Context.—Paget disease is an uncommon skin manifestation of breast cancer, associated with either invasive carcinoma or ductal carcinoma in situ in the underlying breast. In very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis.
Objectives.—To identify a series of cases of Paget disease with direct dermal invasion and to investigate the clinicopathologic features and outcome.
Design.—Cases were identified during a 6-year period from the files of 2 hospitals. The clinical histories, imaging studies, and pathology reports were reviewed.
Results.—Seven patients were identified, 5 with microinvasion (<0.1 cm) and 2 with 0.2- or 0.3-cm invasive carcinomas in the dermis. No lymphovascular invasion was seen. Sentinel nodes were negative in 3 patients who underwent biopsy. Five patients were treated with breast conservation with radiation. Three patients were at high risk for breast cancer because of prior breast cancer, Li-Fraumeni syndrome, or radiation for Hodgkin disease. The latter 2 patients underwent bilateral mastectomies. Three patients received hormonal therapy and 1 oophorectomy. No patient received chemotherapy. At follow-ups ranging from 4 to 66 months (median, 20 months), there have been no recurrences.
Conclusions.—Patients with direct dermal invasion from Paget disease had a favorable outcome during the available follow-up period. This type of dermal involvement must be distinguished from locally advanced invasive carcinomas with skin invasion classified as T4b in the American Joint Cancer Commission staging system, as cancers with other types of skin invasion are associated with a poor prognosis.
Sir James Paget published the first report making a connection between the observation of a scaling crust of the nipple and breast cancer.1 The clinical appearance he noted of skin erythema and an exudate resembling chronic eczema is due to the presence of tumor cells singly and in clusters within the epidermis.2,3 The normal tight junctions between keratinocytes are disrupted, allowing seepage of intercellular fluid to the skin surface. In the majority of cases, carcinoma not only involves nipple skin, but is also present deeper in the breast. The basement membrane of the ducts and lobules is in continuity with the basement membrane of the skin and, therefore, ductal carcinoma in situ (DCIS) can be present in both the epidermis and the breast ductal system in the absence of stromal invasion. About half of cases of Paget disease are due to DCIS alone and the remainder to DCIS associated with an invasive carcinoma located deeper in the breast.4
It is very unusual for Paget cells in the skin to directly invade the dermis. To our knowledge, only 2 patients have been described in previous case reports.5,6 In general, skin invasion by breast cancer carries a poor prognosis, and certain types of involvement are grouped as T4b in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) classification.7 In order to learn more about this rare type of Paget disease and its clinical significance, we identified 7 cases of isolated dermal invasion from overlying epidermal Paget cells in the absence of other areas of stromal invasion and reviewed the clinical, imaging, and pathologic features and subsequent treatment and outcome.
MATERIALS AND METHODS
Pathology databases from Brigham and Women's Hospital and Faulkner Hospital in Boston, Massachusetts, were searched for the diagnosis of Paget disease of the nipple from January 2005 to June 2011. Cases in which direct invasion into the dermis from the epidermis was reported were selected for review. Cases were excluded if invasion was present deeper in the breast, as the goal of the study was to determine outcome when only direct dermal invasion was present. Pathology reports, clinical notes, and breast imaging reports were reviewed. The Office for Human Research Studies determined that this project was exempt from Institutional Review Board review.
Seven patients with Paget disease and direct dermal invasion were identified during the 6½-year period. Five of the patients underwent their first diagnostic biopsy at other hospitals, and these cases were seen in consultation. The 2 cases initially diagnosed at Brigham and Women's Hospital comprised 11% (2 of 18) of all newly diagnosed cases of Paget disease at the hospital during the same time period.
All the patients were female, with ages ranging from 39 to 72 years (median, 62 years), and presented clinically with skin changes of the nipple including erythema with a scaling crust (Table). Two patients experienced bleeding and 1 had a small ulceration. Patients were symptomatic from 2 months to 5 years prior to diagnosis. None of the patients had a palpable mass on breast examination.
Prior history was significant in 3 of the women. One woman had a family history of breast cancer in her sister and both grandmothers (Table, patient 5). She also had a personal history of DCIS in the same breast 12 years previously with a recurrence 4 years later. She had declined radiation or hormonal therapy. The prior surgical sites were not located close to the nipple. The youngest patient was 39 years old and had a family history of Li-Fraumeni syndrome, and a germline mutation in the p53 gene had been documented (Table, patient 6). The second youngest patient, age 59, had a history of Hodgkin disease at the age of 16 and had received mantle radiation (Table, patient 7).
Mammograms were performed in all 7 patients and none revealed significant findings. Three of the 6 patients undergoing magnetic resonance imaging had abnormal findings. The first patient had only skin enhancement (Table, patient 5). The second patient showed skin enhancement and rapid abnormal enhancement in the nipple areolar complex with two 0.4-cm subareolar enhancing foci (Table, patient 1). The third patient was found to have a 2.9-cm area of clumped retroareolar enhancement associated with inversion of the nipple and skin enhancement (Table, patient 4; Figure 1).
Five of the 7 patients underwent breast-conserving therapy with a central excision including the nipple to negative margins followed by radiation. Two of these patients had been diagnosed with invasion on their initial biopsy and also underwent sentinel lymph node biopsies. The woman with Li-Fraumeni syndrome underwent bilateral mastectomies with sentinel lymph node biopsy as well as subsequent hysterectomy and bilateral oophorectomy. The woman with a history of Hodgkin disease also underwent bilateral mastectomies. Three patients were given adjuvant hormonal therapy with tamoxifen or an aromatase inhibitor. None of the women received chemotherapy.
The initial diagnostic biopsy was a punch biopsy of the nipple in 4 patients, a shave biopsy in 1 patient, and an excision in 2 patients. Paget disease was diagnosed in all 7 cases and invasion into the dermis was present in the initial biopsy in 4 cases (Figure 2). The tumor cells in the epidermis were associated with an underlying dermal lymphocytic infiltrate. The areas of invasion consisted of small irregular nests of tumor cells within the lymphocytic infiltrate, typically 0.1 to 0.2 cm below the basement membrane of the epidermis. Immunoperoxidase studies for cytokeratin were used to aid in identification of the tumor cells in stroma in the 4 cases with invasion. In the 2 excisional specimens, involvement of lactiferous sinuses by DCIS was also present.
All patients underwent subsequent definitive surgery. The nipples were completely examined with sequential sectioning. Five patients had dermal invasion in these specimens, including the 3 whose initial biopsies had not shown invasion. Two patients had a grossly evident mass. The first had a 2.8-cm ill-defined fibrotic area deep to the nipple corresponding to the magnetic resonance imaging finding of a 2.9-cm area of retroareolar enhancement. Microscopically, this mass consisted of comedo-type DCIS involving multiple lactiferous sinuses and the overlying epidermis. There was an area of microinvasion into the dermis measuring less than 0.1 cm. Her prior biopsy had also shown microinvasion. The second patient had a gross dermal 0.6-cm irregular firm mass that correlated with a 0.3-cm focus of invasive carcinoma in the dermis associated with Paget cells in the overlying skin. Her initial biopsy had shown microinvasion.
In 1 case, erosion and loss of the overlying epidermis was present, and this patient had presented with nipple bleeding (Figure 3).
The extent of the DCIS was limited to the subareolar region in 6 patients and estimated to involve areas measuring from 1 to 3 cm. The woman with Li-Fraumeni syndrome had extensive DCIS involving an area measuring more than 6 cm in both the superior and inferior portions of the breast.
None of the carcinomas were associated with lymphovascular invasion. The 3 cases with sentinel lymph node biopsies did not reveal metastatic carcinoma.
Only 3 of the 7 carcinomas were estrogen receptor–positive (Table). Four were human epidermal growth factor receptor 2 (HER2)–positive by immunohistochemistry (with a score of 3+), and 1 showed equivocal results (Figure 4).
The woman with Li-Fraumeni syndrome had a clinically occult estrogen receptor–positive and HER2-negative 0.4-cm invasive carcinoma in the contralateral prophylactic mastectomy (Table, patient 6). A later lymph node dissection did not show metastatic disease. The woman with a history of Hodgkin disease was found to have an incidental estrogen receptor–positive and HER2-negative 0.2-cm invasive carcinoma in her contralateral prophylactic mastectomy (Table, patient 7).
Follow-up ranged from 7 to 66 months (median, 20 months) with no evidence of distant metastasis or locoregional recurrence.
Direct invasion into the skin from Paget disease is a rare occurrence.2,3 To our knowledge, there are only 2 previous reports of this finding in the literature, in a 60-year-old man and a 54-year-old woman (Table).5,6 The current report is the first series of cases, and only 7 patients were identified during a 6½-year period from two hospitals when both surgical specimens and consultation cases were included. The 2 patients who underwent initial surgery at Brigham and Women's Hospital constituted only 11% of all patients with a new diagnosis of Paget disease during this time period.
The clinical presentations of the patients in this series were similar to those of patients with Paget disease who do not have invasive carcinoma deeper in the breast. The average age was 66 years (excluding the 3 patients with unusual risk factors), which is similar to the average age of women with Paget disease without invasive carcinoma (64 years), who tend to be slightly older than patients with Paget disease and invasive carcinoma (61 years).4 All the women presented with skin changes of the nipple, often mistaken for inflammatory conditions. None of the women had palpable masses.
Only about one-third of women with Paget disease are reported to have abnormal findings on mammography, if a palpable mass is not present.8,9 In contrast, magnetic resonance imaging detects nipple areolar complex contrast enhancement in the majority of cases.9,10 In this series, mammographic studies did not reveal abnormalities in any of the women. However, half of the magnetic resonance imaging studies (3 of 6) showed enhancement of the nipple skin and dermis. Dermal enhancement can also be present in cases of Paget disease in the absence of invasion.10 Thus, dermal invasion by Paget disease was not predicted by either the clinical presentation or radiologic findings.
There were no unusual pathologic features of the DCIS compared to Paget disease in general.11 All 7 cases were comprised of tumor cells of high nuclear grade; a minority of the cancers were estrogen receptor–positive (3 of 7) and a majority were positive for HER2 (4 of 7). The DCIS was limited to the subareolar region and was less than 3 cm in extent in all but 1 woman, and thus 5 of the women could be treated with breast conservation therapy.12 The 2 women who required mastectomy were at high risk for breast cancer, 1 because of prior radiation therapy and 1 with Li-Fraumeni syndrome whose DCIS involved a large area of the breast.
It was found in this study that Paget disease with dermal invasion can occur in women without strong risk factors (Table, patients 1 to 4), as well as in women with a prior history of cancer, a predisposing germ-line mutation, or mantle radiation (Table, patients 5 to 7). There were no features of the clinical presentation, imaging findings, or pathologic findings of the patients with an identified risk factor that set them apart from those without an identified risk factor, except that 2 women in the former group were the youngest in the series. These 2 women, because of their high risk, underwent bilateral mastectomies and both were found to have contralateral small incidental invasive carcinomas. Thus, for the ultimate determination of long-term prognosis of breast cancer presenting as unilateral Paget disease with dermal invasion, these patients should be excluded.
Invasion into the skin is, in general, a poor prognostic factor for breast cancer. In the first description of the AJCC staging system, breast cancers associated with skin ulceration, edema, or satellite skin nodules were classified as T4b because of their dire prognosis and lack of benefit from surgery.7 The presence of lesser degrees of dermal invasion without these specific features is associated with increased numbers of lymph node metastases, possibly because of the location of breast lymphatics preferentially in a superficial location.13–15 The assignment of carcinomas to the T4b group has not been consistent, and some pathologists may not use the strict AJCC/UICC definition.16 In an international survey, 70.5% of pathologists reported that they would classify cancers with any degree of dermal invasion (ie, without the specific additional features required for AJCC/UICC classification) as T4b.17
Because of the poorer prognosis of breast carcinomas with some types of skin involvement, it was of interest to determine if dermal invasion associated with Paget disease was associated with local or regional spread. In no case was lymphovascular invasion present in the dermis. The 3 patients in this study and the 2 patients reported in the literature undergoing sentinel lymph node biopsy did not have metastases. The most common treatment has been local, with less than half of patients receiving systemic treatment, and this was limited to hormonal therapy. No local or distant recurrences have been reported in the current series or in the 2 case reports. However, the follow-up is less than 6 years for all patients. Nevertheless, particularly in light of the high nuclear grade and frequent adverse hormonal receptor and HER2 positivity patterns, it is notable that the outcome to date has been favorable.
The absence of reported regional or distant disease in cases of dermal invasion by epidermal Paget cells supports AJCC/UICC classification based on the size of the invasive component. In this series, the classifications were either T1mi (microinvasion) or T1a (invasion 0.5 cm or less in size). The skin involvement in this setting must be distinguished from findings resulting in classification as T4b.18
The epidermal involvement by tumor cells in Paget disease can be to such a great extent that the cells overlying the basement membrane are effaced, resulting in the clinical appearance of erosion or ulceration. Bleeding may result, and this was observed in 2 of the patients in this series. This type of ulceration must be distinguished from frank invasion and destruction of the skin with ulceration from an underlying invasive carcinoma. These large, locally advanced carcinomas would be classified as T4b because of the typical poorer prognosis.
Skin edema is another defining feature of T4b cancers. Patients with Paget disease often have skin thickening clinically and radiologically. The underlying pathophysiology is the disruption of the tight junctions of the keratinocytes by tumor cells, exudation, and some degree of inflammatory response. These skin findings can occur in the absence of stromal invasion. The type of edema that carries a poor prognosis is associated with dermal lymphovascular invasion, and, when present to a great degree, the carcinoma is classified as inflammatory carcinoma (AJCC/UICC T4d). Therefore, the finding of nipple areolar complex “edema” alone with Paget disease should not alter the T classification.
Paget disease with skin invasion also should not be considered a satellite skin nodule in the presence of another invasive carcinoma. Satellite skin nodules are generally associated with dermal lymphovascular invasion and are a form of intramammary metastasis from a larger carcinoma lying deeper in the breast.19
Paget disease with dermal invasion must also be distinguished from secondary Paget disease. This occurs when an invasive carcinoma invades into the skin and tumor cells infiltrate the adjacent epidermis. This may be seen in the skin of the breast, as well as at metastatic sites, and with carcinomas arising in other organs. In these cases there is typically a large palpable mass below the ulcerated area. The only situation in which secondary Paget disease might be confused with primary Paget disease with dermal invasion might be a small superficial biopsy in the absence of clinical history.
In summary, 9 cases of Paget disease with direct invasion into the dermis have been reported in this study and in 2 case reports.5,6 In no patient has regional or distant metastasis been reported. These cases support that dermal invasion in this setting has a favorable prognosis and should be classified according to the size of the invasive carcinoma. These carcinomas should not be classified as T4b disease.
The authors have no relevant financial interest in the products or companies described in this article.