Mammary Paget's Disease Research Articles

Dermoscopic features of mammary Paget's disease: a retrospective case-control study by the International Dermoscopy Society.

Mammary Paget's disease (MPD) is a rare intraepidermal adenocarcinoma of the nipple-areola complex, associated with an underlying breast cancer in approximately 90% of cases. Delayed diagnosis of MPD is common. Its dermoscopic features have been ill defined in the literature. To determine the clinical and dermoscopic features of MPD versus other dermatologic entities that involve nipple and areola. Members of the IDS were invited to submit any case of histologically confirmed MPD, as well as other benign and malignant dermatoses that involve the nipple and areola complex. A standardized evaluation of the dermoscopic images was performed and the results were statistically analyzed. Sixty-five lesions were included in the study, 22 (33.8%) of them MPD and 43 (66.2%) controls. The most frequent dermoscopic criteria of MPD were white scales (86.4%) and pink structureless areas (81.8%), followed by dotted vessels (72.7%), erosion/ulceration (68.2%) and white shiny lines (63.6%). The multivariate analysis showed that white scales and pink structureless areas were significant predictors of MPD, posing a 68-fold and a 31-fold probability of MPD, respectively. Split of the population into pigmented and non-pigmented lesions showed that in pigmented MPD, pink structureless areas, white lines and grey granules and dots are positive predictors of the disease. Among non-pigmented lesions, pink structureless areas, white lines, erosion/ulceration and white scales served as predictors of MPD. The most frequent profile of an individual with MPD is an elderly female with unilateral, asymptomatic, erythematous plaque of the nipple, dermoscopically displaying pink structureless areas, fine white scales, dotted and a few short linear vessels. In case of pigmentation we may also observe brown structureless areas and pigmented granules. Small sample size, retrospective design.

Expression of PD-1 and PD-L1 in Extramammary Paget Disease: Implications for Immune-Targeted Therapy.

Extramammary Paget disease (EMPD) is a locally aggressive cutaneous malignancy that usually arises in anogenital or axillary skin. Immune checkpoint inhibitors targeting programmed cell death receptor (PD-1) and/or its ligand (PD-L1) are approved for the treatment of several types of cancer, and response to these generally correlates with increased PD-L1 expression by tumor cells. The expression of PD-L1 and composition and density of the tumor-associated immune infiltrate in EMPD have been little studied. To determine whether EMPD might be amenable to immune checkpoint blockade, we analyzed the expression of PD-1 and PD-L1 and the composition and density of the tumor-associated immune infiltrate in EMPD and evaluated associations between biomarker expression and clinicopathologic parameters. Twenty-one EMPD tumors were evaluated for tumor cell PD-L1 expression and for relative expression and distribution of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate by using a combination of visual and image analysis (Aperio ImageScope). In addition, PD-L1 expression was assessed in 10 cases of mammary Paget disease (MPD). In EMPD cases, PD-L1 was expressed by tumor cells (3/21; 14%) and the tumor-associated immune infiltrate (15/21; 71%), and PD-1 was expressed by the tumor-associated immune infiltrate in all cases analyzed (18/18). However, PD-L1 expression by EMPD tumor cells did not correlate with the density of CD3-, CD8-, or PD-1-positive cells in the tumor-associated immune infiltrate or other clinicopathologic parameters. Furthermore, the density of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate did not correlate with any clinicopathologic parameters evaluated with the exception that CD3 positive values were significantly higher in patients who were still alive (median, 1310 cells/mm2; range, 543–2115;) than in those who died (median, 611 cells/mm2; range, 481–908; p = 0.049). In all MPD cases, PD-L1 was absent in tumor cells but present in the tumor-associated immune infiltrate, and PD-L1 expression in lymphocytes was lower in patients with HER2/neu-positive than in those with HER2/neu-negative disease (p = 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.

Comparative study of breast cancer with or without concomitant Paget disease: An analysis of the SEER database.

BackgroundMost mammary Paget disease (MPD) is associated with underlying in situ or invasive breast cancer. The objective of this study was to compare the clinicopathological characteristics and survival outcomes between breast cancer with Paget disease (PD) and breast cancer alone.MethodsFrom the Surveillance, Epidemiology, and End Results (SEER) database, 2000‐2015, of the US National Cancer Institute, we identified 1569 women who had PD with invasive ductal carcinoma (PD‐IDC) and 1489 women who had PD with ductal carcinoma in situ (PD‐DCIS). Independent demographic and clinicopathological variables as well as survival outcomes of these patients were compared to patients with the corresponding breast cancer without concomitant PD.ResultsPD‐IDC and PD‐DCIS both had worse survival outcomes and poorer tumor characteristics than the corresponding disease without PD. Contrary to in the breast cancer alone groups, in the breast cancer with PD groups, the HR status (P = 0.182 in PD‐IDC and P = 0.371 in PD‐DCIS), HER2 status (P = 0.788 in PD‐IDC and P = 0.643 in PD‐DCIS), and combined molecular subtype (P = 0.196 in PD‐IDC and P = 0.853 in PD‐DCIS) were not found to affect disease prognosis. After matching tumor characteristics and treatment approaches, PD‐IDC as well as PD‐DCIS exhibited no significant difference in disease prognosis with corresponding IDC and DCIS. Finally, by comparative analysis, a kind of PD‐DCIS (ICD‐O‐3 code 8543/3) showed many invasive behaviors (31.8% of 8543/3 patients had stage I‐III cancer) and was associated with worse survival outcomes than the other type of PD‐DCIS.ConclusionsBreast cancer with concomitant PD was associated with more aggressive tumor characteristics and worse survival outcomes. The HR status, HER2 status, and combined molecular subtype could not affect the prognosis of breast cancer with PD. Moreover, a portion of the PD‐DCIS cases were invasive breast cancer cases that required special treatment.

Molecular subtyping of mammary Paget's disease using immunohistochemistry.

Objective:To evaluate the molecular subtypes of Mammary Paget’s disease (MPD) and the associated breast carcinomas.Methods:This retrospective study was carried out at King Khalid University Hospital and King Faisal Specialist Hospital, Riyadh, Saudi Arabia. Data from MPD patient cases from January 2010 to June 2016 were reviewed. The molecular subtypes were determined based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression with immunohistochemical staining. The relative frequencies of the luminal A and B, HER2-enriched and basal-like molecular subtypes were calculated and compared for MPD and the associated breast carcinomas.Results:Among 22 patients with MPD, HER2-enriched was the most frequently occurring molecular subtype and was observed in 11 (50%) patients. Mammary Paget’s disease was classified as basal-like in 5 (22.7%) patients, and luminal A and B were each detected in 3 (13.6%) patients. The molecular subtype of MPD corresponded with the subtype of the associated breast carcinoma in 18 out of 20 patients (90%).Conclusions:The HER2-enriched subtype is the most frequently occurring molecular subtype in MPD. The molecular subtype of the associated breast carcinoma is usually similar to that of MPD. The molecular subtypes vary between MPD associated breast carcinoma and overall breast carcinoma. The HER2-enriched subtype is the most frequently occurring subtype of MPD associated breast carcinoma, while luminal subtypes are more common in overall breast carcinoma.

Breast-Conserving Surgery in Patients With Mammary Paget's Disease

BackgroundWe aimed to analyze the association between Paget's disease (PD) and breast cancer (BC) subtypes and compare the effect of breast-conserving surgery (BCS) as a local treatment with mastectomy for PD. Materials and methodsData of patients with histologic type International Classification of Diseases-0-3 8540-8543 who were treated from 1973 to 2014 were retrieved from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute. A chi-square test was used to identify differences in categorical data among different groups. Overall survival (OS) was analyzed using the Kaplan–Meier method, log-rank test, Cox proportional hazards models, sequential landmark analysis, and propensity score–matched analysis. ResultsThe study cohort included 5398 patients. Triple-negative BC accounted for the fewest patients with PD-only (1/22, 4.54%), Paget's disease-ductal carcinoma in situ (PD-DCIS) (3/48, 6.25%), and Paget's disease-invading ductal carcinoma (PD-IDC) (23/352, 6.53%). According to the results of the log-rank test and Cox analysis, the 10-year OS rates were similar for the BCS and mastectomy subgroups among patients with PD-DCIS or PD-IDC. Furthermore, there were no significant differences in survival benefits among the different surgeries after propensity score matching. Landmark analyses for OS of patients with PD-DCIS or PD-IDC surviving more than 1, 3, and 5 y showed no significant differences in survival. There were statistical differences in 10-year OS rates for patients with PD-DCIS or PD-IDC who underwent radiation therapy, or not, following BCS (both, P < 0.001). ConclusionsFor patients with PD-DCIS or PD-IDC, breast conservation therapy with lumpectomy and radiation is an effective local treatment strategy, compared with mastectomy.

Extramammary Paget disease

In 1874, Sir James Paget first described Paget disease of the nipple, also known as mammary Paget disease. In 1889, extramammary Paget disease (EMPD) of the scrotum and penis was identified. Although mammary and extramammary Paget disease are both characterized by epidermal Paget cells and share a similar clinical presentation, their uniqueness lies in anatomical location and histogenesis. EMPD presents as an erythematous plaque on apocrine gland bearing areas (i.e. vulva, perineum, perianal region, scrotum, and penis) in older men and women. It can be a focal, multifocal, or an ectopic process. Immunohistochemical staining allows for differentiation between primary and secondary EMPD in addition to the many other disease entities that clinically resemble this malignancy. When diagnosing a patient with EMPD, a full history and physical should be performed given the possibility of an underlying malignancy. Surgical excision currently is first line therapy and the prognosis is often favorable. Recent advances within the field have examined the expression of chemokine receptors within tumors, which may be applicable in determining prognosis. This review addresses the history, epidemiology, pathogenesis, clinical presentation, histopathology, differential diagnosis, diagnosis, management, and new observations with respect to extramammary Paget disease.

Prognostic significance of mammary Paget's disease in Chinese women: a 10-year, population-based, matched cohort study.

PurposeTo explore the prognostic significance of mammary Paget’s disease (PD) in breast cancer (BC) patients and to investigate the association between clinical manifestation and outcome in invasive ductal carcinoma patients with PD (PD-IDC).Patients and methodsEighty-five patients diagnosed with mammary PD with underlying BC from 2006 to 2012 at Zhejiang Cancer Hospital were recruited. A matched group comprised 85 patients diagnosed with BC without PD. Patients were matched according to four variables: stage (0–IV), age at diagnosis (within 5 years), histologic subtype, and the year of surgery. The 74 patients diagnosed with PD-IDC were divided into three groups based on their clinical presentation.ResultsCompared with the matched group, the PD group had more HER2 positivity (P<0.01) and hormone receptor negativity (P<0.01), and a worse outcome (Kaplan–Meier analysis, P<0.001 for disease-free survival and P=0.002 for overall survival). Multivariate Cox regression analyses showed that PD was an independent prognostic predictor for BC patients with PD. In addition, the 22 PD-IDC patients who presented with skin lesions in the nipple/areola and a mass in the breast or axilla had a higher risk of disease relapse than patients who presented with a mass in the breast without skin lesions or patients who presented with skin changes without a palpable mass (adjusted hazards ratio, 0.24; 95% CI, 0.08–0.73; P=0.012 and adjusted hazard ratio, 0.30; 95% CI, 0.06–1.40; P=0.124, respectively).ConclusionPD is an independent prognostic indicator of outcome in BC patients with PD. Furthermore, the primary symptoms at presentation may be an available indicator of prognosis in PD-IDC.

Whole-Exome Sequencing Reveals Frequent Mutations in Chromatin Remodeling Genes in Mammary and Extramammary Paget’s Diseases

Paget's disease (PD) is an intraepidermal adenocarcinoma of the skin at the breast (mammary PD) or urogenital locations (extramammary PD [EMPD]). At present, there is lack of clarity on PD's pathogenesis, the relationship between its subtypes, and its lineage link with the underlying invasive carcinomas. Here we describe that mammary PD and EMPD have similar mutational profiles, with the most frequent recurrent mutations occurring in the chromatin remodeling genes, such as KMT2C (MLL3, 39%) and ARID2 (22%), with additional recurrent somatic mutations detected in genes previously not known to be mutated in cancers, such as CDCC168 (34%), FSIP2 (29%), CASP8AP2 (29%), and BIRC6 (24%). In paired mammary PD and underlying breast carcinoma samples, distinct gene mutations were detected, indicating that they represent independent oncogenic events. Finally, multistage EMPD tissue sequencing revealed KMT2C gene occurring early in EMPD oncogenesis, and that multifocal EMPD samples share the same early gene mutations, suggesting clonal origin of multifocal EMPD. Our results reveal similar genomic landscapes between mammary PD and EMPD, including early aberrations in chromatin remodeling genes. In addition, mammary PD and underlying breast ductal carcinomas represent independent oncogenic events. These findings provide approaches for developing diagnostic tools and therapeutic interventions for PD.

Intraepidermal malignancy in breast skin: A tale of two tumours

Mammary Paget's disease most commonly affects the nipple areolar complex and is frequently associated with an underlying in-situ or invasive breast carcinoma. Pagetoid Bowen's disease of the breast is extremely rare and contains cells which morphologically resemble those of Paget's disease and may also express CK7 on immunohistochemistry. Here, we report two unusual cases of a 42-year-old Chinese woman with a recurrence of high grade ductal carcinoma in-situ presenting as mammary Paget's disease away from the nipple areolar complex, and a 65-year-old Chinese woman with pagetoid Bowen's disease of the breast skin. To our knowledge, there are only two case reports that are similar to the former and one to the latter.

Expression of CD3, PD-L1 and CTLA-4 in mammary and extra-mammary Paget disease.

Mammary and extra-mammary Paget disease is a rare form of intra-epithelial glandular neoplasm which is characteristically recurrent and necessitates multiple excisions that have an important impact on morbidity. Local immuno-modulating treatments have been applied with promising results, but the local immune markers of Paget disease have not been studied. To investigate the local immune micro-environment of Paget disease. Sixty-four specimens from 41 patients, including cases with multiple recurrences and underlying primary neoplasm, have been studied for their expression of CD3, PD-L1 and CTLA-4. Nineteen cases were mammary; 22 were extra-mammary and involved the vulva, the anus, the inguinal region and the lower extremity. PD-L1 was not expressed by any neoplastic lesion or the associated lymphocytes. CTLA-4 expression was found in nine cases. Higher stromal CD3 expression and moderate levels of intra-epithelial CD3 expression were present in most cases. Biopsies, subsequent excision specimens and recurrences showed the same immunohistochemical profile of CD3 and PD-L1, although there were different levels of CTLA-4 ina few cases. The underlying lesions in mammary Paget disease showed the same immunohistochemical profile as the intra-epithelial neoplastic cells. The expression of the markers did not correlate with age, sex, localization or recurrence. Paget disease is characterized by an intense lymphocytic response, devoid of the immune-suppressive impact of the PD-L1 pathway, but with occasional CTLA-4 expression.

Transcriptome analyses reveal FOXA1 dysregulation in mammary and extramammary Paget's disease

Paget's disease (PD) is an uncommon intraepithelial adenocarcinoma with unknown pathogenesis. There are two anatomic subtypes: mammary (MPD) and extramammary (EMPD). Little is known about their molecular characteristics. Our objective was to discover novel molecular markers for PD and its subtypes. In the discovery phase, we used transcriptome analyses to uncover the most differentially expressed genes and pathways in EMPD biopsies compared with normal skin. In the validation phase, we performed immunohistochemistry analyses on the most promising marker (FOXA1) and other markers selected from a literature review (GATA3, estrogen receptor [ER], and androgen receptor [AR]) on independent biopsies of MPD (n = 86), EMPD (n = 59), and normal skin (n = 21). Transcriptome analyses revealed 210 genes differentially expressed more than 10-fold between EMPD and normal skin. These genes are involved in mammary and sweat gland development (FOXA1) and immune regulation, as well as epidermal differentiation. Immunohistochemistry staining revealed that FOXA1 was positive in 88% of both MPD and EMPD, whereas GATA3 was positive in 67% of MPD and 77% of EMPD, and ER was positive in 9% of MPD and 19% of EMPD. Finally, AR was positive in 33% of PD and 54% of EMPD. Mammary Paget's disease and EMPD share dysregulation of the glandular developmental regulator gene FOXA1, suggesting similarity in cell-specific transcriptional regulation. Further, FOXA1 may be a useful molecular target for developing PD therapies.

Reflectance confocal microscopy of mammary Paget disease.

Mammary Paget disease is the intraepidermal adenocarcinoma of the nipple area which is characterized usually by a well-demarcated eczematous plaque. Reflectance confocal microscopy (RCM), is an in vivo noninvasive diagnostic tool with a high-resolution imaging of the skin, almost comparable to conventional histology. RCM findings of Paget disease are limited in the literature. Most of the reported cases are the extramammary type. In this report, we aimed to evaluate the RCM findings of a non-pigmented mammary Paget disease in a 65 year-old woman.

Dermoscopy Case of the Month

Abstract Mammary Paget's disease is a rare intraepithelial carcinoma of the nipple/areola complex often associated with ductal breast carcinoma. We report a case of a 55-year-old female patient with a classical form of mammary Paget's disease associated ductal ipsilateral breast carcinoma. Dermoscopy of Paget's disease revealed a whitish-pink area with polymorphous vessels organized in irregular nests separated by pale streak-like structures, with peripheral light brown diffuse pigmentation. Dermoscopic features described in this case are in agreement with rare previous reports and may contribute to better differentiation of mammary Paget's disease from clinically similar lesions.

Spectrum of Changes in Anogenital Mammary-like Glands in Primary Extramammary (Anogenital) Paget Disease and Their Possible Role in the Pathogenesis of the Disease.

To determine whether a subset of primary extramammary Paget disease (EMPD) may originate in anogenital mammary-like glands (AGMLG), the authors studied 181 specimens of EMPD, detailing alterations in AGMLG. The latter were identified in 33 specimens from 31 patients. All patients were women, ranging in age from 38 to 93 years (median, 65 y). In all cases, lesions involved the vulva and in 1 patient the perianal skin was affected. Histopathologically, AGMLG manifested changes identical to columnar cell change (CCC) (87.1%), usual ductal hyperplasia (22.6%), columnar cell hyperplasia (CCH) (9.7%), oxyphilic (apocrine) metaplasia (6.5%), and atypical duct hyperplasia (3.2%). Four cases (12.9%), in addition to intraepidermal carcinoma, harbored invasive carcinoma. In all 4 of these, AGMLG displayed a range of alterations including ductal carcinoma in situ, CCC, and CCH. Three further cases (9.7%) showed ductal carcinoma in situ without any definite invasive carcinoma. Colonization of AGMLG by neoplastic Paget cells was noted in 6 cases. As CCC and CCH may be encountered in normal AGMLG, these alterations are unlikely to play a significant role in the pathogenesis of the disease. However, by analogy with mammary Paget disease, rare cases of primary EMPD may originate in AGMLG with a subsequent upward migration of the neoplastic cells into the epidermis and possible later breach through the basal membrane. Usual ductal hyperplasia and atypical duct hyperplasia can then be regarded as earlier precursor lesions, linking both ends of the spectrum.

Clinical and Sonographic Features of Mammary Paget's Disease.

Objective To summarize the clinical and sonographic features of mammary Paget's disease (MPD). Methods Totally 34 female patients with pathologically confirmed MPD were retrospectively recruited. According to diagnosis,the clinical data and sonographic findings were reviewed and analyzed. Results Among these 34 patients,7 patients had single MPD; in the remaining 27 patients,16 were accompanied by invasive ductal carcinoma (IDC),7 by ductal carcinoma in situ (DCIS),3 by both IDC and DCIS,and 1 by other pathologic types of carcinoma. Twenty-four patients presented with typical clinical features of MPD,whereas 10 patients had no typical features of MPD. Among the 24 patients with typical clinical features,ultrasound examinations showed that 11 had echoic abnormality in nipple-areolar complex,14 had lesions of breast,and 14 had microcalcifications. Among the 10 patients without typical clinical features,ultrasound examinations revealed echoic abnormality in nipple-areolar complex in 3 cases,breast lesions in 9 cases,and microcalcifications in 6 cases. Among the 14 patients with echoic abnormality in nipple-areolar complex,all of them presented as rich blood flow in nipple detected by color Doppler ultrasonography. Conclusions The main clinical feature of MPD is abnormalities in nipple-areolar complex. Sonography can recognize the echoic abnormalities of nipple and lesions of breast. Sonographer should be careful of the nipple-areolar complex when mass is found in breast.

Diagnostic Criteria in Intraepithelial Pagetoid Neoplasms: A Histopathologic Study and Evaluation of Select Features in Paget Disease, Bowen Disease, and Melanoma In Situ

Paget disease, Bowen disease, and malignant melanoma in situ are intraepidermal neoplasms, characterized by the presence of pagetoid scatter of atypical cells in the epidermis. This study reviewed the frequency of select histologic criteria to validate their usefulness in the histologic distinction between these entities. One hundred forty-four specimens with the diagnosis of Bowen disease, 144 specimens with Paget disease (mammary and extramammary), and 144 specimens with malignant melanoma in situ were examined microscopically to define frequencies of select histologic criteria present in each disease. Comparison between mammary Paget and extramammary Paget disease showed no significant differences in the features studied. Crushing of basal keratinocytes, presence of atypical cells in the corneum, and presence of large cells with amphophilic cytoplasm were significantly noted in Paget disease. Transition between the atypical clear cells and surrounding keratinocytes was absent in all cases of melanoma in situ and in 87 (60.4%) cases of Paget disease, but it was significantly associated with Bowen disease (98.6%). Dyskeratotic cells were significantly associated with Bowen disease cases. Our study demonstrated a practical histologic approach to differentiate between intraepidermal pagetoid neoplasms. Careful histologic study of the proposed criteria may reduce reliance on immunohistochemical stains.

Extramammary Paget's Disease of the Perianal Region.

Extramammary Paget's disease (EMPD) is uncommon and only a few cases have been reported in the literature. They are identical to the Mammary Paget's disease. This can occur where the apocrine glands are in abundance, more commonly in the genitalia and perianal area. We report here a case of Extramammary Paget's disease in the perianal region. The colourful background of this ulcer is analysed and the literature reviewed.

Mammary and Extramammary Paget's Disease Presented Different Expression Pattern of Steroid Hormone Receptors.

Background and Objectives Paget's disease (PD) is a rare intraepithelial adenocarcinoma, which is composed of mammary (MPD) and extramammary Paget's disease (EMPD). Currently, the published literature contains scant data on expression pattern of steroid hormone receptors in MPD and EMPD. Methods Expression of estrogen receptor (ER) and androgen receptor (AR) was evaluated in 88 MPD and 72 EMPD by using immunohistochemical staining and H-score method. Results Positive expression of AR was significantly higher in EMPD (61.11%, 44/72) than in MPD (32.95%, 29/88) (P < 0.001), while ER expression was positive 19.44% (14/72) in EMPD and only 9.09% (8/88) in MPD (P = 0.059). ER-AR expression pattern was significantly different between MPD (3.41%, 3/88) and EMPD (16.67%, 12/72) (P < 0.001). No difference of AR (P = 0.301) or ER (P = 0.239) expression was identified between invasive (48.57%, 51/105 of AR, and 11.43%, 12/105 of ER) and noninvasive PD. In MPD, no difference of AR expression between MPD alone (7/18, 38.89%) and MPD with underling ductal carcinoma of breast (22/70, 31.43%) was identified (P = 0.548). In EMPD, expression of AR was 63.33% (38/60) in penoscrotal EMPD. Conclusion Our current results indicate that MPD and EMPD presented different expression pattern of AR and ER and would help to further identify the molecular subtype of MPD and EMPD for adjuvant hormonal therapy, especially for patients with penoscrotal EMPD.

Dermoscopy as a Supportive Instrument in the Early Recognition of Erosive Adenomatosis of the Nipple and Mammary Paget's Disease.

Dermoscopy as a Supportive Instrument in the Early Recognition of Erosive Adenomatosis of the Nipple and Mammary Paget's Disease.

Mimics of Mammary Paget Disease: A Rogues' Gallery.

Mimics of Mammary Paget Disease: A Rogues' Gallery.