Paget’s Disease of the Breast

Epidemiology

PD represents approximately 1% to 3% of all breast cancers. Up to 95% of cases are associated with underlying breast cancers, which might be in situ or invasive in nature. Cases of PD have also been reported in ectopic breast tissue and supernumerary nipples. In addition, recurrence of breast cancer as PD has also been described. Rare cases of bilateral PD have been reported; in one case this was associated with CHEK2 mutations. Analysis of the Surveillance, Epidemiology, and End Results database (SEER) database shows a preponderance of cases affecting White women. Multicentricity of the underlying carcinoma in PD has been reported in 32% to 41% of patients, 20% to 30% of whom are premenopausal women.

Mammary PD has been observed in males and represents approximately 2% of cases in the SEER database. PD comprises 1.45% of all male breast cancers, compared to only 0.68% of all female breast cancers. There are reports linking PD of the male breast to treatment with methotrexate after lymphomatoid papulosis, hyperestrogenic states (including testicular abnormalities), Klinefelter syndrome, liver cirrhosis, obesity, and BRCA2 mutations.

A study in 2006 based on the SEER program registries reported a decline in the age-adjusted incidence of PD from 1.31 per 100,000 women to 0.64 over a period of 15 years; this decline is observed more in patients having associated carcinoma than in those without carcinoma. One of the reasons for the relative decline could be the dramatic increase in the rates of diagnosis of invasive breast cancers in the past few decades.

Pathogenesis

Sir Robert Muir first documented intraepidermal extension of malignant ductal cells through lactiferous ductules into the epidermis. The current theory maintains that luminal lactiferous ductal epithelial cells give rise to Paget cells, which migrate in a retrograde fashion into the overlying epidermis. Paget cells possess features of glandular cells and demonstrate positivity for the human epidermal growth factor receptor 2 (HER2) oncogene similar to underlying duct carcinoma cells. The exact mechanisms are less understood, but interactions between heregulin-alpha produced by nipple epidermal keratinocytes and HER2 on the tumor cells have been implicated in the chemotaxis of PD. Alternative hypotheses for PD include origin from epidermal Toker cells (TCs), which have been considered to be the benign counterparts of Paget cells. Support of this theory provided by studies that report the same phenotypic apomucins (i.e., MUC1, MUC2, and MUC5AC) in PD as in TCs. The immunoprofile and phenotype of the underlying cancer suggest a common source of origin for Paget cells and TCs. There are reports demonstrating that chromosomal alterations in Paget cells are distinct from those in the underlying cancer. More recent whole exome sequencing data, although based on a small number of cases, show similar differences. Another theory suggests PD originates from the in situ transformation of cells in the terminal lactiferous duct at its junction with the epidermis. Cytokeratin (CK) 7–positive cells are identified in 50% of biopsies from nipple skin around the lactiferous duct ostia. This may explain situations in which PD is not associated with underlying carcinoma or is anatomically remote from it. Ultrastructurally, desmosomal attachments between Paget cells and keratinocytes and between Paget cells themselves are noted. These findings suggest that Paget cells may be native to the epidermis and lend support to the in situ transformation theory.

Clinical Presentation

Most patients (85%–98%) present with eczema of the nipple with scaling and pruritus. With progressive disease, bleeding, ulceration, and bloody or serosanguinous nipple discharge is common. The nipple may be thickened, deformed, or inverted. Usually it is unilateral, but bilateral involvement has been reported. PD is an incidental microscopic finding in approximately 15% of cases. PD is also known to occur in ectopic mammary tissue and supernumerary nipples. The pigmented variants of PD (discussed later) are often difficult to diagnose. They present as solitary or multiple papular lesions, often leading to the mistaken diagnosis of melanoma or an eczematous rash. This may often lead to delayed, inappropriate diagnosis and clinical mismanagement. Hence, correlation with clinical and imaging findings and the role of diagnostic nipple biopsies for appropriate management cannot be overemphasized.

Sisti et al analyzed 7,191 cases of PD from the National Cancer Database (NCDB) and found that the median age was 64 years (range, 20–90 years) with 97.9% of patients being women and 85.4% being White. A total of 54.1% of cases were associated with ductal carcinoma in situ (DCIS) only, while the remainder (45%) were associated with early- or late-stage invasive carcinoma. Similarly, Zhao et al analyzed the SEER database from 2000 to 2013 and identified a total of 501, 631 breast cancers of which 469 (~13.6%) were PD only; 1,130 (~32.9%) had PD with coexisting DCIS, and 1,832 (~38.5%) had PD with coexisting invasive cancer.

Clinical Imaging and Diagnosis

The clinical features of PD are somewhat classic. Erythematous/eczematous nipple erosions that persist for a few weeks or more warrant a diagnostic biopsy. Clinical and imaging findings should always be correlated before a diagnosis is made. An associated palpable breast mass may be absent in up to 70% of cases. Mammographic evaluation is mandatory for all cases of PD to detect underlying carcinoma and exclude multifocal disease. The radiographic findings include distortion of the areola or subareolar architecture and nipple retraction or thickening caused by edema. A mass lesion may be noted at the level of the nipple/areolar complex with or without subareolar microcalcifications. A negative mammogram does not always reliably exclude underlying malignancy as a lack of mammographic abnormality is reported in 22% to 50% of patients. Ultrasound imaging and/or magnetic resonance imaging (MRI) may be useful when mammography is negative. Contrast enhancement MRI can help to identify underlying malignancy in a subset of patients with clinically occult disease. Imaging-guided biopsy before surgical treatment can also potentially resolve false-positive MRI findings, allowing conservative treatment to be planned.