Paget’s disease of the nipple with occult ductal carcinoma in situ despite negative conventional imaging: A case report

Abstract

BACKGROUND

Mammary Paget’s disease, also known as Paget’s disease of the breast (PDB), is a rare malignancy of the nipple-areolar complex that is frequently associated with underlying ductal carcinoma in situ (DCIS) or invasive carcinoma. However, the underlying malignancy may remain occult on conventional imaging, potentially delaying diagnosis.

CASE SUMMARY

We report the case of a 75-year-old woman with a 2-year history of a persistent erythematous lesion of the right nipple, initially treated as eczema. Mammography and ultrasonography did not reveal a definite malignant lesion. Contrast-enhanced magnetic resonance imaging demonstrated nipple inversion, skin thickening, and enhancement suspicious for Paget’s disease but did not identify a discrete breast mass. A skin biopsy confirmed Paget’s disease of the nipple. The patient subsequently underwent central partial mastectomy and sentinel lymph node biopsy. Postoperative pathology revealed high-grade multifocal DCIS underlying the nipple-areolar complex.

CONCLUSION

PDB may present as persistent unilateral nipple-areolar dermatitis with inconclusive imaging findings. This case highlights the importance of biopsy when clinical suspicion persists, as negative conventional imaging does not exclude an underlying malignancy.

Key Words: Paget’s disease of the nipple; Paget’s disease of the breast; Ductal carcinoma in situ; Magnetic resonance imaging; Occult malignancy; Imaging-pathology correlation; Case report

Core Tip: Mammary Paget’s disease, also known as Paget’s disease of the breast, may present as chronic nipple eczema without a detectable underlying malignant lesion on conventional imaging. In this case, diagnosis required repeat biopsy and magnetic resonance imaging despite initially benign imaging findings. Clinicians should maintain a high index of suspicion and pursue histopathologic evaluation when unilateral nipple-areolar dermatitis persists, even in the absence of radiologic evidence of malignancy.

INTRODUCTION

Mammary Paget’s disease, also known as Paget’s disease of the breast (PDB), is a rare non-invasive malignancy of the nipple-areolar complex that typically presents with erythema, ulceration, eczema-like changes, or nipple discharge. Nipple flattening is common, and retraction or inversion may indicate an underlying malignancy.

PDB primarily affects postmenopausal women, with a median age of onset of approximately 64 years, although cases in men have been reported. Up to 90% of patients have an associated underlying malignancy, most commonly ductal carcinoma in situ (DCIS) or invasive ductal carcinoma. Despite this strong association, PDB accounts for only about 1%-3% of all breast cancers[1].

Imaging plays a central role in evaluation. Mammography has high sensitivity when a palpable mass is present but is considerably less sensitive in non-palpable disease[2]. Magnetic resonance imaging (MRI) can detect additional occult or multifocal disease and is often used when conventional imaging is inconclusive[3]. Nevertheless, imaging alone may fail to detect an underlying malignancy, underscoring the importance of tissue diagnosis.

CASE PRESENTATION

Chief complaints

A 75-year-old woman presented with a persistent erythematous lesion of the right nipple accompanied by intermittent stabbing pain for 2 years.

History of present illness

The patient noted progressive erythema and intermittent lancinating pain of the right nipple over approximately 2 years. She reported no palpable breast mass or nipple discharge. The lesion was initially diagnosed as eczema at a local clinic and treated with topical corticosteroids without improvement.

Subsequent mammography demonstrated grouped calcifications without significant interval change compared with prior imaging. Breast ultrasonography showed cutaneous changes in the right nipple, raising suspicion for Paget’s disease. A skin biopsy confirmed Paget’s disease, with immunohistochemistry demonstrating equivocal estrogen receptor expression, progesterone receptor negativity, and HER2 overexpression (3+).

MRI revealed nipple inversion, skin thickening, and enhancement consistent with Paget’s disease but no definite underlying invasive mass. Based on these findings, the patient elected to undergo surgical management.

History of past illness

The patient had hypertension for 20 years, which was well controlled with medication.

Personal and family history

The patient reported no family history of breast cancer or other malignancies.

Physical examination

The physical examination revealed an erythematous, ulcerative lesion involving the right nipple-areolar complex with crusting and irregular margins. No palpable mass, nipple discharge, skin dimpling, or axillary lymphadenopathy was identified. The contralateral breast was unremarkable (Figure 1).

Figure 1 Clinical presentation of an ulcerated right nipple lesion. A: Close-up view of an ulcerative lesion of the right nipple characterized by erythema, crusting, and irregular margins, confined to the outlined area; B: Wider field view showing involvement of the right nipple-areolar complex without extension into the surrounding breast parenchyma or the contralateral breast. The left breast appeared normal, with no similar lesions.

Laboratory examinations

Routine laboratory examinations, including complete blood count and biochemical tests, revealed no significant abnormalities.

Imaging examinations

Mammography demonstrated grouped punctate and amorphous calcifications (Figure 2) in the upper outer quadrant and retroareolar region of the right breast without associated mass, distortion, or axillary lymphadenopathy (Breast Imaging Reporting and Data System 0). Ultrasonography revealed small hypoechoic nodules (< 5 mm) consistent with benign changes and poorly visualized nipple abnormalities (Figure 3). Contrast-enhanced MRI showed nipple inversion with skin thickening and enhancement but no discrete mass (Figure 4A). Multiple small enhancing foci were present bilaterally, consistent with fibrocystic changes (Figure 4B).

Figure 2 Breast mammography. A: Right breast mammography. Right craniocaudal and right mediolateral oblique views demonstrated grouped punctate and amorphous calcifications in the upper outer quadrant and retroareolar region of the right breast, without associated mass, architectural distortion, or lymphadenopathy. The findings were stable compared with prior imaging and were categorized as Breast Imaging Reporting and Data System 0; B: Bilateral breast mammography. Benign-appearing calcifications were present in both breasts without suspicious masses, asymmetries, or architectural distortion. No abnormal skin changes, nipple retraction, or axillary lymphadenopathy were identified.

Figure 3 Bilateral breast ultrasonography. Ultrasonography demonstrated scattered subcentimeter hypoechoic nodules (< 5 mm) in both breasts, most consistent with benign complex cysts or fibrocystic changes.

Figure 4 Magnetic resonance imaging. A: Magnetic resonance imaging (MRI) of the right nipple-areolar complex. Axial contrast-enhanced MRI demonstrated right nipple inversion with associated skin thickening and enhancement, consistent with Paget’s disease; B: Bilateral breast MRI. Multiple small enhancing foci are present in both breasts, consistent with benign fibrocystic changes.

MULTIDISCIPLINARY EXPERT CONSULTATION

Pathological findings

Histological examination of the nipple biopsy showed malignant ductal epithelial cells infiltrating the epidermis, with characteristic Paget cells demonstrating high nuclear-to-cytoplasmic ratios, hyperchromatic nuclei, and cytokeratin 7 positivity (Figure 5).

Figure 5 Histopathologic features of Paget’s disease of the nipple. A: Skin, 40 µm; B: Cytokeratin 7 (CK7) immunostaining, 40 µm; C: Skin, 100 µm; D: CK7 immunostaining, 100 µm. Microscopic examination demonstrated malignant ductal epithelial cells spreading along the basal layer and infiltrating upward into the overlying squamous epithelium. Paget cells were ovoid, with high nuclear-to-cytoplasmic ratios, hyperchromatic nuclei, and pale cytoplasm. Immunohistochemistry showed strong CK7 positivity, supporting the diagnosis.

Surgical pathology after partial mastectomy revealed high-grade multifocal DCIS with central necrosis and ductal expansion (Figure 6).

Figure 6 High-grade ductal carcinoma in situ in the partial mastectomy specimen. A and B: Representative sections are shown which demonstrated monotonous tumor cells with enlarged, hyperchromatic nuclei filling and expanding mammary ducts. Central comedo-type necrosis and peripheral reactive lymphoid aggregates were present, consistent with high-grade ductal carcinoma in situ.

FINAL DIAGNOSIS

PDB with underlying high-grade multifocal DCIS.

TREATMENT

The patient underwent central partial mastectomy with sentinel lymph node biopsy, followed by adjuvant radiotherapy.

OUTCOME AND FOLLOW-UP

The postoperative course was uneventful. The patient was discharged on postoperative day 1 and remains without evidence of recurrence on follow-up (Table 1).

Table 1 Clinical timeline.

Time	Clinical events
November 2023	Skin biopsy: Chronic inflammation with granulation tissue
October 2024	Mammography: Grouped calcifications without significant changes compared to previous mammography in a local hospital
	Breast ultrasonography: Cutaneous changes that raise suspicion for Paget’s disease
	Repeat skin biopsy: Confirmed Paget’s disease. Estrogen receptor equivocal staining, progesterone receptor-negative, HER2-positive (3+ 90% of cells)
	MRI: Right nipple inversion and enhancement with thickening of covering skin, compatible with Paget’s disease
October 2024	Surgery: Right breast central type partial mastectomy and sentinel node dissection
November 2024	Pathology: Paget’s disease with high-grade multifocal ductal carcinoma in situ
November 2024	Follow-up: Radiation therapy and outpatient department regular checkup, showing good recovery

DISCUSSION

PDB presents a well-recognized diagnostic challenge because the associated intraductal carcinoma is frequently radiologically occult. In this case, mammography, ultrasonography, and MRI demonstrated superficial changes consistent with Paget’s disease but failed to identify the underlying high-grade multifocal DCIS, which was only detected on postoperative pathology. This discordance underscores a key clinical limitation: Imaging may underestimate or entirely miss clinically significant disease in PDB.

Previous studies have demonstrated that conventional imaging has limited sensitivity in non-palpable PDB. Mammography detects an underlying malignancy in only 30%-50% of cases when no palpable mass is present, particularly when DCIS lacks calcifications or is confined to the superficial retroareolar ductal system[2,4]. Even when abnormalities are identified, mammography may underestimate the true extent of disease. Ultrasonography shows similar variable performance, with reported sensitivities ranging from 8%-50%, largely because DCIS often presents as non-mass abnormalities that overlap with benign ductal or fibrocystic changes[5,6]. Studies reported that approximately 65% of patients have an underlying malignancy that is not apparent on mammography[5,6]. Likewise, Ikeda et al[7] found that mammography appears normal in 29%-50% of Paget’s disease cases and, when positive, often underestimates the extent of the underlying malignancy.

Pathophysiologic mechanisms of occult DCIS

The diagnostic challenge of imaging-negative DCIS reflects the complex pathophysiology of intraductal malignancies. Although up to 75% of DCIS cases present as suspicious microcalcifications on mammography, their detectability depends on both their chemical composition and the underlying biological process of mineral deposition. Calcium phosphate (particularly hydroxyapatite) is often associated with malignancy but may be radiographically indistinguishable from benign calcium oxalate. Moreover, calcification formation results from a combination of active secretory processes and passive degeneration, which may not occur even in high-grade lesions. In the absence of characteristic fine linear branching or pleomorphic morphologies, DCIS may remain mammographically occult[8].

Similarly, the limited sensitivity of ultrasonography (8%-50%) for DCIS is largely attributable to the fact that more than 60% of cases present as non-mass abnormalities, such as subtle hypoechoic areas or minor ductal changes, that overlap with benign duct ectasia[8]. In this patient, the confinement of malignant cells to the superficial ducts, without formation of a discrete mass or significant calcification, likely fell below the spatial resolution of conventional imaging, resulting in a deceptively reassuring radiological appearance despite the presence of high-grade disease.

Limitations of MRI

MRI plays a crucial role in the presurgical evaluation of Paget’s disease of the nipple, particularly when mammography and ultrasound are negative. Contrast-enhanced MRI can identify edema of the nipple-areolar complex, skin thickening, retroareolar masses, ductal dilatation, and parenchymal enhancement; it also provides superior sensitivity in distinguishing normal from abnormal nipple-areolar morphology, particularly when the disease is confined to the epidermis without underlying invasive carcinoma[2].

Although MRI is the most sensitive modality for detecting occult breast malignancy, its performance in identifying DCIS associated with Paget’s disease remains variable. Enhancement patterns of DCIS may be subtle or heterogeneous, and recent studies indicate that MRI detects only a subset of occult DCIS cases in this setting[9]. Trebska-McGowan et al[10] reported that the sensitivity of MRI for DCIS decreases to 44%, whereas it approaches 100% for invasive carcinoma.

Importance of early intervention

Given that PDB is associated with an underlying malignancy in up to 90% of cases, a high index of clinical suspicion is essential. Persistent nipple-areolar skin lesions, particularly those that mimic inflammatory conditions such as eczema, should prompt early skin biopsy and comprehensive breast imaging to enable timely diagnosis. Although PDB often follows an indolent course, delays in diagnosis may allow progression to a high-grade, multifocal disease, as illustrated in this case. Earlier biopsy at symptom onset might have identified the disease at a more localized stage, potentially simplifying surgical management and improving outcomes. Early detection remains critical for the effective management of occult malignancy in Paget’s disease.

CONCLUSION

This case highlights a critical clinical principle: The absence of suspicious findings on conventional imaging does not exclude a significant underlying malignancy in patients with suspected Paget’s disease. Clinicians should prioritize histopathologic evaluation over reassuring radiologic findings. Persistent unilateral nipple dermatitis warrants biopsy, even when appearance is benign on imaging.

ACKNOWLEDGEMENTS

The authors would like to thank the radiology and pathology teams for their contributions to the diagnostic evaluation of this case.