Paget's Disease of the Breast

Written by: Sophie Heywood from Birmingham University,

 

Paget's disease of the breast (or nipple) is an uncommon condition characterised by eczematous-like changes of the nipple (see Image 1), and is strongly associated with an underlying breast cancer.

 

If diagnosed and treated early the prognosis is good. However, every year due to incorrect diagnoses of eczema (either from the patient or a healthcare professional), treatment has subsequently been delayed. Thus it is important to understand Paget's disease of the breast, and how a patient presenting with nipple skin changes should be managed.

 

Sir James Paget

Sir James Paget was a surgeon and lecturer who passed the MRCS at the age of 22! He was modern in his clinical approach: he linked patient's symptoms to the clinical examination.

 

He has many conditions named after him including Paget Disease of the Breast, Paget's abscess and more famously, Paget's Disease of the Bone. 

 

In 1874 Sir James Paget published a short paper: Paget J. On disease of the mammary areola preceding cancer of the mammary gland. St Bartholomew Hosp Rep 1874;10:86.

 

The paper includes 15 women whose nipples and areolas were "florid, intensely red, raw surface, very finely granular, as in nearly the whole thickness of the epidermis were removed". Within two years all of these women developed breast cancer. 

Epidemiology

 

Paget's disease of the breast is rare, and accounts for only 1-2% of all breast cancers diagnosed each year in the UK (the most common is invasive ductal carcinoma which accounts for 70-80%). According to CancerResearchUK 50% of patients presenting with Paget's disease also have a palpable breast lump. Of these 50%, 9 out of 10 lumps will be invasive ductal carcinoma. The remaining 50% of patients without a palpable breast lump are not without risk of an underlying cancer - 4 out of 10 will have in situ carcinoma. This means approximately 65% of people at diagnosis have an underlying carcinoma. (See Diagram 1).

 

Paget's disease of the breast is typically diagnosed in women over the age of 50. However there have been reports of women in their 20's diagnosed with the condition, and although extremely rare men can also be affected.

 

Clinical Features

 

Early symptoms:

  • Erythema
  • Flaky, scaly skin

 

Later symptoms:

  • Itching or burning sensation
  • Scaling and thickening of the skin
  • Nipple retraction
  • Nipple ulceration/erosion
  • Yellow or bloody nipple discharge
  • Pain or sensitivity

 

As Paget's disease of the breast is strongly associated with risk factors that increase the likelihood of having breast cancer, these should also be checked for: age, family history of breast cancer, nulliparity etc.

 

The symptoms of Paget's disease are similar to those of eczema of the nipple. However, if any of the following apply, an urgent referral to the breast cancer clinic should be performed:

 

  • unilateral eczematous skin or nipple change that does not respond to topical treatment
  • nipple distortion of recent onset
  • spontaneous unilateral bloody nipple discharge
  • male, aged 50 years and older with a unilateral, firm subareolar mass with or without nipple distortion or associated skin changes
  •  

    Nipple Inversion or Retraction?

     

    Many people use nipple inversion and nipple retraction interchangably, however, the two suggest very different underlying pathologies:

     

    • Nipple inversion is usually due to tethering of the developing nipple by short ducts, i.e. a benign slit-like appearance ever since breast development.

     

    • Nipple retraction is when the whole nipple is pulled back and this is always suspicious.

     

    Image 3 shows the difference of appearance between nipple inversion and retraction.

     

    Staging

     

    Stage 0: No associated DCIS or invasive disease

    Stage I: DCIS underneath the nipple

    Stage II: Extensive DCIS

    Stage III: Invasive ductal carcinoma

     

    Case Study

     

    A 57 year old female presents with a 4-week history of an itchy eczematous-type rash of her left nipple. Upon taking a history you note that she has hayfever and has had no children. On examination the affected skin is red, flaky and tender. The nipple is mildly retracted and there is a 1cm breast mass felt at 10 o'clock.

     

    Differential Diagnoses:

    • Paget's Disease of the Breast (age, unilateral, tender, nipple retraction, nulliparous, palpable breast mass)
    • Chronic Eczema (itchy, hayfever)
    • Contact Dermatitis
    • Psoriasis
    • Mammary Duct Ectasia

     

    It can be difficult to differentiate between Paget's Disease of the Breast and Eczema of the nipple, but the clinical findings can make one more likely than the other (see Table 1).

     

    Pathogenesis

     

    The cause of Paget's disease is still unknown, however there are two main theories:

     

    1. Epidermotrophic theory

    Paget cells break off from the underlying tumour and move via the ducts to infiltrate the epidermis of the nipple.

    Evidence: This is the most accepted theory as more than 97% of patients diagnosed with Paget's have underlying cancer, including ductal carcinoma in situ (abnormal cells in lining of ducts).

     

    2. In-situ Malignant Transformation theory

    Cells of the nipple spontaneously transform into Paget cells.

    Evidence: This theory is supported by the possibility of having Paget's disease with no underlying cancer, or patient's that have a separate tumour from the Paget's disease.

     

    Diagnosis

     

    Due to the high association of Paget's with underlying breast cancer, clinicians perform the triple assessment:

     

    1. Clinical history and examination
    2. Imaging (bilateral mammogram/USS, MRI)
    3. Histology/Cytology (punch, wedge, or excisional biopsy, scrape or imprint cytology)

     

    N.B. Scrape cytology is when you use a glass slide or wooden spatula to scrape the affected site, whilst imprint cytology is when you press a glass slide against the affected area.

     

    Imaging

     

    Studies have shown that only approximately 60% of patients with Paget's disease of the breast had positive findings on mammography.

     

    Positive mammogram findings are:

    • Nipple and areola thickening (reflects oedema)
    • Subareola microcalcifications
    • Nipple retraction
    • Architectural distortion
    • Mass/es (see Image 4)

     

     

    Even if there are no positive findings on imaging a biopsy should be performed, as a negative mammogram does not rule out Paget's disease.

     

    Histopathology

     

    Paget cells are found between normal keratinocytes of the nipple epidermis (as the keratinocyte layer is disrupted, serous fluid can seep through and produce the crusty/scaly nipple appearance).

     

    In superficial layers you find single Paget cells, whilst towards the basement membrane you can find clusters of Paget cells (see Image 5).

     

    Paget cells classically have the following histological features (Image 5):

    • large
    • ovoid/round nucleus
    • mucin-positive
    • scanty nuclear chromatin
    • pale-staining cytoplasm
    • enlarged, scattered mitichondria

     

    Paget cells can look similar to Pagetoid cells that can be found in melanoma and Bowen's disease (squamous cell carcinoma in situ). If they stain positive with PAS (Periodic Acid-Schiff) and are positive for CEA, Paget's disease can be confirmed.

     

    Positive markers of Paget's are:

    • CEA (Carcinoembryonic Antigen)
    • Low molecular weight keratins e.g CK7 and CAM-5.2
    • EMA (Epithelial Membrane Antigen)
    • erbB-2 (>90%)

     

    Treatment

     

    Paget's disease of the breast is usually treated with surgery (unless the patient is deemed unfit or is a palliative case). Treatment depends on a number of associated factors such as:

     

    • Underlying cancer
    • Invasive
    • Size
    • Location
    • Her-2 (ErbB-2) positive
    • Oestrogen receptor (ER) positive
    • Progesterone receptor (PR) positive
    • Patient choice

     

    Generally speaking, the treatment for Paget's disease of the breast is mastectomy with axillary lymph node sampling. However the 2009 NICE guidelines state that if the Paget's disease is localised the patient should be offered breast conserving surgery (removal of nipple-areolar complex) with axillary lymph node sampling, as an alternative to mastectomy. However, if the Paget's disease is localised but is large in size or located in the middle of the breast, which would give an uncosmetic result, mastectomy with reconstruction may be performed. It is important to remember when coming to a decision on which surgical option is best, the overall cosmetic effect should be considered, and oncoplastic repair should be offered to maximise this (NICE guidelines 2009).

     

    Following surgery the patient may undergo radiotherapy (especially important if the patient has had breast conserving surgery) or chemotherapy (for patients with a high risk or recurrence). Depending on the histological findings from the removed tissue, the patient may be started on biological therapy (Her-2/ErbB-2 positive) or hormone therapy (ER or PR positive), both of which have been found to lower the risk of recurrence.

     

    Biological therapies include:

    • Trastuzumab (Herceptin)
    • Lapatinib (Tyverb) - secondary or locally advancing Her-2 positive cancer
    • Sunitinib (Sutent) - currently in trials
    • Everolimus (Afinitor) - currently in trials

     

    Hormone therapies include:

    • Aromatase inhibitors, e.g. anastrozole, exemestane and letrozole
    • Tamoxifen
    • LHRH blockers, e.g. goserilin (Zoladex) 
    • Oopherectomy (removal of ovaries)

     

                                           ***

     

    If the patient has an underlying breast cancer, the following treatment options are available:

    • Surgery
    • Radiotherapy
    • Chemotherapy
    • Hormone therapy
    • Biological therapy
    • Palliative

     

    If the patient has no underlying breast cancer the treatment options are:

    • Surgery
    • Radiotherapy

     

    Prognosis

     

    As with many diseases, the prognosis depends on a variety of factors. Factors that lower the 5-year survival are:

     

    • Underlying palpable mass
    • Lymph node involvement (5-year survivals of 85% and 32% for positive and negative lymph node status respectively)
    • Erb-B2 positive (more aggressive)
    • Male (perhaps due to a delay in diagnosis)

     

    If the patient has no underlying tumour the 5-year survival rate is approximately 95%. This figure declines to approximately 40% if the patient has an underlying palpable malignant tumour.

     

     

    Bibliography

     

    • Cancer Research UK. Breast Cancer. http://www.cancerhelp.org.uk/type/breast-cancer/ (last accessed 16/05/2011)
    • Kaelin CM. Paget's Disease. In: Harris JR, Lippman ME, Morrow M, Osborne CK, editors. Diseases of the Breast. 3rd ed. Philadelphia: Lippincott Williams and Wilkins, 2004.
    • Kao GF. Mammary Paget Disease Clinical Presentation. http://emedicine.medscape.com/article/1101235-clinical#showall (last accessed 11/05/2011)
    • National Institute for Clinical Excellence (NICE). Advanced breast cancer: diagnosis and treatment, CG81. London: February 2009
    • National Institute for Clinical Excellence (NICE). Early and locally advanced breast cancer: diagnosis and treatment, CG80. London: February 2009
    • Ngan V. Paget’s disease. http://dermnetnz.org/site-age-specific/paget.html (last accessed 11/05/2011)
    • Paget J. On disease of the mammary areola preceding cancer of the mammary gland. St Bartholomew Hosp Rep 1874;10:86
    • Sakorafas GH, Blanchard DK, Sarr MG, Farley DR. Paget's disease of the breast: a clinical perspective. Langerbecks Arch Surg 2001;386(6):444-50
    • Sakoragas GH, Blanchard K, Sarr MG and DR Farley. Tumour Review: Paget’s disease of the breast. Cancer Trtmt Rev 2001;27:9-18.
    • Sawyer RH, Asbury DL. Mammographic appearances in Paget's disease of the breast. Clin Radiol 1994;49:185-8

     

    Images:

    • Image 1: Kao GF. Mammary Paget Disease Clinical Presentation. http://emedicine.medscape.com/article/1101235-clinical#showall (last accessed 11/05/2011)
    • Image 4: Da Costa D, Taddese A, Luz Cure M, Gerson D et al. Common and unusual diseases of the nipple-areolar complex. RadioGraphics 2007;27:S65-77
    • Image 5: Kao GF. Mammary Paget Disease Workup: Histologic Findings. http://emedicine.medscape.com/article/1101235-workup#a0723 (last accessed 16/05/2011)