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10.1245/ASO.2005.05.026
Annals of Surgical Oncology 12:391-397 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Paget’s Disease of the Breast: There Is a Role for Breast-Conserving Therapy

Kazumi Kawase, MD1, Dominick J. DiMaio, MD1, Susan L. Tucker, PhD2, Thomas A. Buchholz, MD3, Merrick I. Ross, MD1, Barry W. Feig, MD1, Henry M. Kuerer, MD, PhD1, Funda Meric-Bernstam, MD1, Gildy Babiera, MD1, Frederick C. Ames, MD1, S. Eva Singletary, MD1 and Kelly K. Hunt, MD, FACS1

1 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 444, Houston, Texas 77030
2 Department of Biomathematics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 237, Houston, Texas 77030
3 Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1202, Houston, Texas 77030

Correspondence: Address correspondence and reprint requests to: Kelly K. Hunt, MD, FACS; E-mail: khunt{at}mdanderson.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The optimal surgical management of Paget’s disease of the breast remains to be defined. Mastectomy has been the standard of care, but several institutions have recently advocated breast-conserving surgery, particularly for patients with minimal disease. In an effort to develop rational treatment guidelines, we examined our institutional experience with Paget’s disease of the breast.

Methods: Patients with Paget’s disease of the breast who had surgical therapy at our institution between 1949 and 1993 were reviewed. In addition to patient and tumor characteristics, charts were reviewed for treatment modalities, locoregional recurrence patterns, and survival. Subgroups were compared for differences in survival in both univariate and multivariate analyses.

Results: A total of 104 patients met the study criteria. The most common presenting symptoms were nipple discharge and eczematous changes of the nipple/areola complex. Ninety-seven patients (93.2%) had an underlying invasive or noninvasive cancer associated with Paget’s disease. Ninety-two patients (88.5%) underwent mastectomy, and 12 (11.5%) had a breast-conserving procedure. On univariate analysis, patients with age <60 years at diagnosis, stage II disease, positive lymph nodes, invasive disease, or a palpable mass had significantly lower 10-year disease-specific and recurrence-free survival. There were four locoregional recurrences (three after mastectomy and one after breast conservation). There were no significant differences in overall, disease-specific, or recurrence-free survival according to the type of surgery.

Conclusions: Paget’s disease of the breast is almost always associated with an underlying breast cancer. Breast-conserving approaches result in local control and survival rates similar to those achieved with mastectomy.

Key Words: Paget’s disease • Breast conservation • Breast cancer • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Paget’s disease of the breast is an uncommon disorder that accounts for 1% to 3% of all mammary tumors.1–3 Clinically, patients with Paget’s disease have erythema and scaling or eczematous changes in the nipple and areola that they often describe as pruritic or burning. These nipple changes later progress to ulcerations and erosion and may occur alone or in conjunction with an underlying palpable mass. Paget’s disease is often mistaken for dermatitis or a benign dermatological condition involving the nipple. It is not unusual for the diagnosis to be delayed for 6 to 12 months before a biopsy is performed.

There are many theories regarding the origin of Paget’s disease: Paget’s cells may have an intraepidermal origin (in situ transformation theory),4 or they may originate from an intraductal cancer and spread by upward migration to the nipple (epidermotropic theory).5,6 Most researchers agree, however, that regardless of their origin, Paget’s cells are a sign of underlying breast cancer.1,2,7,8 Paget suggested in his original description that an underlying cancer succeeded the nipple changes in most cases within 1 year and in all cases within 2 years.9 However, cases of Paget’s disease of the nipple alone, with no underlying cancer, have been reported.10

Published treatment recommendations for Paget’s disease have varied from simple excision or radiotherapy to total mastectomy. Mastectomy has long been considered as a definitive treatment.1,2,11–14 However, the surgical management of breast cancer has changed significantly over the last three decades as a result of several large randomized trials demonstrating that breast-conservation therapy results in survival equal to that after mastectomy in patients with early-stage breast cancer.15–18 Thus, although the rarity of Paget’s disease does not allow for randomized trials comparing treatment modalities, with the aid of improved mammographic and radiotherapy techniques, the breast-conserving approach has been considered as a treatment option in selected patients. 19–22

We initiated this study to examine our institutional experience with Paget’s disease in an attempt to develop rational treatment guidelines.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We conducted a retrospective study of patients diagnosed with Paget’s disease of the breast and treated with primary surgical therapy at the University of Texas M. D. Anderson Cancer Center between 1949 and 1993. Patients were identified through a search of a prospectively compiled institutional database. Patients who had involvement of the nipple as part of a locally advanced cancer were not included. Patient records were reviewed to determine clinical presentation, histopathologic features, treatment modalities, locoregional recurrence patterns, and survival. Patients were restaged according to the 5th American Joint Committee for Cancer tumor-node-metastasis staging manual.23 Survival data were analyzed by using the method of Kaplan and Meier.24 The log-rank test was used to compare disease-specific survival (DSS) and recurrence-free survival (RFS). The {chi}2 test was used to correlate prognostic factors significant in univariate but not multivariate analysis with nodal status. Statistical analysis was performed with Stata statistical software, release 8 (Stata Corp., College Station, TX).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
We identified 113 patients with a diagnosis of Paget’s disease of the breast treated at the M. D. Anderson Cancer Center between 1949 and 1993. Nine patients with stage III or IV disease were excluded from our analysis because nipple involvement in these patients was believed to be a late manifestation of locally advanced or recurrent disease. The remaining 104 patients formed the basis of this study. Of these 104 patients, 2 were men and 102 were women. The median age was 57 years (range, 24–90 years).

Tumor Characteristics
Presenting symptoms are listed in Table 1Go. Most patients had more than one symptom at presentation. The most common presenting symptoms were nipple discharge and eczema or scaling of the nipple (Fig. 1Go). In addition to nipple changes, 36 patients (35%) had a palpable mass. Twelve (33%) of these masses were adjacent or deep to the nipple, and 24 (67%) were located distant from the nipple. Ten patients had a palpable breast mass without obvious nipple changes. Mammography was not commonly performed before 1970. Mammography was performed at presentation in 81 patients, 60 (74%) of whom had abnormal findings.


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  		TABLE 1. Presenting symptoms
 

Figure 1
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  		FIG. 1. Clinical presentation of Paget’s disease. (A) In this patient, the erythema and scaling changes are confined to the nipple. (B) In this patient, changes consistent with Paget’s disease are more extensive, with involvement of the nipple and areola.

 
The histopathologic findings at definitive surgical resection are listed in Table 2Go. Overall, 63 patients (60%) also had invasive carcinoma, 34 patients (33%) had ductal carcinoma-in-situ, and the lesion was confined within the nipple without evidence of invasive or noninvasive disease in 7 patients (7%). Multifocal disease was identified in the breast in 37 patients (36%). Of the 91 patients who had lymph nodes examined, 26 (29%) had metastatic disease on pathologic examination. Forty-one patients (39%) had stage 0 disease, 23 (22%) had stage I disease, and 40 (38%) had stage II disease.


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  		TABLE 2. Histopathologic findings at surgical resection
 
Treatment Modalities
All patients underwent surgical excision as part of their local therapy. Patients were selected for nipple/ areola complex excision alone when the treating surgeon believed that all disease could be encompassed in a single excision. In addition, patients with a mammographic abnormality or palpable mass in addition to the nipple changes were considered candidates for breast-conserving surgery if all disease could be resected with negative margins and without poor cosmesis.

Ninety-two patients (88%) were treated with simple (3 patients), extended simple (13 patients), modified radical (45 patients), or radical (31 patients) mastectomy. Twelve patients were treated with primary breast-conserving therapy in addition to complete excision of the nipple/areola complex: 11 (92%) had segmental mastectomy alone, and 1 (8%) had segmental mastectomy with axillary dissection. Radiotherapy was used in 30 patients (29%), including all 12 patients treated with breast-conserving surgery. The median dose to the breast was 50 Gy. Eighteen patients (17%) were treated with adjuvant chemotherapy—in most cases, a doxorubicin-based combination chemotherapy regimen. Nine patients were treated with both chemotherapy and radiotherapy in addition to surgical resection.

Survival Analysis
At the time of our analysis, 52 patients were alive, 20 had died of breast cancer, and 32 had died of other causes. Among the surviving patients, the median follow-up time was 7 years (range, 10 months to 29 years). The 5-year DSS rate for all patients was 84% ± 8%, and the 10-year DSS rate was 79% ± 9%. There were four locoregional recurrences (three in the mastectomy group and one in the breast-conservation group). RFS rates were calculated from the date of surgery to the date of recurrence or last follow-up. The 5-year RFS rate was 79% ± 8%, and the 10-year RFS rate was 75% ± 9%. Subgroups of patients were compared for differences in DSS and RFS as shown in Table 3Go. For both DSS and RFS, the only adverse factor selected by multivariate analysis at a significance level of p ≤ .05 was positive nodal status. The type of surgical treatment did not result in differences in DSS and RFS (p = .697 and .953, respectively). For DSS, the relative risk associated with positive nodal status was 9.1 (95% confidence interval [CI], 2.8–23.0). For RFS, the relative risk associated with positive nodal status was 9.8 (95% CI, 3.5–27.2). After correction for nodal status, the only factor close to statistical significance was age, with a relative risk in younger patients of 4.0 (95% CI, .9–17.5; p = .067) for DSS and 3.3 (95% CI, .97–11.4; p = .056) for RFS. All of the prognostic factors that predicted decreased DSS and RFS on univariate analysis, except for age, were correlated with nodal status (Table 4Go).


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  		TABLE 3. Analyses of factors possibly influencing disease-specific survival (DSS) and recurrence-free survival (RFS)
 

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  		TABLE 4. Prognostic factors identified by univariate analysis and their relationship to nodal status
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Over 44 years (1949 to 1993), we identified 113 patients treated at our institution for Paget’s disease of the breast. We excluded 9 patients who had locally advanced or metastatic disease, leaving a total of 104 patients. The median age was 57 years. This finding is similar to those of other series—it has previously been noted that Paget’s disease often presents at a slightly older age than breast carcinoma without Paget’s disease. There were 2 men in our series, adding to the approximately 40 cases in men reported in the literature to date. The most frequently reported symptoms in our patients were nipple discharge and scaling or eczematous changes. Most patients had two or more symptoms at presentation. In the literature, approximately 40% to 50% of patients with Paget’s disease present with an associated palpable mass,1,7–9 and 20% to 60% of these masses are remote from the nipple.2,8 In our series, one third of the patients had a palpable mass at presentation, and clinically, 67% of these palpable masses were distant from the nipple/areola complex.

In our study, mammography was performed on 81 patients at presentation. Of these patients, 60 (74%) had abnormalities recognized by the mammographer. A mammographic abnormality has been reported in 40% to 50% of cases described in the literature. One possible explanation for the higher rate of mammographic abnormalities in our study is the fact that diagnostic mammography was used: this may result in a higher yield than standard screening mammography. Breast ultrasonography and magnetic resonance imaging have been proposed as potential modalities for screening and diagnosis.25,26 These modalities can be used to confirm mammographically detected abnormalities or to detect mammographically occult lesions in patients with Paget’s disease.

The incidence of underlying carcinoma associated with Paget’s disease has been reported in 82% to 100% of cases.1,6–8,27,28 The finding of underlying carcinoma reaches almost 100% when a palpable mass is also present.6,8,27 Multifocal or multicentric carcinoma associated with Paget’s disease has been reported in 32% to 41% of patients.8,28 In our study, 93% of patients had an associated underlying carcinoma; of these, 33% were ductal carcinoma-in-situ only, and 36% had multifocal disease. These results are consistent with other studies and confirm the high frequency of underlying carcinoma associated with Paget’s disease.

The surgical treatment of Paget’s disease has been controversial. Historically, mastectomy with or without axillary lymph node dissection was the standard therapy, and this approach was supported by the observation that there was almost always an underlying invasive or noninvasive carcinoma. Several reports have shown that 20% to 40% of mastectomy specimens from patients with Paget’s disease have multifocal or multicentric disease, and this disease was often underestimated on mammography.2,3,27,28 In the literature, almost all patients treated with local excision, radiotherapy, or both had the clinical presentation of Paget’s disease without a palpable mass.

Dixon et al.3 reported a high local recurrence rate of 40% with a median follow-up time of 56 months in 10 patients treated with local excision alone whose mammograms suggested in situ changes confined to the immediate nipple area. Polgar et al.29 reported a local recurrence rate of 33% with a median follow-up time of 6 years in 33 patients treated with local excision alone with or without underlying ductal carcinoma-in-situ confined to the nipple/areola complex. They concluded that local excision alone was not an appropriate treatment for patients with Paget’s disease of the nipple.

However, increasing numbers of clinicians suggest that breast-conserving therapy is effective for selected patients. Stockdale et al.19 reviewed 28 patients with Paget’s disease of the nipple treated with radiotherapy alone. Sixteen (84%) of 19 patients without a palpable mass and no abnormality seen on mammography remained free of disease at a median follow-up time of 63 months. Six patients had no palpable mass but either had a mammographically detected underlying tumor or did not undergo screening mammography. Of these six patients, five (83%) had relapsed at the time of their report. Of the three patients with a palpable underlying tumor, one had concomitant systemic metastasis, and two had local recurrences. Fourquet et al.20 reported on 20 patients with Paget’s disease of the breast confined to the nipple without clinical or radiological signs of an associated intraductal or infiltrating breast tumor who were treated conservatively with radiotherapy alone or limited surgery and radiotherapy. The actuarial 7-year probability of freedom from disease in these patients was 81%.

Bijker et al.21 reported the results of a prospective study conducted by the European Organization for Research and Treatment of Cancer. In this study, 61 patients with Paget’s disease of the breast were treated with complete excision of the nipple/areola complex, including the underlying breast tissue, with tumor-free margins, followed by irradiation of the entire breast. Ninety-seven percent of patients presented without an associated palpable mass, and 84% had no abnormality on mammography. At a median follow-up time of 6.4 years, four patients (7%) had a local recurrence; three of those were invasive cancer. The authors concluded that breast-conserving therapy was a feasible alternative for patients with Paget’s disease and a limited extent of underlying ductal carcinoma-in-situ.

Marshall et al.22 reported the long-term follow-up results of breast-conserving surgery with radiotherapy in a study of 38 patients with Paget’s disease of the breast without a palpable mass or mammographic density. Of these patients, 94% underwent complete or partial excision of the nipple/areola complex, 100% underwent irradiation of the breast, and 97% also received a boost to the remaining nipple or tumor bed. The actuarial local control rate for breast recurrence as a component of first failure was 91%, 83%, and 76% at 5, 10, and 15 years, respectively.

A treatment algorithm based on the clinical and pathologic features in patients with Paget’s disease of the breast is outlined in Fig. 2Go. At our institution, patients were considered for nipple/areola complex excision alone when they presented without a palpable mass or mammographic abnormality. In addition, patients with a mammographic abnormality or palpable mass were considered candidates for breast-conserving surgery if all disease could be resected with negative margins and without poor cosmesis. All patients who had breast-conserving surgery underwent adjuvant radiotherapy with a median dose of 50 Gy. In our study, at a median follow-up time of 7 years, locoregional recurrence was observed in only 1 (8%) of 12 patients treated with breast-conserving surgery. In addition, there was no difference in DSS or RFS between patients selected for breast-conserving surgery and those selected for mastectomy. However, because the 2 treatment groups (12 breast-conserving surgery vs. 92 mastectomy) were highly biased toward mastectomy, this study may not have had the statistical power to detect a significant difference.


Figure 2
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  		FIG. 2. A treatment algorithm based on the clinical and pathologic features of patients presenting with Paget’s disease of the breast.

 
Recent reports from several large randomized studies with long-term follow-up have shown that breast-conserving surgery is equivalent to mastectomy in terms of overall and disease-free survival in patients with breast cancer.11–14 Although the number of patients in our study is very small, our results are similar to these randomized trial results in terms of local recurrence rates, DSS, and RFS. This would suggest that for selected patients, breast-conserving surgery is an appropriate treatment for Paget’s disease of the breast. Once multicentric disease has been ruled out by careful examination and imaging studies, surgical treatment of Paget’s disease of the breast can be chosen according to the stage and histological subtype of the underlying carcinoma.

Traditionally, axillary lymph node dissection has been used as the preferred approach to evaluate the status of the regional nodes; however, sentinel lymph node dissection has emerged as a reliable strategy to predict axillary lymph node status for patients with invasive breast carcinoma.30 The treatment of patients with Paget’s disease of the breast should incorporate these recent developments.

It is clear that prognosis is different in patients with a palpable mass and those without a palpable mass. Patients with a palpable mass almost always have an associated underlying invasive carcinoma (75%–100%) and a high rate of axillary lymph node metastasis (45%–65%), whereas patients without a palpable mass have an associated invasive carcinoma in only 20% to 30% of cases and positive axillary lymph nodes in 10% to 20% of cases,1,7–9,15,16,27 Overall survival has been shown to be affected by lymph node status and is reported to be 75% to 95% in patients with negative lymph nodes and as low as 20% to 25% in those with positive lymph nodes.1,8 The survival analysis in our study demonstrated a 10-year DSS rate of 47% in patients with positive nodes and 93% in those with negative nodes, and this is consistent with other studies (Table 3Go). Univariate analysis confirmed that tumor stage, invasiveness, and palpability were related to nodal status (Table 4Go), as has been suggested in the literature.1,6,7,27 Therefore, adjuvant treatment (radiotherapy, chemotherapy, or hormonal therapy) is recommended on the basis of lymph node status and features of the primary tumor as determined by final pathologic examination.

In summary, Paget’s disease of the nipple is almost always associated with an underlying invasive or noninvasive breast cancer. Breast-conserving therapy results in local control and survival rates similar to those achieved with mastectomy. The surgical treatment plan must be chosen on the basis of careful clinical and imaging assessment of each patient. Because prognosis is determined largely by nodal status, postoperative adjuvant therapies should be based on the final tumor-node-metastasis stage.


   ACKNOWLEDGMENTS
 
The authors thank Stephanie Deming for her critical reading of the manuscript.


   FOOTNOTES
 
Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, December 2–6, 2003.

Received for publication May 22, 2004. Accepted for publication January 5, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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