Paget’s Disease: Diagnosis, Management, and Insights into the Breast (PDB)

Paget’s disease of the breast is a rare kind of breast cancer that mostly affects the skin around the nipple. It happens in only a small number of breast cancer cases because it’s linked to certain gene changes and other types of breast tumors. Doctors notice it more in women who have stopped having periods (postmenopausal women). Things like what you eat, where you live, and how often you get check-ups can change your chances of having this disease.

Paget’s disease of the breast is found more often in countries like the United States and those in Western Europe, compared to places in Asia. This could be because people in those countries have more access to doctors, tests, and information about breast health. Even though this disease is not very common, it’s important to pay attention to it because it can be connected to other serious breast tumors. Catching and treating it early helps people have better results and stay healthier in the long run.

Table of Contents:

• What is Paget’s Disease of the Breast?
• Risk Factors and Epidemiology
• Diagnosis
• Treatment
• Prognosis and Outcomes
• Closing Thoughts
• References

What is Paget’s Disease of the Breast?

Paget’s disease of the breast is a rare breast cancer that affects the skin of the nipple and sometimes the areola. It is characterized by a rash or eczema like appearance on the nipple and areola which can be accompanied by itching, redness and discharge. It is often associated with an underlying breast cancer which can be invasive or non-invasive (ductal carcinoma in situ, DCIS). Paget’s disease of the breast is named after Sir James Paget, a 19th century British doctor who first described the condition.

Pathophysiology

The pathogenesis of PDB is explained by two theories:

The first theory is the epidermotropic theory which suggests that Paget cells come from an underlying ductal carcinoma in situ (DCIS) or invasive breast carcinoma. These cells retain their malignant properties and contribute to the histopathological findings of Paget’s disease. These cancer cells are thought to migrate from an underlying carcinoma through the lactiferous ducts to the nipple epidermis.

The second theory is the in situ transformation theory which suggests that Paget cells arise as a primary intraepidermal malignancy independent of any underlying breast carcinoma. This theory is supported by cases where no underlying breast tumor is found.

Epidermotropic Theory: This is the most widely accepted theory which suggests that malignant ductal cells migrate from an underlying carcinoma through the lactiferous ducts to the epidermis of the nipple. These cells retain their malignant properties and contribute to the histopathological findings of Paget’s disease. This theory is supported by the frequent finding of underlying DCIS or invasive carcinoma in patients with PDB. In some cases this underlying carcinoma can be an invasive breast cancer which affects the prognosis and treatment.

In Situ Transformation Theory: This is an alternative theory which suggests that malignant cells arise de novo within the epidermis of the nipple possibly due to local field effects or genetic mutations. Although this theory is less accepted, it highlights the complexity of the disease. Further research is needed to understand the molecular mechanisms.

Characteristic features are large, pale, vacuolated Paget cells in the epidermis often with HER2 overexpression. The strong association with DCIS or invasive carcinoma emphasizes the need for full evaluation. ^[2] Recent studies have looked at molecular pathways including HER2 signaling and immune evasion mechanisms as potential targets for treatment. For example HER2 targeted therapy like trastuzumab has shown promise in improving outcomes.

Risk Factors and Epidemiology

Paget’s disease of the breast is a rare condition and accounts for about 1-4% of all breast cancer. The exact cause of Paget’s disease is not known but it is associated with underlying breast cancer. The risk factors for Paget’s disease are similar to breast cancer:

• Age: Paget’s disease is more common in women above 50. ^[3]
• Family history: Women with family history of breast or ovarian cancer are at higher risk.
• Genetic mutations: Women with BRCA1 or BRCA2 gene mutations are at higher risk.
• Dense breast tissue: Women with dense breast tissue are at higher risk.
• Radiation exposure: Women who have been exposed to radiation especially at a young age are at higher risk.

Knowing these risk factors is important for early detection and prevention. Regular screenings and genetic counseling can help identify those at higher risk and can be managed proactively. ^[4]

Clinical Presentation of Breast Cancer

Typical Patients

• Postmenopausal Women: The most common affected group, probably because of the overall epidemiology of breast cancer. Hormonal changes post-menopause may also play a role in the pathogenesis.
• Peripartum Women: Rarely PDB can occur during pregnancy or lactation and can mimic benign conditions like mastitis or eczema and delay diagnosis. Clinicians should be aware of this to avoid misdiagnosis in this population.

Symptoms

PDB usually presents with changes in the nipple-areola complex:

• Erythema and scaling
• Crusting or ulceration
• Pruritus or burning sensation
• Nipple discharge (serous or bloody)
• Flattening or inversion of the nipple

Unilateral symptoms are common but bilateral symptoms are rare and should prompt consideration of other diagnoses. Symptom progression varies; early cases may present with subtle scaling and advanced cases may have ulceration and nipple destruction. Recognizing these stages is important for timely interventions. Case studies show that early detection of these subtle signs can improve prognosis.

Diagnosis

Diagnosis of PDB is a combination of clinical evaluation, imaging and histopathological assessment. If an underlying cancer is suspected, a sentinel lymph node biopsy may be done to assess the spread of cancer to the axillary lymph nodes. ^[5]

Imaging

1. Mammography: The first line of imaging, useful for detecting underlying DCIS or invasive cancer. Sensitivity may be limited in dense breast tissue and may need supplemental imaging.
2. Ultrasound: Complements mammography by identifying subareolar masses or ductal abnormalities. Useful in younger patients and those with dense breasts.
3. MRI: Highly sensitive for occult malignancies especially in cases with negative mammography or ultrasound results. MRI is also useful for multifocal or multicentric disease and preoperative planning. MRI has been shown to detect additional malignant foci in up to 30% of cases and can change surgical planning and outcome.

A comparison of imaging modalities shows that MRI is more sensitive than mammography and ultrasound especially in younger patients or those with dense breasts. However, the cost and false positive results should be considered. Advanced techniques like diffusion-weighted imaging (DWI) and contrast-enhanced mammography are emerging as promising tools to improve diagnostic accuracy.

Tissue Sampling and Sentinel Lymph Node Biopsy

1. Core Needle Biopsy: The gold standard for diagnosis, allows histological evaluation of underlying malignancy.
2. Nipple/Skin Scrape Cytology: Useful for identifying Paget cells in exfoliative samples but less commonly done due to lower sensitivity.
3. Punch Biopsy: Useful for sampling the nipple-areola complex when lesions are confined to the epidermis.

Immunohistochemistry: HER2 is overexpressed in 80-100% of cases, ER and PR status varies depending on the underlying cancer. Advances in molecular diagnostics including next-generation sequencing is helping us understand the genetic basis of PDB. For example, TP53 and PIK3CA mutations have been linked to disease progression and potential targets for therapy.

Treatment

Treatment of PDB depends on the extent of disease and presence of underlying cancer. Treatment options are surgery, radiation and systemic therapy.

Radiation Therapy: Reduces local recurrence, especially after BCS. Whole breast radiation therapy is usually recommended after BCS to make sure any remaining cancer cells are killed and reduce the risk of recurrence.

Surgical Options

1. Breast-Conserving Surgery (BCS):

• For patients with localized disease and no extensive underlying cancer.
• Usually with radiation.
• Outcomes are similar to total mastectomy in selected patients ^[4].

2. Total Mastectomy (TM):

• Historically the standard of care.
• Indicated for extensive disease or cases not suitable for BCS.

Oncoplastic surgery has improved the cosmetic outcome for BCS patients. Nipple-sparing mastectomy is also becoming popular, balancing oncological safety and aesthetic preservation. 3D imaging and intraoperative margin assessment has further improved surgical precision.

Adjuvant Therapy including Whole Breast Radiation Therapy

• Radiation Therapy: Reduces local recurrence, especially after BCS.
• Chemotherapy: For invasive cancer or nodal involvement.
• Endocrine Therapy: For hormone receptor positive tumors, tamoxifen or aromatase inhibitors are used.
• Targeted Therapy: HER2 positive tumors benefit from trastuzumab and other HER2 directed therapy ^{[1], [5]}.

Emerging therapies like antibody-drug conjugates (e.g. trastuzumab deruxtecan) and immune checkpoint inhibitors are being studied in clinical trials and may add to the treatment options for PDB. Combination therapy targeting both HER2 and PD-1/PD-L1 are showing promising results in early phase trials and may be the future of personalized medicine.

Prognosis and Outcomes

Prognosis of Paget’s disease of the breast depends on the underlying cancer and stage of the disease. If the underlying cancer is non-invasive (DCIS), prognosis is good, 5 year survival is over 90%. If the underlying cancer is invasive, prognosis is poor, 5 year survival is 50-60%. Prognosis is poorer if the cancer has spread to the nodes or other parts of the body.

Early detection and comprehensive treatment is key to better outcomes. Advances in imaging and targeted therapy has improved the management of Paget’s disease and hope for better survival and quality of life.

Special Considerations

In peripartum women presenting with nipple-areola complex changes, PDB should be included in the differential diagnosis. PDB is often associated with tumors in the same breast tissue so it is important to evaluate the same breast for any underlying tumors. Diagnostic delays are common because PDB looks like benign conditions.

Multidisciplinary management is important to balance maternal and fetal well being while ensuring prompt treatment ^[2]. Case reports have shown the challenges of managing PDB during pregnancy and the importance of individualized care plan. Imaging modalities like ultrasound which is non-ionizing radiation is preferred during pregnancy.

Modern Treatment TrendsBreast conserving approach is the trend now with improvements in imaging, surgery and adjuvant therapy. Personalized treatment plan based on tumor biology and patient preference has resulted to better functional and cosmetic outcome. AI is also being integrated in imaging and pathology to aid in earlier detection and more accurate diagnosis of PDB.

Patient Education and Awareness

Patient education and awareness is key in the diagnosis and treatment of Paget’s disease of the breast. Women should be aware of the signs and symptoms of Paget’s disease, a rash or eczema like appearance on the nipple and areola, itching, redness and discharge. Women should also be aware of their risk for breast cancer and take steps to reduce their risk, get regular mammograms and do breast self exam.

Educational campaigns and resources can help women to seek medical attention if they notice any changes in their breast tissue. Early intervention can make a big difference in prognosis and treatment outcome.

Multidisciplinary Approach

Multidisciplinary approach is important in the diagnosis and treatment of Paget’s disease of the breast. A team of healthcare professionals including breast surgeon, medical oncologist, radiation oncologist and pathologist should work together to develop a treatment plan that is individualized to the patient. Treatment may include surgery, radiation therapy, chemotherapy and hormone therapy depending on the underlying cancer and stage of the disease.

Team work among specialists ensures comprehensive care of all aspects of the disease. This team based approach not only improves clinical outcome but also the overall well being of the patient and provide holistic treatment experience.

Closing Thoughts

Paget’s disease of the breast is a rare but significant malignancy that requires high index of suspicion for early diagnosis. Mammary Paget disease which involves the nipple-areola complex requires thorough understanding of its clinical presentation and underlying pathology.

Advances in imaging, histopathology and systemic therapy has improved diagnostic accuracy and treatment outcome. Breast conserving surgery when possible is a trend towards less invasive management which is patient centered.

Future research should focus on the molecular mechanism of PDB and identification of new therapeutic targets to further improve outcome. Development of AI driven diagnostic tool and precision therapy will be the game changer in PDB management in the coming years.

References

^{[1] Hudson-Phillips, S., Cox, K., Patel, P., & Al Sarakbi, W. (2023). Paget’s disease of the breast: diagnosis and management. British journal of hospital medicine (London, England : 2005), 84(1), 1–8. https://doi.org/10.12968/hmed.2022.0439}

^{[2] Gilmore, R., Prasath, V., & Habibi, M. (2020). Paget Disease of the Breast in Pregnancy and Lactation. Advances in experimental medicine and biology, 1252, 133–136. https://doi.org/10.1007/978-3-030-41596-9_18}

^{[3] Karakas C. (2011). Paget’s disease of the breast. Journal of carcinogenesis, 10, 31. https://doi.org/10.4103/1477-3163.90676}

^{[4] Dalton, J. C., & Plichta, J. K. (2024). Paget’s disease of the breast: Insights from imaging to guide surgical management. American journal of surgery, 231, 16–17. https://doi.org/10.1016/j.amjsurg.2024.03.013}

^{[5] Sakorafas, G. H., Blanchard, K., Sarr, M. G., & Farley, D. R. (2001). Paget’s disease of the breast. Cancer treatment reviews, 27(1), 9–18. https://doi.org/10.1053/ctrv.2000.0203}