Bilateral

Female Reproductive System & Breast


Diagnosis and reasoning

This 50-year-old woman has presented with eczema and itching of both nipples. No other signs or symptoms are present. Bilateral eczematous changes of the nipples are most often due to an inflammatory dermopathy—e.g., atopic or contact dermatitis. Malignancies such as Paget's disease of the breast can mimic this appearance, but are rarely bilateral at the time of presentation.


Breast examination shows no untoward findings (e.g., a palpable mass, axillary lymphadenopathy, or nipple discharge), making a benign etiology even more likely. However, to be comprehensive (and to give the patient peace of mind), it is rational to request cytological analysis of nipple scrapings—a test that is simple, noninvasive, and inexpensive. Doing so turns out to be an excellent decision, as this reveals numerous Paget cells. In other words, this is Paget's disease of the breast.


Imaging studies are an essential next step. Given her age and post-menopausal state, a mammogram is a good first study. Ho

wever, this turns out to be normal—a not unsurprising finding in Paget's disease. Where mammography is negative, follow-up ultrasound imaging may be fruitful; however, her sonographic findings are also nonspecific.


Further imaging via magnetic resonance imaging (MRI) is mandatory. This reveals findings suggestive of bilateral ductal carcinoma in situ (DCIS). Core biopsies of both breasts confirm this. With respect to staging, as per the tumor node metastasis (TNM) classification, her disease is Tis-N0-M0—i.e., this is stage 0 breast cancer. Note that in early-stage breast cancer (as is seen here), a detailed investigative workup for distant metastasis is generally not indicated.


While mastectomy was long considered the treatment of choice for Paget's disease of the breast, central lumpectomy (including removal of the nipple-areolar complex) with or without radiotherapy is an option in patients without multifocal or multicentric disease


Neoadjuvant chemotherapy is not indicated in the management of stage 0 breast cancer. Topical corticosteroids would have been appropriate in the case of eczema or psoriasis. As there is no history of infection or contact with tuberculosis, antituberculous therapy is not indicated here either.

Discussion

Paget's disease of the breast is a rare form of cancer of the nipple-areola complex that is often associated with an underlying in situ or invasive carcinoma. It is typically encountered in post-menopausal women who are 50 years or older; the mean age at diagnosis is 57 years. However, Paget's disease can occur in adolescents, the elderly, and even in men. According to the National Cancer Institute, breast cancer is more common in Caucasian females; however, data on the racial predilection of Paget's disease is limited.


In general, tumorigenesis in breast cancer involves the slow accumulation of mutations that lead to abnormal cells, followed by a progression to atypical ductal hyperplasia, ductal carcinoma in-situ (DCIS), and finally invasive ductal carcinoma. There are two main hypotheses as to the pathogenesis of Paget's disease: the epidermotropic theory and in situ malignant transformation. The first of these states that Paget cells derive from cancerous ductal cells that migrate along the basal membrane of the nipple, leading to the characteristic findings. The in-situ theory suggests that the Paget cells arise de novo from existing keratinocytes, and are separate from, or may precede, another malignancy.


Persons with a positive family history are at an increased risk of Paget's disease. Other risk factors include a past history of breast cancer, advanced age, obesity, radiation exposure, and the use of oral contraceptive pills or hormone replacement therapy. Light to moderate alcohol consumption has also been implicated as a risk factor for the development of breast cancer in women (but not in men).


Mammary Paget's disease presents as a pruritic or painful eczematous lesion, usually of one nipple, although it rarely can be bilateral. The nipple may be thickened, pigmented, weeping, or crusted, with irregular borders. Early disease may simply present as scaling and redness, and is easily mistaken for chronic eczema. Topical treatments seem to reduce the inflammatory component; this adds to the confusion and delay in diagnosis. The characteristic morphological irregularity is usually limited to the nipple-areolar complex, but can involve the surrounding skin in advanced cases.


Advanced disease presents as well-defined, round, ovoid or polycyclic eczema-like plaques with a pink or red hue. There may also be ulceration and destruction of the nipple-areola complex, or a serous or bloody discharge. Retraction of the nipple is a late finding. Patients who present as such may show systemic signs and symptoms.


Mammography may show a mass correlating to invasive carcinoma or calcification, indicative of an invasive ductal carcinoma. However, they are of low sensitivity overall. Ultrasound should be considered as part of the initial evaluation, especially if mammography is negative. However, findings in Paget's disease are usually nonspecific, showing parenchymal heterogeneity, hypoechoic areas, discrete masses, skin thickening, or dilated ducts. MRI is sensitive and is indicated in patients with a positive ultrasound, or in women with negative imaging despite suspicious clinical findings. Cytology of the affected nipple is required to make a diagnosis, with the hallmark finding being invasion of the epidermis by Paget cells. Immunohistochemistry is also helpful to diagnose Paget's disease and to exclude other types of cancer.


The management of Paget's disease of the breast varies depending on regional guidelines. In the United States, the national comprehensive cancer network (NCCN) guidelines are applicable. As per NCCN guidelines, women with associated DCIS or invasive breast cancer should be managed similar to other patients with these forms of breast cancer.


Where isolated Paget's disease is present, options include central lumpectomy with radiotherapy, central lumpectomy alone with or without sentinel lymph node biopsy, and total mastectomy with or without sentinel lymph node biopsy and with or without breast reconstruction.


Complications of Paget's disease include local extension and metastasis. The prognosis depends on the presence or absence of lymph node involvement; the latter group shows significantly higher overall survival rates. Overall though, these patients have a lower 10-year survival than patients with other forms of breast cancer.

Take home messages

  1. Paget's disease of the breast should be considered in the differential diagnosis of eczematous changes of the nipple.
  2. Most cases are in post-menopausal women; however, Paget's disease is encountered at all ages—and even in men.
  3. Mammography and ultrasound have relatively low sensitivity; MRI may be required to obtain imaging evidence.
  4. While mastectomy has been considered the standard of care in the past, recent evidence suggests that local excision may be effective for selected patients.

References

  1. CAO YIN, WILLETT WALTER C, RIMM ERIC B, STAMPFER MEIR J, GIOVANNUCCI EDWARD L. Light to moderate intake of alcohol, drinking patterns, and risk of cancer: results from two prospective US cohort studies. [online] 2015 August [viewed 23 December 2015] Available from: doi:10.1136/bmj.h4238
  2. KARAKAS CANSU. Paget′s disease of the breast. J Carcinog [online] 2011 December [viewed 21 December 2015] Available from: doi:10.4103/1477-3163.90676
  3. KOTHARI ASHUTOSH S., BEECHEY-NEWMAN NICOLAS, HAMED HISHAM, FENTIMAN IAN S., D'ARRIGO CORRADO, HANBY ANDREW M., RYDER KEN. Paget disease of the nipple. Cancer [online] December, 95(1):1-7 [viewed 21 December 2015] Available from: doi:10.1002/cncr.10638
  4. LLOYD J, FLANAGAN AM. Mammary and extramammary Paget's disease. J Clin Pathol [online] 2000 Oct, 53(10):742-9 [viewed 10 December 2015] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11064666
  5. LOPES FILHO LAURO LOURIVAL, LOPES IONE MARIA RIBEIRO SOARES, LOPES LAURO RODOLPHO SOARES, ENOKIHARA MILVIA M. S. S., MICHALANY ALEXANDRE OSORES, MATSUNAGA NOBUO. Mammary and extramammary Paget's disease. An. bras. dermatol. [online] 2015 April, 90(2):225-231 [viewed 20 December 2015] Available from: doi:10.1590/abd1806-4841.20153189
  6. LOPES FILHO LL, LOPES IM, LOPES LR, ENOKIHARA MM, MICHALANY AO, MATSUNAGA N. Mammary and extramammary Paget's disease. An Bras Dermatol [online] 2015 Mar-Apr, 90(2):225-31 [viewed 10 December 2015] Available from: doi:10.1590/abd1806-4841.20153189
  7. SCHEDIN PEPPER, ELIAS ANTHONY. . Breast Cancer Res [online] 2004 December [viewed 23 December 2015] Available from: doi:10.1186/bcr772
  8. TREBSKA-MCGOWAN K, TERRACINA KP, TAKABE K. Update on the surgical management of Paget's disease Gland Surg [online] 2013/08/01 00:00, 2(3):137-142 [viewed 20 December 2015] Available from: doi:10.3978/j.issn.2227-684X.2013.08.03