Paget Disease of the Breast

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Paget Disease of the Breast

BASICS

DESCRIPTION

No known genetic pattern, although studies suggest up to 88% display Her2/Neu overexpression (2)[B]

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].

Possible breast reconstructive surgery with plastic surgery, physical therapy, counseling services, support groups

Admission Criteria/Initial Stabilization

Dependent on cancer histology, size, and stage (see topic on "Breast Cancer " )

View LargeStage5-yr relative survivalI96%II78%III46%IV14%

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.

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 NACPaget 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

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

EPIDEMIOLOGY

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)

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 theoryDuctal 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).

Ductal carcinoma cells migrate from underlying mammary ducts to epidermis of the nipple to become Paget cells (4,6,7).

Epidermal cells of nipple/areola transform into Paget cells that can invade the basement membrane into the dermis (4,6,7).

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].

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:DoxorubicinCyclophosphamidePaclitaxelDocetaxelCarboplatinTrastuzumabPertuzumab

Doxorubicin
Cyclophosphamide
Paclitaxel
Docetaxel
Carboplatin
Trastuzumab
Pertuzumab

ISSUES FOR REFERRAL

Surgery
Medical oncology
Radiation oncology

ADDITIONAL THERAPIES

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 radiationTotal mastectomy +/ ’ sentinel node biopsyCentral 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 infectionRecommended 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].

Central lumpectomy including the NAC + whole breast radiation
Total mastectomy +/ ’ sentinel node biopsy
Central lumpectomy including the NAC +/ ’ sentinel node biopsy without radiation therapy.

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].

INPATIENT CONSIDERATIONS

Surgery
Radiotherapy
Chemotherapy
Hormone therapy

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

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).

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 massMultifocal diseaseLymph node enlargementVascular invasion/invasive diseaseHigher stage of diseaseHer2/Neu overexpressionAge <60 years
Prognosis by presence/absence of palpable mass22% 10-year survival if palpable mass present prior to excision82% 10-year survival if no palpable mass prior to excision
Prognosis by lymph node status47% 10-year survival if positive nodes93% 10-year survival if negative nodes
Prognosis by stage of underlying breast carcinoma(See http://www.cancer.org for breast cancer staging descriptions)

Palpable breast mass
Multifocal disease
Lymph node enlargement
Vascular invasion/invasive disease
Higher stage of disease
Her2/Neu overexpression
Age <60 years

22% 10-year survival if palpable mass present prior to excision
82% 10-year survival if no palpable mass prior to excision

47% 10-year survival if positive nodes
93% 10-year survival if negative nodes

(See http://www.cancer.org for breast cancer staging descriptions)

COMPLICATIONS

Axillary lymph node metastases
Underlying invasive cancer
Palpable mass on presentation
Negative hormone receptor expression
Her2/Neu overexpression

REFERENCES

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

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.