BASICS
DESCRIPTION
- Rare disease of the nipple-areolar complex (NAC) typically associated with underlying in situ or invasive carcinoma
- Characterized by eczematous changes of the nipple, erythema, ulceration, crusting, bleeding, and/or itching
- Divided into three categories (1)
- Paget disease of the nipple without ductal carcinoma in situ (DCIS)
- Paget disease of the nipple with associated DCIS in the underlying lactiferous ducts of the NAC
- Paget disease of the nipple with associated DCIS in the underlying lactiferous ducts of the NAC and associated DCIS or invasive breast cancer elsewhere in the breast at least 2 cm from the NAC
- System(s) affected: skin/exocrine
EPIDEMIOLOGY
Incidence
- 1 " 3% of breast cancers in females (2)
- 0.4% of invasive female breast cancer (3)
- Incidence of Paget disease of the breast has been decreasing since 1988, despite an increased incidence of breast cancer (4,5).
- Median age at diagnosis = 64 years (5)
- Extremely uncommon in males but prognosis is worse in men (6)
Prevalence
<1% of population
ETIOLOGY AND PATHOPHYSIOLOGY
- Cause is unknown, but risk factors for Paget disease are similar to those for developing breast cancer in general (see below).
- Epidermotropic theory
- Ductal carcinoma cells migrate from underlying mammary ducts to epidermis of the nipple to become Paget cells (4,6,7).
- Transformation theory (not favored)
- Epidermal cells of nipple/areola transform into Paget cells that can invade the basement membrane into the dermis (4,6,7).
Genetics
No known genetic pattern, although studies suggest up to 88% display Her2/Neu overexpression (2)[B]
RISK FACTORS
- Same risk factors apply as for noninherited breast cancers.
- Female gender
- Age >40 years
- Previous breast cancer
- Benign breast disease (atypical ductal/lobular hyperplasia, fibroadenoma, sclerosing adenosis, intraductal papilloma)
- First-degree relative with history of breast cancer
- Caucasian
- Menarche <12 years of age
- Menopause >50 years of age
- Nulliparity or first child after age 34 years
- History of ionizing radiation exposure
- History of alcohol abuse
- Hormone replacement
- Excess weight gain
COMMONLY ASSOCIATED CONDITIONS
- Largest study, using surveillance, epidemiology, and end result (SEER) data representing 1,763 women with confirmed Paget disease, reports an underlying in situ or invasive breast cancer in 87% of patients, although there is often no associated breast mass or mammographic abnormality (5).
- The underlying carcinomas are multifocal/multicentric in 32 " 41% of patients (2)[B].
DIAGNOSIS
HISTORY
- Scaly, raw, vesicular, or ulcerated lesion that begins on the nipple and then spreads to the areola
- Pain, burning, and pruritus may be present even before clinically evident disease.
- Nipple/areolar skin changes that have not responded to conservative topical treatment
- Median duration of symptoms is 9 months prior to histologic diagnosis.
PHYSICAL EXAM
- Eczematous nipple changes
- Nipple erythema and scaling
- Nipple erosion or ulceration
- Bloody or serous nipple discharge
- Nipple retraction
- Nipple fissures with crusting
- Palpable breast mass is noted in approximately 50% of patients; when present, mass is often >2 cm from NAC (6)[C].
- Thickening in breast tissue without nipple change
DIFFERENTIAL DIAGNOSIS
- Eczema/atopic dermatitis
- Contact dermatitis
- Duct ectasia
- Psoriasis
- Bowen disease
- Squamous cell carcinoma
- Basal cell carcinoma
- Superficially spreading malignant melanoma
- Lichen simplex chronicus
- Erosive adenomatosis of the nipple
DIAGNOSTIC TESTS & INTERPRETATION
- Bilateral breast imaging should be performed in all cases to evaluate for synchronous invasive cancer or DCIS (1)[C].
- Mammographic appearance can be normal in 22 " 50% of cases (1)[C].
- If mammography and US negative or inconclusive, further evaluation with MRI is recommended (1,6,7)[C],(8)[B].
- Sensitivity for detecting invasive cancer and DCIS are 79% and 39%, respectively, for mammogram; 74% and 19%, respectively, for US; and 100% and 44%, respectively, for MRI (8)[B].
- Due to increased sensitivity in detecting multifocal or multicentric breast cancer, MRI is becoming a diagnostic standard. Despite higher false-positive rate, some recommend MRI for all new Paget disease patients (6)[C],(8)[B].
- MRI is also suggested in those patients with abnormalities limited to the central breast tissue on mammogram or US (1)[C],(8)[B].
- If considering breast-conserving surgery, MRI greatly aids preoperative planning (1,6,7)[C],(8)[B].
- In one study, 57% of cancers diagnosed with MRI were missed on mammography during initial workup (6)[C].
Diagnostic Procedures/Other
The diagnostic standard is a core biopsy of any breast lesion and full-thickness skin biopsy of the NAC. These tests provide a definitive diagnosis and should be performed in all patients presenting with a skin lesion suspicious for Paget disease (6)[C].
Test Interpretation
- Histologic evidence of Paget cells with abundant pale cytoplasm and hyperchromatic nuclei
- Immunohistochemistry positive for cytokeratin 7, carcinoembryonic antigen (CEA), and epithelial membrane antigen (EMA) and about 50% positive for hormone receptor expression (7)[C]
TREATMENT
MEDICATION
- Systemic adjuvant chemotherapy and/or endocrine therapy is based on the stage and hormone receptor status of the associated cancer.
- In Paget disease without an associated cancer, or in estrogen-receptor positive DCIS, consider tamoxifen (9)[C].
- In Paget disease with associated invasive breast cancer, treat per oncology study protocols. See "http://www.nccn.org " for the most recent guidelines (9)[A].
- Possible agents include the following:
- Doxorubicin
- Cyclophosphamide
- Paclitaxel
- Docetaxel
- Carboplatin
- Trastuzumab
- Pertuzumab
ISSUES FOR REFERRAL
- Surgery
- Medical oncology
- Radiation oncology
ADDITIONAL THERAPIES
Possible breast reconstructive surgery with plastic surgery, physical therapy, counseling services, support groups
SURGERY/OTHER PROCEDURES
- Surgical options range from mastectomy with axillary dissection, to breast conservation therapy followed by adjuvant radiation therapy, depending on extent and location of malignancy (1,6,7)[C],(2)[B].
- Approaches for patients with isolated Paget disease of the nipple include: (9)[A]
- Central lumpectomy including the NAC + whole breast radiation
- Total mastectomy +/ ’ sentinel node biopsy
- Central lumpectomy including the NAC +/ ’ sentinel node biopsy without radiation therapy.
- Multicentric lesions or diffuse calcifications require mastectomy.
- Sentinel node biopsy (SNB)
- Can avoid side effects seen with full axillary dissection, such as lymphedema, pain, and infection
- Recommended in patients with biopsy-proven or MRI evidence of invasive cancer (6)[C],(8)[B]
- Recommended in patients without clinical or MRI evidence of nodal involvement who are undergoing mastectomy (6)[C],(8)[B]
- Consider in all confirmed cases of Paget disease due to high likelihood of underlying malignancy, even with negative radiographic studies (10)[B].
- Patients with axillary node metastases diagnosed preoperatively should undergo axillary clearance instead of SNB (8)[B].
- Studies show no difference in long-term survival or disease-free interval with mastectomy versus breast-conserving surgery on carefully selected surgical candidates (5)[B],(6,7)[C].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Dependent on cancer histology, size, and stage (see topic on "Breast Cancer " )
- Surgery
- Radiotherapy
- Chemotherapy
- Hormone therapy
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Oncology consultation
Patient Monitoring
- After successful treatment for Paget disease of the breast, patients should start an individualized cancer surveillance program to include regular history, physical examination, and mammograms.
- Routine screening for average-risk women who have never been diagnosed with breast cancer or Paget disease is per USPSTF guidelines.
- Biennial screening mammography for women ages 50 to 74 years (USPSTF Grade B recommendation).
PATIENT EDUCATION
- National Cancer Institute, Department of Health and Human Services, Public Inquiries Section, Office of Cancer Communications, Building 31, Room 101-18, 9000 Rockville Pike, Bethesda, MD 20892; 301-496-5583
- http://www.cancer.gov/types/breast/paget-breast-fact-sheet
PROGNOSIS
- Factors of unfavorable prognosis (2)
- Palpable breast mass
- Multifocal disease
- Lymph node enlargement
- Vascular invasion/invasive disease
- Higher stage of disease
- Her2/Neu overexpression
- Age <60 years
- Prognosis by presence/absence of palpable mass
- 22% 10-year survival if palpable mass present prior to excision
- 82% 10-year survival if no palpable mass prior to excision
- Prognosis by lymph node status
- 47% 10-year survival if positive nodes
- 93% 10-year survival if negative nodes
- Prognosis by stage of underlying breast carcinoma
- (See http://www.cancer.org for breast cancer staging descriptions)
View LargeStage5-yr relative survivalI96%II78%III46%IV14%
COMPLICATIONS
Risk factors for recurrence:
- Axillary lymph node metastases
- Underlying invasive cancer
- Palpable mass on presentation
- Negative hormone receptor expression
- Her2/Neu overexpression
REFERENCES
11 Lim HS, Jeong SJ, Lee JS, et al. Paget disease of the breast: mammographic, US, and MR imaging findings with pathologic correlation. Radiographics. 2011;31(7):1973 " 1987.22 Caliskan M, Gatti G, Sosnovskikh I, et al. Paget 's disease of the breast: the experience of the European Institute of Oncology and review of the literature. Breast Cancer Res Treat. 2008;112(3):513 " 521.33 Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2012/. Accessed April 2015.44 Sandoval-Leon AC, Drews-Elger K, Gomez-Fernandez CR, et al. Paget 's disease of the nipple. Breast Cancer Res Treat. 2013;141(1):1 " 12.55 Chen CY, Sun LM, Anderson BO. Paget disease of the breast: changing patterns of incidence, clinical presentation, and treatment in the U.S. Cancer. 2006;107(7):1448 " 1458.66 Trebska-McGowan K, Terracina KP, Takabe K. Update on the surgical management of Paget 's disease. Gland Surg. 2013;2(3):137 " 142.77 Karakas C. Paget 's disease of the breast. J Carcinog. 2011;10:31.88 Siponen E, Hukkinen K, Heikkil € P, et al. Surgical treatment in Paget 's disease of the breast. Am J Surg. 2010;200(2):241 " 246.99 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (version 2.2015). http://www.nccn.org/.1010 Sukumvanich P, Bentrem DJ, Cody HSIII, et al. The role of sentinel lymph node biopsy in Paget 's disease of the breast. Ann Surg Oncol. 2007;14(3):1020 " 1023.
ADDITIONAL READING
- American Cancer Society. How is breast cancer staged? http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging.
- Dalberg K, Hellborg H, W €rnberg F. Paget 's disease of the nipple in a population based cohort. Breast Cancer Res Treat. 2008;111(2):313 " 319.
- Kanitakis J. Mammary and extramammary Paget 's disease. J Eur Acad Dermatol Venereol. 2007;21(5):581 " 590.
- Kawase K, Dimaio DJ, Tucker SL, et al. Paget 's disease of the breast: there is a role for breast-conserving therapy. Ann Surg Oncol. 2005;12(5):391 " 397.
- Kim HS, Seok JH, Cha ES, et al. Significance of nipple enhancement of Paget 's disease in contrast enhanced breast MRI. Arch Gynecol Obstet. 2010;282(2):157 " 162.
- Laronga C, Hasson D, Hoover S, et al. Paget 's disease in the era of sentinel lymph node biopsy. Am J Surg. 2006;192(4):481 " 483.
- Li YJ, Huang XE, Zhou XD. Local breast cancer recurrence after mastectomy and breast-conserving surgery for Paget 's disease: a meta-analysis. Breast Care (Basel). 2014;9(6):431 " 434.
- Lohsiriwat V, Martella S, Rietjens M, et al. Paget 's disease as a local recurrence after nipple-sparing mastectomy: clinical presentation, treatment, outcome, and risk factor analysis. Ann Surg Oncol. 2012;19(6):1850 " 1855.
- Morrogh M, Morris EA, Liberman L, et al. MRI identifies otherwise occult disease in select patients with Paget disease of the nipple. J Am Coll Surg. 2008;206(2):316 " 321.
- Nardelli AA, Stafinski T, Menon D. Effectiveness of photodynamic therapy for mammary and extra-mammary Paget 's disease: a state of the science review.
- National Cancer Institute. Paget disease of the breast. http://www.cancer.gov/cancertopics/factsheet/Sites-Types/paget-breast.
- BMC Dermatol. 2011;11:13.
- Sanders MA, Dominici L, Denison C, et al. Paget disease of the breast with invasion from nipple skin into the dermis: an unusual type of skin invasion not associated with an adverse outcome. Arch Pathol Lab Med. 2013;137(1):72 " 76.
- Sek P, Zawrocki A, Biernat W, et al. HER2 molecular subtype is a dominant subtype of mammary Paget 's cells. An immunohistochemical study. Histopathology. 2010;57(4):564 " 571.
- Zakhireh J, Gomez R, Esserman L. Converting evidence to practice: a guide for the clinical application of MRI for the screening and management of breast cancer. Eur J Cancer. 2008;44(18):2742 " 2752.
CODES
ICD10
- C50.019 Malignant neoplasm of nipple and areola, unsp female breast
- C50.011 Malignant neoplasm of nipple and areola, right female breast
- C50.012 Malignant neoplasm of nipple and areola, left female breast
ICD9
174.0 Malignant neoplasm of nipple and areola of female breast
SNOMED
- Pagets disease of nipple (disorder)
- Neoplasm of breast primary tumor staging category Tis (Paget's) (finding)
- pTis Paget disease without invasive carcinoma (breast) (finding)
- Tis: Carcinoma in situ, breast: Intraductal carcinoma, lobular carcinoma in situ, or Paget's disease of the nipple with no tumor (finding)
- Malignant neoplasm of nipple and areola of female breast
CLINICAL PEARLS
- Any chronic or nonhealing nipple or breast lesions should be biopsied to rule out malignancy.
- Further imaging is indicated to rule out additional underlying breast malignancy.
- Breast mammography and ultrasound are not as sensitive as MRI in detecting potential occult breast lesions.
- Treatment is evaluated on a case-by-case basis and is guided by extent of disease, staging, and tumor location.