical examination, potentially allowing directed treatment of the ipsilateral breast. However, a negative preoperative study cannot reliably exclude an underlying cancer. The use of MRI for breast cancer is discussed in detail elsewhere. (See "MRI of the breast and emerging technologies".)

Skin biopsy and histology — Nipple scrape cytology can accurately diagnose PDB [50,51], but the diagnosis is usually established by full-thickness punch or wedge biopsy of the nipple. Punch biopsy is more widely used. Wedge biopsy may contain lactiferous ducts, which may identify DCIS as the etiology of PDB. (See "Skin biopsy techniques".)

Paget cells — The histologic hallmark of PDB is the presence of malignant, intraepithelial adenocarcinoma cells (Paget cells) occurring singly or in small groups within the epidermis of the nipple (picture 2). The cells are often large but may be similar in size to keratinocytes. The cytoplasm is pale to clear, and nuclei are usually high-grade with prominent nucleoli. In many instances, the Paget cells retract from the surrounding keratinocytes and appear to be within a vacuole.

Immunohistochemistry — A useful immunohistochemistry (IHC) diagnostic panel for a nipple biopsy without underlying invasive cancer or DCIS may include CK7, carcinoembryonic antigen (CEA; polyclonal), p63, estrogen receptor, HER2, and either SOX10, MART-1(MelanA), or HMB-45 if melanoma is also in the biopsy differential diagnosis [52].

●Distinguishing PDB from malignant melanoma – Histologically, PDB can mimic malignant melanoma, particularly if the cells have incorporated melanin from the adjacent epidermis. The presence of cytoplasmic mucin vacuoles can aid in the diagnosis, as can special stains such as mucicarmine, which may highlight the vacuoles. IHC may also be helpful in diagnostically difficult cases (table 1) [53]. PDB can be distinguished from malignant melanoma by positive IHC for CEA (polyclonal) and negative IHC for S-100 protein; however, some cases of PDB are S-100 positive [54], and CEA may not always be expressed. MART-1, SOX10, or HMB-45 may be more useful than S-100 in confirming malignant melanoma.

●Distinguishing PDB from Bowen disease – Paget cells are positive for low molecular weight cytokeratins, a feature that can help distinguish PDB from squamous carcinoma of the epidermis (Bowen disease), which typically expresses high molecular weight cytokeratins and p63 [55,56]. CK7 is probably the most useful marker, but caution must be exercised in interpreting CK7 stains in the absence of other typical histologic features of PDB.

●Distinguishing PDB from Toker cell hyperplasia – Although positive in PDB, CK7 may also be expressed in benign Toker cell hyperplasia [57,58], and some breast carcinomas may not express CK7 [59]. Toker cells in the nipple may be derived from or related to lactiferous duct epithelium, and malignant transformation of these cells may explain some cases of PDB without associated ductal carcinoma [25]. Toker cell hyperplasia may be present in a higher proportion of females transitioning to males compared to cisgender females [60]. Care should be taken when considering a pathologic diagnosis of PDB during the examination of trans-male breast specimens.

Hormone receptors — When an underlying mass is identified in patients with PDB, it is important to obtain estrogen receptor, progesterone receptor, and HER2 status from the underlying mass, not the epidermal cells, to guide management. If present, estrogen and/or progesterone receptor positivity is extremely helpful. Unfortunately, approximately one-half of PDB cases do not express hormone receptors, a finding that is not surprising considering the frequent association with high-grade invasive ductal carcinomas that are also likely to be hormone receptor-negative and/or HER2 positive.

HER2 overexpression is more prevalent in patients with PDB. HER2 overexpression has been reported in between 58 and 86 percent of cases [61,62]. This may be one reason why the prognosis of invasive breast cancer with Paget disease is intrinsically worse than invasive breast cancer without Paget disease [63-65]. (See "HER2 and predicting response to therapy in breast cancer".)

Dermal invasion — In some cases of PDB without a mass or mammographic abnormality, the pathologic evaluation of the nipple/areolar complex may detect secondary invasion into the subjacent dermis. In one series of six cases with secondary dermal invasion, there was no underlying breast carcinoma in one case, DCIS only in three cases, DCIS with microinvasion in one case, and invasive carcinoma in one case. Treatment was determined by the underlying disease. One patient died of unrelated causes, and the remainder were alive at the last follow-up [66]. In a second series of seven patients, five patients had microinvasive (<1 mm) dermal foci, and the two remaining patients had 2 and 3 mm foci of dermal invasion. Two patients at high risk for breast cancer underwent mastectomy, and the average-risk patients were treated with breast-conserving therapy and RT; no recurrences were reported (median follow-up 20 months [range 4 to 66 months]) [67]. While there is limited information available on patients with secondary dermal invasion, this finding does not indicate more adverse outcomes and should be distinguished from locally advanced breast cancer with skin involvement (T4b).

Biopsy of underlying abnormalities — In addition to nipple biopsy, any underlying masses or mammographic abnormalities must be biopsied to assist in decisions about local treatment of the breast and the need for evaluation of the axilla. (See "Breast biopsy".)

STAGING — 

The presence of PDB does not change the stage of an underlying breast cancer. If an associated invasive breast cancer or ductal carcinoma in situ is not identified, Paget disease is classified as pTis (Paget). (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)

TREATMENT — 

The standard treatment of PDB is surgical excision. The prognosis of PDB is based upon the underlying breast cancer, and thus treatment should be guided by the stage of the tumor and other prognostic and/or predictive factors. (See 'Prognosis' below.)

Breast surgery — Both mastectomy and breast-conserving surgery followed by whole-breast radiotherapy (RT) are acceptable treatment options for PDB with or without a palpable mass or imaging abnormalities. When there is a palpable mass or imaging abnormalities, breast-conserving surgery and RT should only be performed when a nipple-areolar resection and wide local excision of the underlying cancer can be performed with an acceptable cosmetic result and negative margins.

Simple mastectomy has been the historic standard treatment for PDB. However, the widespread use of breast-conserving treatment (BCT) for invasive and in situ breast carcinoma has led to its use for PDB. Most studies report that BCT achieves similar oncologic results to mastectomy as long as negative margins are ascertained and adjuvant radiation therapy is administered. However, unlike invasive breast cancer, there have been no randomized trials comparing BCT to mastectomy for PDB. (See "Breast-conserving therapy" and "Mastectomy" and "Ductal carcinoma in situ: Treatment and prognosis".)

●A 2015 systematic review of 43 studies concluded that patients with PDB are candidates for breast conservation with appropriate preoperative investigations to identify underlying breast cancer. Oncological outcomes are equivalent to those of mastectomy if surgical margins are achieved and adjuvant radiotherapy is given [68].

●A retrospective analysis of 5398 patients with PDB treated between 1973 and 2014 from the Surveillance, Epidemiology, and End Results (SEER) database found similar 1, 3, 5, and 10-year overall survival after BCS and mastectomy for both PDB with ductal carcinoma in situ (DCIS) and PDB with invasive cancer [69]. Ten-year overall survival is worse without radiation.

●A retrospective analysis of more than 7000 American patients who were treated for PDB from 2004 to 2015 found that 65 and 30 percent underwent mastectomy and BCT, respectively [3]. Another database analysis of over 2600 American patients who were treated for PDB from 2000 to 2011 found that 47, 69, and 89 percent underwent mastectomy for PDB of the nipple only, PDB plus DCIS, and PDB plus invasive cancer, respectively [9].

Mastectomy — Many patients who have PDB and underlying cancer will require a mastectomy because of the distance between the primary tumor and the nipple-areolar complex [5]. If resection of both the nipple-areolar complex and the palpable mass with a negative margin would result in an unacceptable cosmetic result, women may elect for simple mastectomy with or without breast reconstruction. Women with multicentric cancer or diffuse calcifications should be treated by mastectomy. (See "Mastectomy", section on 'Indications for mastectomy'.)

Even in the absence of a palpable mass or mammographic abnormality, underlying carcinoma is present in most patients with PDB [37]. The majority will have DCIS, but invasive cancer is present in one-fourth to one-third of cases [31,32,70]. Thus, simple mastectomy with or without breast reconstruction remains a reasonable option for patients with PDB alone [71,72]. In a series of 37 patients treated by simple mastectomy alone, the local recurrence rate was only 5 percent, with a median follow-up of 40 months [71]. However, some authors argue that mastectomy is an overtreatment for patients who do not have an associated underlying cancer on final pathology [5].

Breast-conserving surgery — If nipple-areolar resection and wide local excision of the palpable mass or area of mammographic abnormality can be performed with an acceptable cosmetic result and negative margins, breast-conserving surgery is an appropriate local treatment option for PDB with underlying cancer (picture 3). If the breasts are large, resection of the palpable mass and nipple-areolar complex with nipple reconstruction and elective contralateral breast reduction can achieve an acceptable breast contour and symmetry [73]. (See "Breast-conserving therapy", section on 'Patient selection for BCT'.)

Data also suggest that complete resection of the nipple-areolar complex with central lumpectomy, as clinically appropriate, followed by whole-breast RT is a reasonable alternative to mastectomy for women with PDB and no palpable mass or mammographic abnormality provided good cosmetic outcome and negative margins can be achieved, particularly for any associated DCIS [21,36,74]. A variety of techniques can be used to reconstruct the nipple-areolar complex, and cosmesis has been assessed as good to excellent in the majority of patients so treated [73,75]. (See "Oncoplastic breast surgery", section on 'Central breast resection'.)

Others (nonstandard) — Mastectomy and BCT (surgery plus whole-breast RT) represent standard approaches to the treatment of PDB without an underlying mass or mammographic abnormality. Less aggressive approaches have been examined, including ipsilateral breast RT following only a diagnostic nipple biopsy [76-79] and breast-conserving surgery without RT (table 2) [71,72,80,81]; however, only small numbers of patients have been studied, and reported results are variable. Thus, neither of these approaches can be considered a standard treatment option for most patients with PDB in the absence of an underlying mass [82].

Management of the axilla — Evaluation and treatment of the axilla in PDB are the same as for any breast cancer and depend on the underlying cancer (see "Overview of management of the regional lymph nodes in breast cancer"):

●Patients with DCIS do not require axillary investigation unless the disease is extensive enough to merit mastectomy. If mastectomy is planned, either by disease necessity or patient choice, sentinel lymph node (SLN) biopsy is often (and appropriately) performed preemptively in order to avoid complete axillary lymph node dissection (ALND) in cases with an invasive component identified at final pathology. (See "Overview of sentinel lymph node biopsy in breast cancer", section on 'DCIS with planned mastectomy'.)

●If invasive disease has been identified, patients with clinically node-negative disease should undergo SLN biopsy at the time of wide excision. An SLN can be successfully identified in 97 percent of patients with PDB [83]. Management of a positive SLN is discussed in detail elsewhere. (See "Overview of sentinel lymph node biopsy in breast cancer", section on 'Management after SLNB'.)

●Patients with a clinically positive or suspicious axilla should undergo an initial ultrasound-guided fine needle aspiration (FNA) or core needle biopsy of the palpable axillary nodes; if the FNA or core biopsy is negative, SLN biopsy should be performed. If axillary nodal metastasis is confirmed histologically, either a full ALND is performed at the time of breast surgery, or surgical management of the axilla is deferred until after neoadjuvant chemotherapy and reevaluation. (See "General principles of neoadjuvant management of breast cancer", section on 'Positive axilla prior to treatment'.)

●For patients with pure PDB without an associated mass and a clinically negative axilla, there is some controversy as to the need for axillary evaluation when breast conservation is planned. Given the high incidence of DCIS alone in these patients, SLN biopsy may not be necessary and can be considered as a second operation if invasive disease is discovered [83]. In a series of 19 patients with PDB only, an invasive component was found in 27 percent and positive SLNs in 11 percent [70]. Based on these numbers, some consider the likelihood of invasive disease high enough to recommend an SLN biopsy in this situation routinely. (See "Overview of sentinel lymph node biopsy in breast cancer", section on 'DCIS with suspicious features'.)

Adjuvant radiotherapy — For patients who undergo BCT for PDB, whole-breast radiation therapy is standard after breast-conserving surgery [82]. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients treated with breast-conserving surgery'.)

●Invasive cancer – For patients who have invasive cancer, adjuvant radiotherapy to the remaining breast and axilla is clearly indicated to irradicate any residual microscopic disease, reduce recurrences, and prolong survival. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Rationale'.)

●Ductal carcinoma in situ – Few areas in breast cancer treatment are as contentious as the obligate need for RT as a component of BCT in women with DCIS. Proponents of RT for all women with DCIS argue that local recurrence rates are substantially higher when RT is withheld and that one-half of all local recurrences are invasive. Others contend that RT represents overly aggressive therapy for many women with DCIS and that by weighing factors of prognostic importance (ie, grade, size, age, and distance to margins), a sizable subset can be identified who have excellent recurrence-free survival with excision alone. RT for DCIS is discussed in detail elsewhere. (See "Ductal carcinoma in situ: Treatment and prognosis", section on 'Radiation therapy' and "Ductal carcinoma in situ: Treatment and prognosis", section on 'Omission of RT for low-risk disease'.)

Because the DCIS associated with Paget disease is typically high grade and often HER2 positive, RT is typically employed for DCIS associated with Paget disease.

However, in the rare circumstances of pure Paget disease on wide local excision of the nipple-areolar complex without evidence of secondary dermal invasion, DCIS, or invasive cancer on pathology or breast imaging, close clinical follow-up and deferral of RT can be considered [80]. (See 'Others (nonstandard)' above.)

For patients who have undergone mastectomy for PDB, the indication for postmastectomy radiotherapy (PMRT) is solely determined by the pathology of any underlying lesion (invasive ductal cancer or DCIS) and not by the presence of PDB. Although PDB involves the nipple/areolar skin, it should be distinguished from locally advanced breast cancer with skin involvement (T4b). The indications for PMRT are discussed in another topic. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients treated with mastectomy'.)

Adjuvant chemotherapy or endocrine therapy — If an invasive breast cancer is identified, it should be treated like any other invasive breast cancer, with consideration of adjuvant systemic therapy.

There are no data addressing the efficacy of endocrine therapy, including tamoxifen, in reducing the risk for local recurrence in patients with PDB without an underlying invasive carcinoma or DCIS who are treated with breast-conserving therapy. Recommendations regarding endocrine therapy (tamoxifen or aromatase inhibitors) as well as other forms of adjuvant systemic therapy such as chemotherapy and trastuzumab should be based solely upon the characteristics of any associated invasive carcinoma or DCIS. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer" and "Ductal carcinoma in situ: Treatment and prognosis", section on 'Systemic treatment'.)

PROGNOSIS — 

The prognosis of PDB is dependent upon the presence of an underlying invasive ductal carcinoma or axillary node metastases. Tumor stage is a better indicator of prognosis than the presence of Paget disease per se. The survival and prognosis of patients with breast cancer are discussed in other topics. (See "Prognostic and predictive factors in early, non-metastatic breast cancer".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Paget disease of the breast (PDB) is clinically characterized by a persistent scaling, eczematous, or ulcerated lesion involving the nipple-areolar complex. PDB is associated with underlying breast cancer (in situ [ductal carcinoma in situ; DCIS] and/or invasive) in 85 to 88 percent of cases, often without an associated breast mass or mammographic abnormality. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of PDB can usually be established by punch or full-thickness wedge biopsy demonstrating intraepithelial adenocarcinoma cells (Paget cells) within the epidermis of the nipple. (See 'Diagnosis' above.)

●Diagnostic evaluation – The diagnostic workup of all patients with PDB should include careful physical examination of both breasts and bilateral mammography and/or ultrasound. Breast MRI may be added in a patient with a negative physical examination and mammogram/ultrasound. Biopsy of any underlying mass or mammographic abnormality is required to assist in decisions about local treatment of the breast and the need for evaluation of the axilla. (See 'Diagnostic evaluation' above.)

●Treatment – The prognosis of PDB is based upon the underlying breast cancer, thus, treatment should be guided by the stage of the tumor and other prognostic and/or predictive factors. (See 'Treatment' above.)

•Breast surgery – Both mastectomy and breast-conserving surgery followed by whole-breast radiotherapy (RT) are acceptable treatment options for PDB with or without a palpable mass or imaging abnormalities. When there is a palpable mass or imaging abnormalities, breast-conserving surgery and RT should only be performed when a nipple-areolar resection and wide local excision of the underlying cancer can be performed with an acceptable cosmetic result and negative margins. (See 'Breast surgery' above.)

•Axillary surgery – Evaluation and treatment of the axilla in PDB are the same as for any breast cancer and depend on the underlying cancer identified and the planned surgical procedure (breast-conserving surgery or mastectomy). Patients with known invasive disease and/or those who undergo mastectomy should undergo sentinel lymph node (SLN) biopsy; otherwise, those who undergo breast-conserving surgery may defer SLN biopsy until final pathology shows invasive ductal cancer. (See 'Management of the axilla' above.)

•Adjuvant therapies – For most patients undergoing breast-conserving surgery for PDB, we suggest whole-breast radiation (Grade 2C). Other recommendations regarding the use of adjuvant systemic therapy in patients with PDB should be based on the characteristics of the underlying carcinoma. There are no data to support the use of endocrine therapy in women with PDB without an associated invasive cancer or DCIS. (See 'Adjuvant chemotherapy or endocrine therapy' above.)

●Prognosis – The prognosis of PDB is dependent upon the presence of an underlying invasive ductal carcinoma or axillary node metastases. Tumor stage is a better indicator of prognosis than the presence of Paget disease per se. (See 'Prognosis' above.)