Abstract: Paget’s disease of the breast is a rare malignancy of the nipple-areola complex and accounts for 1%–4% of all breast cancers. The disease is frequently associated with an underlying in-situ or invasive carcinoma in the breast tissue that extends to the nipple and areola. Paget’s disease is characterized clinically by eczema-like inflammatory skin changes and histologically by malignant cell infiltration in the dermis (Paget’s cells). Although Paget’s presents less commonly than a palpable mass or mammography abnormality, it is an important consideration in the differential diagnosis of a persisting nipple-areola abnormality. Diagnosis may be delayed by several months or even years because of Paget’s seemingly benign appearance. The following case demonstrates this particular situation. Biopsy of a chronic wound that shows no evidence of healing over time is of paramount importance, especially in the case of a chronic breast lesion.
Address correspondence to: Moises Menendez, MD, FACS, CWS Wound Care Associates 411 N. Washington Ave.,Suite 5000 Dallas, TX 75246 Phone: 214-828-0702 E-mail: mmenendez@Baylorhealth.edu
Paget’s disease (PD) of the breast is a rare malignancy of the nipple-areola complex and accounts for 1%–4% of all breast cancers.1 The disease is frequently associated with an underlying in-situ or invasive carcinoma in the breast tissue that extends to the nipple and areola. It is characterized clinically by eczema-like inflammatory skin changes and histologically by infiltration of the dermis by malignant cells (Paget’s cells). Although less common a presentation than a palpable mass or mammography abnormality, Paget disease of the breast is an important consideration in the differential diagnosis of a persisting nipple-areola abnormality.2 Because of its seemingly benign appearance, the diagnosis may be delayed by several months or even years, as in the following case. In general, it is of paramount importance to biopsy chronic wounds, which show no evidence of healing over time, especially in the case of a chronic breast wound.
A 75-year-old woman was referred to one of the authors at the Wound Healing Center of South Arkansas for treatment of a chronic wound in the nipple-areola complex of the left breast. Approximately 4 years prior, the patient was referred to the authors for care of a breast lesion, which was suspected to be malignant. She had changed primary care physicians when her condition had not improved. At that time, several biopsies were performed once the clinical suspicion of PD was entertained; however, the pathological impression showed only chronic inflammation with no evidence of malignancy. The patient was subsequently lost to follow up, and was seen by two separate dermatologists within that period. The patient’s comorbidities included rheumatoid arthritis, arterial hypertension, adult-onset diabetes, and obesity. She underwent multiple surgeries on the right shoulder that rendered her with significantly limited range of motion. Her past surgical history also included a cholecystectomy and a hysterectomy. Her medications included corticosteroids, antihypertensives, and oral diabetic agents. Physical examination found chronic rheumatoid changes on the joints with severe limitation in range of motion of the right shoulder and elbow, and moderate obesity. Examination of the left breast showed areas of eczematoid changes around the nipple-areolar complex. There was marked erythema with crusting of the surface of the skin. A moderate amount of bleeding was produced by inspection and palpation. The most striking feature was obliteration of the nipple compared to the contralateral breast (Figure 1). At times, the wound appeared to form an eschar (Figure 2). There were no palpable breast masses or axillary/supraclavicular adenopathy. The examination of the contralateral breast was benign. The patient’s laboratory work up was unremarkable except for moderate hyperglycemia. A chest x-ray was negative. The complete blood count (CBC) showed mild anemia. A mammogram of the affected breast was negative. The clinical impression was very strong for PD, despite the original negative pathology. Therefore, the patient agreed to undergo wide local excision of the nipple-areola complex, which included a minimal swath of underlying breast tissue. The patient declined more extensive breast surgery. The final pathological report showed PD of the breast and underlying high-grade ductal carcinoma in situ with positive margins. No evidence of invasive carcinoma was found (Figure 3). A CT/PET scan indicated no evidence of metastasis. An extended central lumpectomy and sentinel lymph node biopsy was planned because the margins were positive for high-grade ductal carcinoma in situ (DCIS) in the setting of a chronic wound. Prior to the surgery, a lymphoscintigraphy was performed indicating the location of the sentinel node in the left axilla. A wide local excision/partial mastectomy was performed with sentinel lymph node biopsy. The final pathological exam showed no evidence of in-situ or invasive disease; ER and PR receptors were negative. The sentinel node biopsy was also negative. Her postoperative course was uneventful. The patient eventually underwent external beam radiation therapy. Presently, there is no evidence of recurrent disease in the left breast.
Cutaneous malignancies may present either as wounds or develop from wounds. Nonmelanoma skin cancer, lymphomas, and sarcomas may ulcerate as they outgrow their blood supply.3 Malignancy can also develop from chronic wounds, most commonly squamous cell carcinoma, and Marjolin’s ulcer.4 Malignant melanomas could be misdiagnosed as diabetic ulcers when in the lower extremity.5 However, PD of the breast is a malignant condition that arises de novo without an ulceration or previous skin lesion, although it can develop from a congenital absence of the nipple1 or from an irradiated breast, which can complicate or even delay true diagnosis.6 Early identification of the malignancy, using biopsy techniques, is of paramount importance especially in chronic wounds that will not heal or deteriorate despite standard therapy. It is vital the clinician is aware of the limitations of biopsies performed too superficially or sparingly that may create an illusion of definite diagnosis in a lesion that does not heal utilizing standard therapy. Repeat biopsy is also important since an initial biopsy may have insufficient tissue for diagnosis, as seen in the present case. The presumptive diagnosis of PD was made, thus a biopsy was performed. However, the final report indicated no evidence of malignancy. This may indicate that the biopsy was too superficial or that the specimen was not representative enough to make a definitive diagnosis. Therefore, it is imperative when the clinical suspicion exists for a chronic wound or ulcer, that a biopsy involving all layers of soft tissue is undertaken. Punch, wedge, or excisional biopsy of the nipple-areola complex, which includes the dermal and subcutaneous tissue for detailed microscopic examination, provides an adequate sample for the accurate diagnosis of mammary PD. The pathological slides of the first biopsy were reviewed and reevaluated by one of the authors, confirming the absence of malignant cells. Unfortunately, the patient was lost for follow up. She subsequently moved out of state, and was then followed by two dermatologists who did not repeat the biopsy. The differential diagnosis of PD of the breast (PDB) includes eczema, erosive dermatoses, Bowen’s disease, basal cell carcinoma, superficial spreading malignant melanoma, nipple adenoma, and pemphigus vulgaris.2 Paget’s disease of the breast is often confused with other skin conditions, such as eczema, dermatitis, or psoriasis. These misdiagnoses often lead to delays in appropriate treatment. Misdiagnosis is more common when both breasts are affected and no lump in the breast is detected. A correct diagnosis is more likely in the setting of mammographic findings or evidence of a palpable mass.7 Therefore, in order to avoid delay in definite diagnosis, any persistent abnormality should be considered suspicious and biopsied. In a Swedish study of 223 women with PDB studied from 1976 to 2001, 98% of the patients diagnosed with PD presented with eczema or ulceration of the nipple. The diagnosis of the underlying breast neoplasia was established in 80% of the patients before surgery. Patients with noninvasive PD of the nipple had an excellent outcome and selected patients with PDB were treated with breast conserving surgery with survival rates similar to those achieved with mastectomy.8 In the presented case, the patient was followed by two dermatologists who treated the patient based on the first biopsy report. There is a possibility that the biopsy was insufficient to render an accurate diagnosis at that time, and therefore a second biopsy should have been attempted. Regarding the patient’s treatment course, it was believed that due to her multiple comorbidities, a limited resection with sentinel node biopsy and external beam irradiation would be better than a mastectomy. One study supported the recommendation of local excision and definitive breast irradiation as an alternative to mastectomy in the treatment of patients with PD presenting without a palpable mass or mammographic density, as seen in this patient.9 Failure to educate patients about the potential for invasive breast carcinoma associated with mammary PD is a pitfall. Without this knowledge patients may further delay diagnostic mammography examination or a diagnostic biopsy, and possibly detection of underlying breast cancer.10
It is essential to educate the medical public about chronic wounds of the breast that fail to show evidence of healing over time. Not only is a biopsy highly recommended, but a repeat biopsy could be necessary when the objective signs suggest a malignancy, as evidenced in the presented case.